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Sepsis is a global health priority associated with high mortality. Clinical decision support systems have been developed to support clinicians with sepsis management. Ordering blood cultures (BCs) for suspected sepsis patients are strongly recommended by clinical guidelines. However, limited evidence exists investigating BC ordering following sepsis alerts and subsequent patient outcomes. This study aimed to investigate this issue using electronic health record data from an acute care hospital in Australia. Of 4,092 patients, only 16.6% had a BC ordered following a sepsis alert. The median time from the first sepsis alert to a BC order was 15.3 hours. Patients had 5.89 times higher odds of being diagnosed with sepsis if a BC was ordered following a sepsis alert than those without BC ordered (p<0.0001). Further investigation is needed to understand reasons behind the delay or failure to order a BC despite receiving electronic sepsis alerts and how decision support can be optimized to improve patient outcomes.
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Registros Eletrônicos de Saúde , Sepse , Humanos , Hemocultura , Registros , Sepse/diagnóstico , AustráliaRESUMO
This study addresses the role of natural hazard insurance in two European countries with different insurance markets and socioeconomic conditions: Sweden and Portugal. The analyses were conducted at the national, regional (Southern Sweden and Lisbon Metropolitan Area - LMA), and local (Malmö and Lisbon cities) scales. Most damage caused by weather and climate-related (WCR) hazards during the 1980-2019 period was not covered by insurance companies in Sweden (71%) and Portugal (91%). An insurance affordability analysis was performed using income for the national and regional scales. Unaffordability is higher in Southern Sweden than in LMA, implying that better socioeconomic conditions do not necessarily mean a higher average capacity to pay for insurance. At the local scale, urban flooding was analysed for Malmö (1996-2019) and Lisbon (2000-2011) using insurance databases, in which the most relevant 21st century rainfall events for each city are included (2014 and 2008, respectively). The influence of terrain features on flooding claims and payouts was determined using Geographic Information Systems (GIS) spatial analyses. The flat Malmö favours ponding and extensive flooding, while the distance to the drainage network and flow accumulation are key factors to promote flooding along valley bottoms in the hilly Lisbon. Flooding hotspots tend to result from a combination of higher depths/lower velocities (accumulation of floodwaters and ponding) and not from a pattern of lower depths/higher velocities (shallow overland flow). More detailed data on insurance, flooding, and socioeconomic conditions, at regional and mainly local scales, is needed to improve affordability and urban flooding risk assessments.
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Inundações , Seguro , Cidades , Portugal , SuéciaRESUMO
Global climate change is manifest by local-scale changes in precipitation and temperature patterns, including the frequency of extreme weather events (EWEs). EWEs are associated with a myriad range of adverse environmental and societal consequences, including negative impacts to agriculture and food production. This study focuses on EWEs and their effect on adaptation strategies by potato and onion farmers in Zeeland, a Dutch coastal province in the Rhine delta that can serve as a model for other intensive agricultural landscapes in industrialized nations impacted by extreme weather events. The research approach combines quantitative trend analysis of long-term climatic data (temperature, precipitation) with a formal survey of Zeelandic farmers to statistically test four specific hypotheses regarding the frequency of EWEs in the Netherlands and farmer awareness and adaptation. Trend analyses reveal a strong (statistically significant) increase in extreme heat, a small increase in extreme rainfall and drought, and a strong decrease in frost occurrence. Survey results indicate Zeelandic farmers perceive high risk and awareness of changes to the frequency of EWEs. Many farmers have experienced financial losses from EWEs, particularly between 2017 and 2020. For extreme heat, droughts, and frost, the proportion of farmers that incurred financial damages annually is statistically correlated to the actual occurrence of EWEs. Farmers who incurred more financial losses between 2000 and 2020 due to heat and lack of frost had a higher risk perception of these extremes. Further, almost all farmers have already implemented one or more adaptation strategies. A third of surveyed farmers reduced or stopped with potato and onion cultivation in response to climate change and EWEs. Awareness, exposure to, and risk perception of EWEs contribute to adaptation support by farmers. The high perceived risk of climate change and EWEs among respondents and the high incidence of financial losses from extremes in the past two decades highlights the importance of adaptation in the agricultural sector, including in temperate regions where growing seasons are expanding. Study results support the current 'Rural Development Program' and future 'National Strategic Plan' policies in the Netherlands, both part of the European Union's Common Agricultural Policy (CAP), that provides accessibility to adaptation measures for farmers to avoid financial loss.
