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Feline leukaemia virus (FeLV) is a retrovirus associated with fatal disease in progressively infected cats. While testing/removal and vaccination led to a decreased prevalence of FeLV, recently, this decrease has reportedly stagnated in some countries. This study aimed to prospectively determine the prevalence of FeLV viraemia in cats taken to veterinary facilities in 32 European countries. FeLV viral RNA was semiquantitatively detected in saliva, using RT-qPCR as a measure of viraemia. Risk and protective factors were assessed using an online questionnaire to report geographic, demographic, husbandry, FeLV vaccination, and clinical data. The overall prevalence of FeLV viraemia in cats visiting a veterinary facility, of which 10.4% were shelter and rescue cats, was 2.3% (141/6005; 95% CI: 2.0%–2.8%) with the highest prevalences in Portugal, Hungary, and Italy/Malta (5.7%–8.8%). Using multivariate analysis, seven risk factors (Southern Europe, male intact, 1–6 years of age, indoor and outdoor or outdoor-only living, living in a group of ≥5 cats, illness), and three protective factors (Northern Europe, Western Europe, pedigree cats) were identified. Using classification and regression tree (CART) analysis, the origin of cats in Europe, pedigree, and access to outdoors were important predictors of FeLV status. FeLV-infected sick cats shed more viral RNA than FeLV-infected healthy cats, and they suffered more frequently from anaemia, anorexia, and gingivitis/stomatitis than uninfected sick cats. Most cats had never been FeLV-vaccinated; vaccination rates were indirectly associated with the gross domestic product (GDP) per capita. In conclusion, we identified countries where FeLV was undetectable, demonstrating that the infection can be eradicated and highlighting those regions where awareness and prevention should be increased. |
[Image: see text] Antiviral therapy is crucial for the circumvention of viral epidemics. The unavailability of a specific antiviral drug against the chikungunya virus (CHIKV) disease has created an alarming situation to identify or develop potent chemical molecules for remedial management of CHIKV. In the present investigation, in silico studies of dihydrorugosaflavonoid derivatives (5a–f) with non-structural protein-3 (nsP3) were carried out. nsP3 replication protein has recently been considered as a possible antiviral target in which crucial inhibitors fit into the adenosine-binding pocket of the macrodomain. The 4′-halogenated dihydrorugosaflavonoids displayed intrinsic binding with the nsp3 macrodomain (PDB ID: 3GPO) of CHIKV. Compounds 5c and 5d showed docking scores of −7.54 and −6.86 kcal mol(–1), respectively. Various in vitro assays were performed to confirm their (5a–f) antiviral potential against CHIKV. The non-cytotoxic dose was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and was found to be <100 μM. The compounds 5c and 5d showed their inhibitory potential for CHIKV, which was determined through cytopathic effect assay and plaque reduction assay, which show inhibition up to 95 and 92% for 70 μM concentration of the compounds, respectively. The quantitative real-time polymerase chain reaction assay result confirmed the ability of 5c and 5d to reduce the viral RNA level at 70 μM concentration of compounds to nearly 95 and 93% concentration, respectively, in cells with CHIKV infection. Further, the CHIKV-inhibitory capacity of these compounds was corroborated by execution of immunofluorescence assay. The executed work will be meaningful for the future research of studied dihydrorugosaflavonoids against prime antiviral entrants, leading to remedial management to preclude CHIKV infection. |
Predicting disease emergence and outbreak events is a critical task for public health professionals and epidemiologists. Advances in global disease surveillance are increasingly generating datasets that are worth more than their component parts for prediction-oriented work. Here, we use a trait-free approach which leverages information on the global community of human infectious diseases to predict the biogeography of pathogens through time. Our approach takes pairwise dissimilarities between countries’ pathogen communities and pathogens’ geographical distributions and uses these to predict country–pathogen associations. We compare the success rates of our model for predicting pathogen outbreak, emergence and re-emergence potential as a function of time (e.g. number of years between training and prediction), pathogen type (e.g. virus) and transmission mode (e.g. vector-borne). With only these simple predictors, our model successfully predicts basic network structure up to a decade into the future. We find that while outbreak and re-emergence potential are especially well captured by our simple model, prediction of emergence events remains more elusive, and sudden global emergences like an influenza pandemic are beyond the predictive capacity of the model. However, these stochastic pandemic events are unlikely to be predictable from such coarse data. Together, our model is able to use the information on the existing country–pathogen network to predict pathogen outbreaks fairly well, suggesting the importance in considering information on co-occurring pathogens in a more global view even to estimate outbreak events in a single location or for a single pathogen. |
BACKGROUND: Clinical and epidemiological differences between acute respiratory distress syndrome (ARDS) that presents at the initiation of mechanical ventilation [MV] (ARDS at MV onset) and that which develops during the course of MV (ARDS after MV onset) are not well understood. We conducted an observational study in five Peruvian ICUs to characterize differences between ARDS at MV onset and after MV onset and identify risk factors for the development of ARDS after MV onset. METHODS: We consecutively enrolled critically ill patients with acute respiratory failure requiring at least 24 h of mechanical ventilation and followed them prospectively during the first 28 days and compared baseline characteristics and clinical outcomes by ARDS status. RESULTS: We enrolled 1657 participants on MV (mean age 60.0 years, 55% males) of whom 334 (20.2%) had ARDS at MV onset and 180 (10.9%) developed ARDS after MV onset. Average tidal volume at the initiation of MV was 8.7 mL/kg of predicted body weight (PBW) for participants with ARDS at MV onset, 8.6 mL/kg PBW for those who developed ARDS after MV onset, and 8.5 mL/kg PBW for those who never developed ARDS (p = 0.23). Overall, 90-day mortality was 56% and 55% for ARDS after MV onset and ARDS at MV onset, respectively, as compared to 46% among those who never developed ARDS (p < 0.01). Adults with ARDS had a higher body mass index (BMI) than those without ARDS (27.3 vs 26.5 kg/m(2), p < 0.01). Higher peak pressure (adjusted interquartile OR = 1.51, 95% CI 1.21–1.88), higher mean airway pressure (adjusted interquartile OR = 1.41, 95% CI 1.13–1.76), and higher positive end-expiratory pressure (adjusted interquartile OR = 1.29, 95% CI 1.10–1.50) at MV onset were associated with a higher odds of developing ARDS after MV onset. CONCLUSIONS: In this study of mechanically ventilated patients, 31% of study participants had ARDS at some point during their ICU stay. Optimal lung-protective ventilation was not used in a majority of patients. Patients with ARDS after MV onset had a similar 90-day mortality as those with ARDS at MV onset. Higher airway pressures at MV onset, higher PEEP, and higher BMI were associated with the development of ARDS after MV onset. |
BACKGROUND: Increasing numbers of aging individuals with chronic co-morbidities travel to regions where falciparum malaria is endemic. Non-communicable diseases are now leading risk factors for death in such countries. Thus, the influence of chronic diseases on the outcome of falciparum malaria is an issue of major importance. Aim of the present study was to assess whether non-communicable diseases increase the risk for severe imported falciparum malaria. METHODS: A retrospective observational study of all adult cases with imported falciparum malaria hospitalized between 2001 and 2015 in the tertiary care Charité University Hospital, Berlin, was performed. RESULTS: A total of 536 adult patients (median age 37 years; 31.3% female) were enrolled. Of these, 329 (61.4%) originated from endemic countries, 207 patients (38.6%) from non-endemic regions. Criteria for severe malaria were fulfilled in 68 (12.7%) cases. With older age, lack of previous malaria episodes, being a tourist, and delayed presentation, well-characterized risk factors were associated with severe malaria in univariate analysis. After adjustment for these potential confounders hypertension (adjusted odds ratio aOR, 3.06 95% confidence interval, CI 1.34–7.02), cardiovascular diseases (aOR, 8.20 95% CI 2.30–29.22), and dyslipidaemia (aOR, 6.08 95% CI 1.13–32.88) were individual diseases associated with severe disease in multivariable logistic regression. Hypertension proved an independent risk factor among individuals of endemic (aOR, 4.83, 95% CI 1.44–16.22) as well as of non-endemic origin (aOR, 3.60 95% CI 1.05–12.35). CONCLUSIONS: In imported falciparum malaria hypertension and its related diseases are risk factors for severe disease. |