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Agricultura , Mudança Climática , Clima Extremo , Fazendeiros , Agricultura/métodos , Feminino , Humanos , Países Baixos , Tempo (Meteorologia)RESUMO
OBJECTIVE: To explore the effect of maternal BMI class pre-pregnancy (overweight/obese v. healthy weight/underweight) on childhood diet quality and on childhood overweight/obesity risk. DESIGN: Dietary data were collected using 3-d parental-completed food records for their children at ages 18 and 43 months. An index of diet quality was derived by classification of food items into core and non-core foods. Adjusted multiple linear regression analyses were used to explore the effect of maternal BMI class on diet quality in their children. SETTING: Avon, UK. PARTICIPANTS: A 10% subsample of the Avon Longitudinal Study of Parents and Children. Nine-hundred and eighty children provided complete dietary data at 18 months and 769 at 43 months. RESULTS: Children with overweight/obese mothers consumed greater amounts of energy from non-core foods than children with healthy weight/underweight mothers (0·20 MJ (48 kcal)/d more at 18 months (P < 0·001); 0·19 MJ (45 kcal)/d more at 43 months (P = 0·008)) in adjusted models. Diet quality deteriorated between 18 and 43 months (children reduced their dietary energy intake from core foods (P < 0·001) and increased intake from non-core foods (P < 0·001)). However, this change was not associated with maternal BMI class in adjusted models. Having an overweight/obese mother was associated with an increased odds of the child being overweight/obese at 43 months (OR 1·74 (1·17, 2·58)). CONCLUSIONS: Children aged 18 and 43 months with overweight/obese mothers are likely to have a poorer quality diet than those with healthy/underweight mothers. Parents should be supported in discouraging the consumption of non-core foods in children at these ages.
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Obesidade Infantil , Índice de Massa Corporal , Criança , Pré-Escolar , Dieta , Feminino , Humanos , Lactente , Estudos Longitudinais , Mães , Sobrepeso/epidemiologia , Pais , Obesidade Infantil/epidemiologia , GravidezRESUMO
Insights into the dynamics of human behavior in response to flooding are urgently needed for the development of effective integrated flood risk management strategies, and for integrating human behavior in flood risk modeling. However, our understanding of the dynamics of risk perceptions, attitudes, individual recovery processes, as well as adaptive (i.e., risk reducing) intention and behavior are currently limited because of the predominant use of cross-sectional surveys in the flood risk domain. Here, we present the results from one of the first panel surveys in the flood risk domain covering a relatively long period of time (i.e., four years after a damaging event), three survey waves, and a wide range of topics relevant to the role of citizens in integrated flood risk management. The panel data, consisting of 227 individuals affected by the 2013 flood in Germany, were analyzed using repeated-measures ANOVA and latent class growth analysis (LCGA) to utilize the unique temporal dimension of the data set. Results show that attitudes, such as the respondents' perceived responsibility within flood risk management, remain fairly stable over time. Changes are observed partly for risk perceptions and mainly for individual recovery and intentions to undertake risk-reducing measures. LCGA reveal heterogeneous recovery and adaptation trajectories that need to be taken into account in policies supporting individual recovery and stimulating societal preparedness. More panel studies in the flood risk domain are needed to gain better insights into the dynamics of individual recovery, risk-reducing behavior, and associated risk and protective factors.