Dysregulated leukocyte responses underlie the pathobiology of sepsis, which is a leading cause of death. However, measures of leukocyte function are not routinely available in clinical care. Here we report the development and testing of an inertial microfluidic system for the label-free isolation and downstream functional assessment of leukocytes from 50 μl of peripheral blood. We used the system to assess leukocyte phenotype and function in serial samples from 18 hospitalized patients with sepsis and 10 healthy subjects. The sepsis samples had significantly higher levels of CD16(dim) and CD16(−) neutrophils and CD16(+) ‘intermediate’ monocytes, as well as significantly lower levels of neutrophil-elastase release, O(2)(−) production and phagolysosome formation. Repeated sampling of sepsis patients over 7 days showed that leukocyte activation (measured by isodielectric separation) and leukocyte phenotype and function were significantly more predictive of the clinical course than complete-blood-count parameters. We conclude that the serial assessment of leukocyte function in microlitre blood volumes is feasible and that it provides significantly more prognostic information than leukocyte counting. |
Old World camels have served humans in cross‐continental caravans, transporting people and goods, connecting different cultures and providing milk, meat, wool and draught since their domestication around 3000–6000 years ago. In a world of modern transport and fast connectivity, these beasts of burden seem to be out‐dated. However, a growing demand for sustainable milk and meat production, especially in countries affected by climate change and increasing desertification, brings dromedaries (Camelus dromedarius) and Bactrian camels (Camelus bactrianus) back onstage and into the focus of animal breeders and scientists. In this review on the molecular genetics of these economically important species we give an overview about the evolutionary history, domestication and dispersal of Old World camels, whereas highlighting the need for conservation of wild two‐humped camels (Camelus ferus) as an evolutionarily unique and highly endangered species. We provide cutting‐edge information on the current molecular resources and on‐going sequencing projects. We cannot emphasise enough the importance of balancing the need for improving camel production traits with maintaining the genetic diversity in two domestic species with specific physiological adaptation to a desert environment. |
Ribonucleases (RNases) are a large number of enzymes gathered into different bacterial or eukaryotic superfamilies. Bovine pancreatic RNase A, bovine seminal BS-RNase, human pancreatic RNase 1, angiogenin (RNase 5), and amphibian onconase belong to the pancreatic type superfamily, while binase and barnase are in the bacterial RNase N1/T1 family. In physiological conditions, most RNases secreted in the extracellular space counteract the undesired effects of extracellular RNAs and become protective against infections. Instead, if they enter the cell, RNases can digest intracellular RNAs, becoming cytotoxic and having advantageous effects against malignant cells. Their biological activities have been investigated either in vitro, toward a number of different cancer cell lines, or in some cases in vivo to test their potential therapeutic use. However, immunogenicity or other undesired effects have sometimes been associated with their action. Nevertheless, the use of RNases in therapy remains an appealing strategy against some still incurable tumors, such as mesothelioma, melanoma, or pancreatic cancer. The RNase inhibitor (RI) present inside almost all cells is the most efficacious sentry to counteract the ribonucleolytic action against intracellular RNAs because it forms a tight, irreversible and enzymatically inactive complex with many monomeric RNases. Therefore, dimerization or multimerization could represent a useful strategy for RNases to exert a remarkable cytotoxic activity by evading the interaction with RI by steric hindrance. Indeed, the majority of the mentioned RNases can hetero-dimerize with antibody derivatives, or even homo-dimerize or multimerize, spontaneously or artificially. This can occur through weak interactions or upon introducing covalent bonds. Immuno-RNases, in particular, are fusion proteins representing promising drugs by combining high target specificity with easy delivery in tumors. The results concerning the biological features of many RNases reported in the literature are described and discussed in this review. Furthermore, the activities displayed by some RNases forming oligomeric complexes, the mechanisms driving toward these supramolecular structures, and the biological rebounds connected are analyzed. These aspects are offered with the perspective to suggest possible efficacious therapeutic applications for RNases oligomeric derivatives that could contemporarily lack, or strongly reduce, immunogenicity and other undesired side-effects. |
BACKGROUND: There is a marked paucity of data concerning AKI in Sub-Saharan Africa, where there is a substantial burden of trauma and HIV. METHODS: Prospective data was collected on all patients admitted to a multi-disciplinary ICU in South Africa during 2017. Development of AKI (before or during ICU admission) was recorded and renal recovery 90 days after ICU discharge was determined. RESULTS: Of 849 admissions, the mean age was 42.5 years and mean SAPS 3 score was 48.1. Comorbidities included hypertension (30.5%), HIV (32.6%), diabetes (13.3%), CKD (7.8%) and active tuberculosis (6.2%). The most common reason for admission was trauma (26%). AKI developed in 497 (58.5%). Male gender, illness severity, length of stay, vasopressor drugs and sepsis were independently associated with AKI. AKI was associated with a higher in-hospital mortality rate of 31.8% vs 7.23% in those without AKI. Age, active tuberculosis, higher SAPS 3 score, mechanical ventilation, vasopressor support and sepsis were associated with an increased adjusted odds ratio for death. HIV was not independently associated with AKI or hospital mortality. CKD developed in 14 of 110 (12.7%) patients with stage 3 AKI; none were dialysis-dependent. CONCLUSIONS: In this large prospective multidisciplinary ICU cohort of younger patients, AKI was common, often associated with trauma in addition to traditional risk factors and was associated with good functional renal recovery at 90 days in most survivors. Although the HIV prevalence was high and associated with higher mortality, this was related to the severity of illness and not to HIV status per se. |
BACKGROUND: The use of extracorporeal membrane oxygenation (ECMO) in awake, spontaneously breathing and non-intubated patients (awake ECMO) may be a novel therapeutic strategy for severe acute respiratory distress syndrome (ARDS) patients. The purpose of this study is to assess the feasibility and safety of awake ECMO in severe ARDS patients receiving prolonged ECMO (> 14 days). METHODS: We describe our experience with 12 consecutive severe ARDS patients (age, 39.1 ± 16.4 years) supported with awake ECMO to wait for native lung recovery during prolonged ECMO treatment from July 2013 to January 2018. Outcomes are reported including the hospital mortality, ECMO-related complications and physiological data on weaning from invasive ventilation. RESULTS: The patients received median 26.0 (15.5, 64.8) days of total ECMO duration in the cohort. The longest ECMO support duration was 121 days. Awake ECMO and extubation was implemented after median 10.2(5.0, 42.9) days of ECMO. Awake ECMO was not associated with increased morbidity. The total invasive ventilation duration, lengths of stay in the ICU and hospital in the cohort were 14.0(12.0, 37.3) days, 33.0(22.3, 56.5) days and 46.5(27.3, 84.8) days, respectively. The hospital mortality rate was 33.3% (4/12) in the cohort. Survivors had more stable respiratory rate and heart rate after extubation when compared to the non-survivors. CONCLUSIONS: With carefully selected patients, awake ECMO is a feasible and safe strategy for severe pulmonary ARDS patients receiving prolonged ECMO support to wait for native lung recovery. |
OBJECTIVES: Feline immunodeficiency virus (FIV) and feline leukaemia virus (FeLV) are retroviruses affecting cats worldwide. The objectives of the study were to estimate the prevalence of these retroviruses in domestic cats in Hungary and to characterise the phylogenetic relationships of FIV strains. METHODS: A total of 335 anticoagulated whole-blood samples obtained from both a healthy and ill cat population were examined for the presence of FIV and FeLV with two methods: ELISA and PCR. Statistical analysis was carried out to analyse the data obtained. Sequencing and phylogenetic analysis of partial polymerase (pol) gene sequences was performed to describe circulating FIV subtypes. RESULTS: Statistical analysis showed 11.8% and 9.9% true prevalence of FeLV and FIV, respectively, with ELISA. The apparent prevalence calculated from the PCR results were 17.3% for FeLV and 13.1% for FIV. Phylogenetic analysis of partial pol gene sequences obtained from 22 FIV strains showed that all observed Hungarian strains belonged to FIV subtype B. The strains were grouped into several monophyletic subgroups reflecting the geographic locations of the origin of the samples. The overall mean genetic similarity between the analysed strains was 98.2%. CONCLUSIONS AND RELEVANCE: We report the first thorough overview of the prevalence of FeLV and FIV in Hungary, which is relatively high, and give insight into the genetic diversity of Hungarian strains of FIV. |