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Comportamento , Inundações , Atitude , Mudança Climática , Humanos , Intenção , Gestão de Riscos/organização & administraçãoRESUMO
The affordability of property-level adaptation measures against flooding is crucial due to the movement toward integrated flood risk management, which requires the individuals threatened by flooding to actively manage flooding. It is surprising to find that affordability is not often discussed, given the important roles that affordability and social justice play regarding flood risk management. This article provides a starting point for investigating the potential rate of unaffordability of flood risk property-level adaptation measures across Europe using two definitions of affordability, which are combined with two different affordability thresholds from within flood risk research. It uses concepts of investment and payment affordability, with affordability thresholds based on residual income and expenditure definitions of unaffordability. These concepts, in turn, are linked with social justice through fairness concerns, in that, all should have equal capability to act, of which affordability is one avenue. In doing so, it was found that, for a large proportion of Europe, property owners generally cannot afford to make one-time payment of the cost of protective measures. These can be made affordable with installment payment mechanisms or similar mechanisms that spread costs over time. Therefore, the movement toward greater obligations for flood-prone residents to actively adapt to flooding should be accompanied by socially accessible financing mechanisms.
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Numerous animal models of systemic orthopoxvirus disease have been developed to evaluate therapeutics against variola virus (VARV), the causative agent of smallpox. These animal models do not resemble the disease presentation in human smallpox and most used surrogate Orthopoxviruses. A rodent model using VARV has a multitude of advantages, and previous investigations identified the CAST/EiJ mouse as highly susceptible to monkeypox virus infection, making it of interest to determine if these rodents are also susceptible to VARV infection. In this study, we inoculated CAST/EiJ mice with a range of VARV doses (102-106 plaque forming units). Some animals had detectable viable VARV from the oropharynx between days 3 and 12 post inoculation. Despite evidence of disease, the CAST/EiJ mouse does not provide a model for clinical smallpox due to mild signs of morbidity and limited skin lesions. However, in contrast to previous rodent models using VARV challenge (i.e. prairie dogs and SCID mice), a robust immune response was observed in the CAST/EiJ mice (measured by Immunoglobulin G enzyme-linked immunosorbent assay). This is an advantage of this model for the study of VARV and presents a unique potential for the study of the immunomodulatory pathways following VARV infection.
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Modelos Animais de Doenças , Camundongos , Varíola/imunologia , Vírus da Varíola/imunologia , Vírus da Varíola/patogenicidade , Animais , Feminino , Humanos , Camundongos SCID , Varíola/fisiopatologia , Varíola/virologiaRESUMO
As genetic testing is increasingly integrated into medical care, the genetic counselor (GC) has emerged as a key member of multidisciplinary (MD) teams. Prior research has demonstrated the importance of role clarification when subspecialties are introduced to these teams given the potential differences in team member expectations regarding the division of responsibilities in clinic. To assess perceptions of a GC's role in four pediatric hematology/oncology clinics, Accreditation Council for Genetic Counseling (ACGC) competencies were used to develop two separate surveys for providers and patients and their caregivers. Providers (n = 25) perceived roles related to genetic expertise and coordination of care to be primarily the role of a GC significantly more often than psychosocial roles (p < .0001). Several potential GC roles were perceived as a shared role or the role of another provider, such as eliciting psychosocial history. Patients/caregivers (n = 70) perceived genetic-centric roles as significantly more important than roles related to coordination of care (p = .03) and psychosocial skills (p < .0001). Our findings from a pediatric specialty department suggest that GCs may maximize their potential in MD clinics by functioning as genetic subject matter experts with care coordination responsibilities related to genetic testing. Further communication between team members may be indicated to clarify the division of responsibilities.
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Conselheiros , Aconselhamento Genético , Hematologia , Oncologia , Equipe de Assistência ao Paciente , Pediatria , Papel Profissional , Cuidadores , Criança , Comunicação , Feminino , Testes Genéticos , Humanos , Percepção , Inquéritos e QuestionáriosRESUMO
Because human patients with monkeypox virus (MPXV) infection report painful symptoms, it is reasonable to assume that animals infected with MPXV experience some degree of pain. Understanding whether and how analgesics affect MPXV disease progression is crucial when planning in vivo challenge experiments. In the current study, we challenged prairie dogs with a low dose (4 ×10³ pfu) of MPXV and treated with meloxicam (NSAID) or buprenorphine (opioid); control animals did not receive analgesia or received analgesia without MPXV challenge. Subsets of animals from each group were serially euthanized during the course of the study. Disease progression and viral kinetics were similar between groups, but MXPVinfected, meloxicam-treated animals showed increasing trends of morbidity and mortality compared with other groups. Differences between no-analgesia MPXV-infected control animals and MPXV-infected animals treated with buprenorphine were minimal. The findings in the current study allow more informed decisions concerning the use of analgesics during experimental MPXV challenge studies, thereby improving animal welfare. In light of these findings, we have modified our pain scale for this animal model to include the use of buprenorphine for pain relief when warranted after MPXV challenge.
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Analgesia , Buprenorfina , Meloxicam , Mpox , Manejo da Dor , Dor , Sciuridae , Animais , Feminino , Analgesia/veterinária , Analgésicos Opioides , Anti-Inflamatórios não Esteroides , Buprenorfina/uso terapêutico , Modelos Animais de Doenças , Meloxicam/uso terapêutico , Mpox/complicações , Mpox/veterinária , Monkeypox virus , Dor/etiologia , Dor/prevenção & controle , Dor/veterinária , Manejo da Dor/veterináriaRESUMO
INTRODUCTION: Traditionally, paper based observation charts have been used to identify deteriorating patients, with emerging recent electronic medical records allowing electronic algorithms to risk stratify and help direct the response to deterioration. OBJECTIVE(S): We sought to compare the Between the Flags (BTF) calling criteria to the Modified Early Warning Score (MEWS), National Early Warning Score (NEWS) and electronic Cardiac Arrest Risk Triage (eCART) score. DESIGN AND PARTICIPANTS: Multicenter retrospective analysis of electronic health record data from all patients admitted to five US hospitals from November 2008-August 2013. MAIN OUTCOME MEASURES: Cardiac arrest, ICU transfer or death within 24h of a score RESULTS: Overall accuracy was highest for eCART, with an AUC of 0.801 (95% CI 0.799-0.802), followed by NEWS, MEWS and BTF respectively (0.718 [0.716-0.720]; 0.698 [0.696-0.700]; 0.663 [0.661-0.664]). BTF criteria had a high risk (Red Zone) specificity of 95.0% and a moderate risk (Yellow Zone) specificity of 27.5%, which corresponded to MEWS thresholds of >=4 and >=2, NEWS thresholds of >=5 and >=2, and eCART thresholds of >=12 and >=4, respectively. At those thresholds, eCART caught 22 more adverse events per 10,000 patients than BTF using the moderate risk criteria and 13 more using high risk criteria, while MEWS and NEWS identified the same or fewer. CONCLUSION(S): An electronically generated eCART score was more accurate than commonly used paper based observation tools for predicting the composite outcome of in-hospital cardiac arrest, ICU transfer and death within 24h of observation. The outcomes of this analysis lend weight for a move towards an algorithm based electronic risk identification tool for deteriorating patients to ensure earlier detection and prevent adverse events in the hospital.
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Deterioração Clínica , Parada Cardíaca/diagnóstico , Mortalidade Hospitalar , Escores de Disfunção Orgânica , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Área Sob a Curva , Diagnóstico Precoce , Registros Eletrônicos de Saúde , Parada Cardíaca/mortalidade , Humanos , Pessoa de Meia-Idade , Transferência de Pacientes/estatística & dados numéricos , Estudos Retrospectivos , Medição de Risco , Sensibilidade e EspecificidadeRESUMO
Virus purification in a high-containment setting provides unique challenges due to barrier precautions and operational safety approaches that are not necessary in lower biosafety level (BSL) 2 environments. The need for high risk group pathogen diagnostic assay development, anti-viral research, pathogenesis and vaccine efficacy research necessitates work in BSL-3 and BSL-4 labs with infectious agents. When this work is performed in accordance with BSL-4 practices, modifications are often required in standard protocols. Classical virus purification techniques are difficult to execute in a BSL-3 or BSL-4 laboratory because of the work practices used in these environments. Orthopoxviruses are a family of viruses that, in some cases, requires work in a high-containment laboratory and due to size do not lend themselves to simpler purification methods. Current CDC purification techniques of orthopoxviruses uses 1,1,2-trichlorotrifluoroethane, commonly known as Genetron®. Genetron® is a chlorofluorocarbon (CFC) that has been shown to be detrimental to the ozone and has been phased out and the limited amount of product makes it no longer a feasible option for poxvirus purification purposes. Here we demonstrate a new Orthopoxvirus purification method that is suitable for high-containment laboratories and produces virus that is not only comparable to previous purification methods, but improves on purity and yield.