BACKGROUND: Ebolavirus (EBOV) outbreaks, while sporadic, cause tremendous morbidity and mortality. No therapeutics or vaccines are currently licensed; however, a vaccine has shown promise in clinical trials. A critical step towards development of effective therapeutics is a better understanding of factors that govern host susceptibility to this pathogen. As macrophages are an important cell population targeted during virus replication, we explore the effect of cytokine polarization on macrophage infection. METHODS/MAIN FINDINGS: We utilized a BSL2 EBOV model virus, infectious, recombinant vesicular stomatitis virus encoding EBOV glycoprotein (GP) (rVSV/EBOV GP) in place of its native glycoprotein. Macrophages polarized towards a M2-like anti-inflammatory state by combined IL-4 and IL-13 treatment were more susceptible to rVSV/EBOV GP, but not to wild-type VSV (rVSV/G), suggesting that EBOV GP-dependent entry events were enhanced by these cytokines. Examination of RNA expression of known surface receptors that bind and internalize filoviruses demonstrated that IL-4/IL-13 stimulated expression of the C-type lectin receptor DC-SIGN in human macrophages and addition of the competitive inhibitor mannan abrogated IL-4/IL-13 enhanced infection. Two murine DC-SIGN-like family members, SIGNR3 and SIGNR5, were upregulated by IL-4/IL-13 in murine macrophages, but only SIGNR3 enhanced virus infection in a mannan-inhibited manner, suggesting that murine SIGNR3 plays a similar role to human DC-SIGN. In vivo IL-4/IL-13 administration significantly increased virus-mediated mortality in a mouse model and transfer of ex vivo IL-4/IL-13-treated murine peritoneal macrophages into the peritoneal cavity of mice enhanced pathogenesis. SIGNIFICANCE: These studies highlight the ability of macrophage polarization to influence EBOV GP-dependent virus replication in vivo and ex vivo, with M2a polarization upregulating cell surface receptor expression and thereby enhancing virus replication. Our findings provide an increased understanding of the host factors in macrophages governing susceptibility to filoviruses and identify novel murine receptors mediating EBOV entry. |
Recent genome-wide association studies have identified numerous loci associated with neuropsychiatric disorders. The majority of these are in non-coding regions, and are commonly assigned to the nearest gene along the genome. However, this approach neglects the three-dimensional organisation of the genome, and the fact that the genome contains arrays of extremely conserved non-coding elements termed genomic regulatory blocks (GRBs), which can be utilized to detect genes under long-range developmental regulation. Here we review a GRB-based approach to assign loci in non-coding regions to potential target genes, and apply it to reanalyse the results of one of the largest schizophrenia GWAS (SWG PGC, 2014). We further apply this approach to GWAS data from two related neuropsychiatric disorders—autism spectrum disorder and bipolar disorder—to show that it is applicable to developmental disorders in general. We find that disease-associated SNPs are overrepresented in GRBs and that the GRB model is a powerful tool for linking these SNPs to their correct target genes under long-range regulation. Our analysis identifies novel genes not previously implicated in schizophrenia and corroborates a number of predicted targets from the original study. The results are available as an online resource in which the genomic context and the strength of enhancer–promoter associations can be browsed for each schizophrenia-associated SNP. |
Children are more vulnerable to the risks of air pollution, including susceptibility to acquiring chronic diseases in their developing lungs. Despite these, there are no specific masks designed for and tested in children that are available to protect our young from the common particulate air pollutants today. We evaluated safety, fit and comfort of a specially designed paediatric N95 mask with an optional micro ventilator (micro fan, MF) in healthy children aged 7–14 years, in a randomized, two-period crossover design. The subjects’ cardiorespiratory physiological measurements were assessed in different states of physical activity under different interventions (mask without and with MF). A total of 106 subjects were recruited between July-August 2016. The use of the mask without MF increased the End-Tidal CO(2) (ETCO(2)) and Fractional concentration of Inspired CO(2) (FICO(2)) at rest and on mild exertion, as expected. The use of the mask with MF brought FICO(2) levels comparably closer to baseline levels without the mask for both activities. The mask, with or without the MF, was found to be well fitting, comfortable and safe for use in children at rest and on mild exertion. The N95 mask tested offers a promising start for more studies in the paediatric population. |
BACKGROUND: Pristine carbon dots (CDs) derived from citric acid pyrolysis are used in a variety of biomedical research such as imaging and drug delivery. However, potential cytotoxic effects of pyrolysis temperature on cells is underexplored. To address this need, we studied toxicity of the CDs to breast cancer cells using MTT and LDH assays. In addition, we investigated photo-induced cytotoxicity of the synthesized CDs in a wide concentration range under white light. RESULTS: Our results suggest little cytotoxicity of the CDs after 24 h exposure of cells. Only the high quantum yield CDs caused a significant toxicity to cells at the highest concentrations of 2.0 and 1.5 mg/ml compared to other CDs at similar concentrations. The synthesized CDs entered the cells without any significant cytotoxicity. The CDs also caused a concentration- and irradiation time-dependent photo-induced cytotoxicity. CONCLUSION: The optimization of synthesis conditions from this study may help develop safe and efficient CDs for imaging and drug delivery. |