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Orthopoxvirus/isolamento & purificação , Virologia/métodos , Animais , Contenção de Riscos Biológicos , Humanos , Laboratórios , Fatores de TempoRESUMO
Human protein disulphide isomerase (hPDI) is an endoplasmic reticulum (ER) based isomerase and folding chaperone. Molecular detail of ligand recognition and specificity of hPDI are poorly understood despite the importance of the hPDI for folding secreted proteins and its implication in diseases including cancer and lateral sclerosis. We report a detailed study of specificity, interaction and dissociation constants (Kd) of the peptide-ligand Δ-somatostatin (AGSKNFFWKTFTSS) binding to hPDI using (19)F ligand-observe and (15)N,(1)H-HSQC protein-observe NMR methods. Phe residues in Δ-somatostatin are hypothesised as important for recognition by hPDI therefore, step-wise peptide Phe-to-Ala changes were progressively introduced and shown to raise the Kd from 103 + 47 µM until the point where binding was abolished when all Phe residues were modified to Ala. The largest step-changes in Kd involved the F11A peptide modification which implies the C-terminus of Δ-somatostatin is a prime recognition region. Furthermore, this study also validated the combined use of (19)F ligand-observe and complimentary (15)N,(1)H-HSQC titrations to monitor interactions from the protein's perspective. (19)F ligand-observe NMR was ratified as mirroring (15)N protein-observe but highlighted the advantage that (19)F offers improved Kd precision due to higher spectrum resolution and greater chemical environment sensitivity.
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Ressonância Magnética Nuclear Biomolecular , Fenilalanina/química , Isomerases de Dissulfetos de Proteínas/química , Somatostatina/química , Alanina/química , Substituição de Aminoácidos , Humanos , Ligantes , Modelos Moleculares , Conformação Molecular , Ressonância Magnética Nuclear Biomolecular/métodos , Peptídeos/química , Peptídeos/metabolismo , Ligação Proteica , Isomerases de Dissulfetos de Proteínas/metabolismo , Somatostatina/metabolismoRESUMO
AIMS AND OBJECTIVES: The focus of this research was to standardise an emergency observation chart, the Adult Emergency Department Flow Chart, which incorporates elements designed to allow clinicians to more readily recognise the trends of patient deterioration. BACKGROUND: Patients present to the Emergency Department with some form of instability. Core skills and principles of Emergency Department care are to rapidly and continually assess the clinical condition of the patient, prioritise their care and treat accordingly. Often, however, deterioration of these patients is missed. The incidence of missed deterioration is set within a background of increasing presentations to Emergency Departments, greater complexity of the patient health status, longer length of stay within the Emergency Department and an ageing population. DESIGN: This quantitative research study comprised a retrospective medical record audit. Only those records containing notes relating to an Emergency Department admission were included. METHODS: An online data collection tool based on the Adult Emergency Department Flow Chart was developed. A total of 181 medical records were reviewed: 80 during the pre-implementation audit and 101 during the post-implementation audit. RESULTS: The Adult Emergency Department Flow Chart enabled clinicians to better identify deteriorating patients, with a higher number of abnormal vital signs being identified at the post-implementation audit. Identification of pain also dramatically increased at the post-implementation audit. Documentation of notification to Medical Officers also increased, as did documentation of the number of patients receiving medication to help treat the abnormal vital sign. CONCLUSION: The introduction of the Adult Emergency Department Flow Chart facilitated the essential role of nurses in the identification, documentation and monitoring of the unstable or deteriorating patient in the Emergency Department. Further research is required with larger samples to determine the impact of the Adult Emergency Department Flow Chart on the timely management of abnormal vital signs. RELEVANCE TO CLINICAL PRACTICE: The Adult Emergency Flow Chart provides a valuable tool for the early identification and subsequent management of an unstable / deteriorating adult in the emergency department, particularly for clinicians with limited experience.
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Emergências/enfermagem , Prontuários Médicos/normas , Avaliação em Enfermagem , Registros , Adulto , Idoso , Enfermagem de Cuidados Críticos , Serviço Hospitalar de Emergência/estatística & dados numéricos , Feminino , Humanos , Masculino , Auditoria Médica , New South Wales , Estudos Retrospectivos , Sinais VitaisRESUMO
Naturally occurring smallpox has been eradicated but remains a considerable threat as a biowarfare/bioterrorist weapon (F. Fleck, Bull. World Health Organ. 81:917-918, 2003). While effective, the smallpox vaccine is currently not recommended for routine use in the general public due to safety concerns (http://www.bt.cdc.gov/agent/smallpox/vaccination). Safe and effective countermeasures, particularly those effective after exposure to smallpox, are needed. Currently, SIGA Technologies is developing the small-molecule oral drug, tecovirimat (previously known as ST-246), as a postexposure therapeutic treatment of orthopoxvirus disease, including smallpox. Tecovirimat has been shown to be efficacious in preventing lethal orthopoxviral disease in numerous animal models (G. Yang, D. C. Pevear, M. H. Davies, M. S. Collett, T. Bailey, et al., J. Virol. 79:13139-13149, 2005; D. C. Quenelle, R. M. Buller, S. Parker, K. A. Keith, D. E. Hruby, et al., Antimicrob. Agents Chemother., 51:689-695, 2007; E. Sbrana, R. Jordan, D. E. Hruby, R. I. Mateo, S. Y. Xiao, et al., Am. J. Trop. Med. Hyg. 76:768-773, 2007). Furthermore, in clinical trials thus far, the drug appears to be safe, with a good pharmacokinetic profile. In this study, the efficacy of tecovirimat was evaluated in both a prelesional and postlesional setting in nonhuman primates challenged intravenously with 1 × 10(8) PFU of Variola virus (VARV; the causative agent of smallpox), a model for smallpox disease in humans. Following challenge, 50% of placebo-treated controls succumbed to infection, while all tecovirimat-treated animals survived regardless of whether treatment was started at 2 or 4 days postinfection. In addition, tecovirimat treatment resulted in dramatic reductions in dermal lesion counts, oropharyngeal virus shedding, and viral DNA circulating in the blood. Although clinical disease was evident in tecovirimat-treated animals, it was generally very mild and appeared to resolve earlier than in placebo-treated controls that survived infection. Tecovirimat appears to be an effective smallpox therapeutic in nonhuman primates, suggesting that it is reasonably likely to provide therapeutic benefit in smallpox-infected humans.
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Antivirais/uso terapêutico , Benzamidas/uso terapêutico , Isoindóis/uso terapêutico , Infecções por Poxviridae/tratamento farmacológico , Vírus da Varíola/efeitos dos fármacos , Vírus da Varíola/patogenicidade , Animais , Antivirais/administração & dosagem , Benzamidas/administração & dosagem , Isoindóis/administração & dosagem , Macaca , Masculino , Infecções por Poxviridae/sangue , Distribuição Aleatória , Resultado do TratamentoRESUMO
A gene-centric Human Proteome Project has been proposed to characterize the human protein-coding genes in a chromosome-centered manner to understand human biology and disease. Here, we report on the protein evidence for all genes predicted from the genome sequence based on manual annotation from literature (UniProt), antibody-based profiling in cells, tissues and organs and analysis of the transcript profiles using next generation sequencing in human cell lines of different origins. We estimate that there is good evidence for protein existence for 69% (n = 13985) of the human protein-coding genes, while 23% have only evidence on the RNA level and 7% still lack experimental evidence. Analysis of the expression patterns shows few tissue-specific proteins and approximately half of the genes expressed in all the analyzed cells. The status for each gene with regards to protein evidence is visualized in a chromosome-centric manner as part of a new version of the Human Protein Atlas ( www.proteinatlas.org ).