BACKGROUND: Thrombotic thrombocytopenic purpura is an autoimmune disease that carries a high mortality. Very few case reports in the literature have described a relationship between Graves disease and thrombotic thrombocytopenic purpura. We present a case of a patient with Graves disease who was found to be biochemically and clinically hyperthyroid with concurrent thrombotic thrombocytopenic purpura. CASE PRESENTATION: Our patient was a 30-year-old African American woman with a history of hypertension and a family history of Graves disease who had recently been diagnosed with hyperthyroidism and placed on methimazole. She presented to our hospital with the complaints of progressive shortness of breath and dizziness. Her vital signs were stable. On further evaluation, she was diagnosed with thrombotic thrombocytopenic purpura, depending on clinical and laboratory results, and also was found to have highly elevated free T4 and suppressed thyroid-stimulating hormone. She received multiple sessions of plasmapheresis and ultimately had a total thyroidectomy. The patient’s hospital course was complicated by pneumonia and acute respiratory distress syndrome. Her platelets stabilized at approximately 50,000/μl, and her ADAMTS13 activity normalized despite multiple complications. The patient ultimately had a cardiac arrest with pulseless electrical activity and died despite multiple attempts at cardiopulmonary resuscitation. CONCLUSION: Graves disease is an uncommon trigger for the development of thrombotic thrombocytopenic purpura, and very few cases have been reported thus far. Therefore, clinicians should be aware of this association in the appropriate clinical context to comprehensively monitor hyperthyroid patients during treatment. |
In recent years, the outbreak of infectious disease caused by Zika virus (ZIKV) has posed a major threat to global public health, calling for the development of therapeutics to treat ZIKV disease. Here, we have described the different stages of the ZIKV life cycle and summarized the latest progress in the development of small-molecule inhibitors against ZIKV infection. We have also discussed some general strategies for the discovery of small-molecule ZIKV inhibitors. |
The purpose of this study was to develop a tool for community-based health organisations (CBHOs) to evaluate the preparedness in biohazards concerning epidemics or bioterrorism. We searched concepts on partnerships of CBHOs with health systems in guidelines of the Centers for Disease Control and Prevention and literature. Then, we validated the researcher-made tool by face validity, content validity, exploratory factor analysis (EFA), confirmatory factor analysis (CFA) and criterion validity. Data were collected by sending the tool to 620 CBHOs serving under supervision of Iran’s ministry of health. Opinions of health professionals and stakeholders in CBHOs were used to assess face and content validity. Factor loads in EFA were based on three-factor structure that verified by CFA. We used SPSS V.18 and Mplus7 software for statistical analysis. About 105 health-based CBHOs participated. After conducting face validity and calculating content validity ratio and content validity index, we reached 54 items in the field of planning, training and infrastructure. We conducted construct validity using 105 CBHOs. Three items exchanged between the fields according to factor loads in EFA, and CFA verified the model fit as Comparative Fit Index, Tucker-Lewis index and root mean square error of approximation were 0.921, 0918 and 0.052, respectively. The Cronbach’s of the whole tool was 0.944. Spearman correlation coefficient confirmed criterion validity as coefficient was 0.736. Planning, training and infrastructure fields are the most important aspects of preparedness in health-based CBHOs. Applying the new assessment tool in future studies will show the weaknesses and capabilities of health-based CBHOs in biohazard and clear necessary intervention actions for health authorities. |