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Anticorpos/química , Cromossomos Humanos/química , Projeto Genoma Humano , Proteínas de Neoplasias/isolamento & purificação , Neoplasias/química , Proteoma/isolamento & purificação , Linhagem Celular , Linhagem Celular Tumoral , Expressão Gênica , Perfilação da Expressão Gênica , Genoma Humano , Humanos , Microscopia de Fluorescência , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Proteoma/genética , Proteoma/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
Monkeypox virus (MPXV) causes a smallpox-like disease in humans. Clinical and epidemiological studies provide evidence of pathogenicity differences between two geographically distinct monkeypox virus clades: the West African and Congo Basin. Genomic analysis of strains from both clades identified a â¼10 kbp deletion in the less virulent West African isolates sequenced to date. One absent open reading frame encodes the monkeypox virus homologue of the complement control protein (CCP). This modulatory protein prevents the initiation of both the classical and alternative pathways of complement activation. In monkeypox virus, CCP, also known as MOPICE, is a â¼24 kDa secretory protein with sequence homology to this superfamily of proteins. Here we investigate CCP expression and its role in monkeypox virulence and pathogenesis. CCP was incorporated into the West African strain and removed from the Congo Basin strain by homologous recombination. CCP expression phenotypes were confirmed for both wild type and recombinant monkeypox viruses and CCP activity was confirmed using a C4b binding assay. To characterize the disease, prairie dogs were intranasally infected and disease progression was monitored for 30 days. Removal of CCP from the Congo Basin strain reduced monkeypox disease morbidity and mortality, but did not significantly decrease viral load. The inclusion of CCP in the West African strain produced changes in disease manifestation, but had no apparent effect on disease-associated mortality. This study identifies CCP as an important immuno-modulatory protein in monkeypox pathogenesis but not solely responsible for the increased virulence seen within the Congo Basin clade of monkeypox virus.
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Ativação do Complemento , Monkeypox virus/imunologia , Monkeypox virus/patogenicidade , Mpox/imunologia , Mpox/virologia , Proteínas Virais/imunologia , Animais , Sequência de Bases , Proteína de Ligação ao Complemento C4b/imunologia , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Masculino , Dados de Sequência Molecular , Monkeypox virus/genética , Fases de Leitura Aberta/genética , Recombinação Genética , Sciuridae , Carga Viral , Proteínas Virais/genéticaRESUMO
Type 1 interferons (T1-IFNs) play a major role in antiviral defense, but when or how they protect during infections that spread through the lympho-hematogenous route is not known. Orthopoxviruses, including those that produce smallpox and mousepox, spread lympho-hematogenously. They also encode a decoy receptor for T1-IFN, the T1-IFN binding protein (T1-IFNbp), which is essential for virulence. We demonstrate that during mousepox, T1-IFNs protect the liver locally rather than systemically, and that the T1-IFNbp attaches to uninfected cells surrounding infected foci in the liver and the spleen to impair their ability to receive T1-IFN signaling, thus facilitating virus spread. Remarkably, this process can be reversed and mousepox cured late in infection by treating with antibodies that block the biological function of the T1-IFNbp. Thus, our findings provide insights on how T1-IFNs function and are evaded during a viral infection in vivo, and unveil a novel mechanism for antibody-mediated antiviral therapy.
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Anticorpos Antivirais/farmacologia , Vírus da Ectromelia/metabolismo , Ectromelia Infecciosa/imunologia , Receptor de Interferon alfa e beta/antagonistas & inibidores , Proteínas Virais/antagonistas & inibidores , Fatores de Virulência/antagonistas & inibidores , Animais , Anticorpos Antivirais/imunologia , Linhagem Celular , Cricetinae , Vírus da Ectromelia/imunologia , Vírus da Ectromelia/patogenicidade , Ectromelia Infecciosa/tratamento farmacológico , Ectromelia Infecciosa/metabolismo , Feminino , Fígado/imunologia , Fígado/metabolismo , Fígado/virologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Receptor de Interferon alfa e beta/imunologia , Receptor de Interferon alfa e beta/metabolismo , Baço/imunologia , Baço/metabolismo , Baço/virologia , Vírus da Varíola/imunologia , Vírus da Varíola/metabolismo , Proteínas Virais/imunologia , Proteínas Virais/metabolismo , Fatores de Virulência/imunologia , Fatores de Virulência/metabolismo , Ligação Viral/efeitos dos fármacosRESUMO
OBJECTIVE: An unmet need is represented in angioplasty catheters that permit the predilation stage of treating complex coronary anatomy oftentimes not amenable to conventional device therapies. BACKGROUND: Lesion preparation with balloon angioplasty prior to stent placement remains the most common method of percutaneous coronary revascularization. METHODS: Clinical and angiographic outcomes were evaluated following a treatment strategy of coronary artery disease that included predilation with a low-profile, 1.25-mm angioplasty catheter prior to stent placement. The study primary end point of procedural success was defined as successful device delivery and lesion treatment, including the absence of clinically significant perforation, arrhythmia, flow-limiting dissection, or reduction in baseline Thrombolysis In Myocardial Infarction (TIMI) grade with final achievement of TIMI 3 flow. RESULTS: Among 51 patients (54 lesions), predilation using a 1.25 mm angioplasty catheter was associated with procedural and device-related success rates of 100%. In-hospital target lesion failure occurred in one patient (2.0%) related to postprocedural myocardial infarction. Patient and angiographic characteristics included diabetes, 43.1%; lesion length ≥ 20 mm, 20.4%; bifurcation lesion, 31.5%; lesion classification B2/C, 74.1%; and baseline TIMI 0/1 flow, 13.0%. No subsequent in-hospital adverse events occurred. CONCLUSIONS: Percutaneous coronary revascularization involving a predilation strategy with a low profile, 1.25-mm angioplasty catheter is associated with favorable procedural safety and efficacy and may represent an effective initial treatment for complex coronary anatomy.
Assuntos
Angioplastia Coronária com Balão/instrumentação , Catéteres , Estenose Coronária/terapia , Idoso , Angioplastia Coronária com Balão/efeitos adversos , Angiografia Coronária , Circulação Coronária , Estenose Coronária/diagnóstico por imagem , Estenose Coronária/fisiopatologia , Desenho de Equipamento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio , Estudos Prospectivos , Índice de Gravidade de Doença , Stents , Fatores de Tempo , Resultado do Tratamento , Estados UnidosRESUMO
OBJECTIVE: To determine the safety and efficacy of dual-axis rotational coronary angiography (DARCA) by directly comparing it to standard coronary angiography (SA). BACKGROUND: Standard coronary angiography (SA) requires numerous fixed static images of the coronary tree and has multiple well-documented limitations. Dual-axis rotational coronary angiography (DARCA) is a new rotational acquisition technique that entails simultaneous LAO/RAO and cranial/caudal gantry movement. This technological advancement obtains numerous unique images of the left or right coronary tree with a single coronary injection. We sought to assess the safety and efficacy of DARCA as well as determine DARCA's adequacy for CAD screening and assessment. METHODS: Thirty patients underwent SA following by DARCA. Contrast volume, radiation dose (DAP) and procedural time were recorded for each method to assess safety. For DARCA acquisitions, blood pressure (BP), heart rate (HR), symptoms and any arrhythmias were recorded. All angiograms were reviewed for CAD screening adequacy by two independent invasive cardiologists. RESULTS: Compared to SA, use of DARCA was associated with a 51% reduction in contrast, 35% less radiation exposure, and 18% shorter procedural time. Both independent reviewers noted DARCA to be at least equivalent to SA with respect to the ability to screen for CAD. CONCLUSION: DARCA represents a new angiographic technique which is equivalent in terms of image quality and is associated with less contrast use, radiation exposure, and procedural time than SA.