Despite the global zoonotic disease burden, the underlying exposures that drive zoonotic disease emergence are not understood. Here, we aimed to assess exposures to potential sources of zoonotic disease and investigate the demographics, attitudes, and behavior of individuals with sustained occupational animal contact in Vietnam. We recruited 581 animal workers (animal-raising farmers, slaughterers, animal health workers, and rat traders) and their families in southern and central Vietnam into a cohort. Cohort members were followed for 3 years and interviewed annually regarding (1) demography and attitudes regarding zoonotic disease, (2) medical history, (3) specific exposures to potential zoonotic infection sources, and (4) socioeconomic status. Interview information over the 3 years was combined and analyzed as cross-sectional data. Of the 297 cohort members interviewed, the majority (79.8%; 237/297) reported raising livestock; almost all (99.6%; 236/237) reported being routinely exposed to domestic animals, and more than a quarter (28.7%; 68/237) were exposed to exotic animals. Overall, 70% (208/297) reported slaughtering exotic animals; almost all (99.5%; 207/208) reported consuming such animals. The consumption of raw blood and meat was common (24.6%; 73/297 and 37%; 110/297, respectively). Over half (58.6%; 174/297) reported recent occupational animal-induced injuries that caused bleeding; the use of personal protective equipment (PPE) was limited. Our work demonstrates that individuals working with animals in Vietnam are exposed to a wide range of species, and there are limited procedures for reducing potential zoonotic disease exposures. We advocate better education, improved animal security, and enforced legislation of PPE for those with occupational animal exposure in Vietnam. |
Spotted fever group and related rickettsia (SFGR) are a neglected group of pathogens that belong to the genus Rickettsia. SFGR are zoonotic and are transmitted by arthropod vectors, primarily ticks, fleas and mites to accidental hosts. These emerging and re-emerging infections are widely distributed throughout the world. Land-use change and increasing human–wildlife conflict compound the risk of SFGR infection to local people in endemic areas and travelers to these regions. In this article, we discuss the rickettsial organisms causing spotted fever and related diseases, their arthropod vectors in Asia and the impact of land-use change on their spread. |
Npl4 is likely to be the most upstream factor recognizing Lys48-linked polyubiquitylated substrates in the proteasomal degradation pathway in yeast. Along with Ufd1, Npl4 forms a heterodimer (UN), and functions as a cofactor for the Cdc48 ATPase. Here, we report the crystal structures of yeast Npl4 in complex with Lys48-linked diubiquitin and with the Npl4-binding motif of Ufd1. The distal and proximal ubiquitin moieties of Lys48-linked diubiquitin primarily interact with the C-terminal helix and N-terminal loop of the Npl4 C-terminal domain (CTD), respectively. Mutational analysis suggests that the CTD contributes to linkage selectivity and initial binding of ubiquitin chains. Ufd1 occupies a hydrophobic groove of the Mpr1/Pad1 N-terminal (MPN) domain of Npl4, which corresponds to the catalytic groove of the MPN domain of JAB1/MPN/Mov34 metalloenzyme (JAMM)-family deubiquitylating enzyme. This study provides important structural insights into the polyubiquitin chain recognition by the Cdc48–UN complex and its assembly. |
Rotavirus (RV) replicates in round-shaped cytoplasmic viral factories, although how they assemble remains unknown. During RV infection, NSP5 undergoes hyperphosphorylation, which is primed by the phosphorylation of a single serine residue. The role of this posttranslational modification in the formation of viroplasms and its impact on virus replication remain obscure. Here, we investigated the role of NSP5 during RV infection by taking advantage of a modified fully tractable reverse-genetics system. A trans-complementing cell line stably producing NSP5 was used to generate and characterize several recombinant rotaviruses (rRVs) with mutations in NSP5. We demonstrate that an rRV lacking NSP5 was completely unable to assemble viroplasms and to replicate, confirming its pivotal role in rotavirus replication. A number of mutants with impaired NSP5 phosphorylation were generated to further interrogate the function of this posttranslational modification in the assembly of replication-competent viroplasms. We showed that the rRV mutant strains exhibited impaired viral replication and the ability to assemble round-shaped viroplasms in MA104 cells. Furthermore, we investigated the mechanism of NSP5 hyperphosphorylation during RV infection using NSP5 phosphorylation-negative rRV strains, as well as MA104-derived stable transfectant cell lines expressing either wild-type NSP5 or selected NSP5 deletion mutants. Our results indicate that NSP5 hyperphosphorylation is a crucial step for the assembly of round-shaped viroplasms, highlighting the key role of the C-terminal tail of NSP5 in the formation of replication-competent viral factories. Such a complex NSP5 phosphorylation cascade may serve as a paradigm for the assembly of functional viral factories in other RNA viruses. IMPORTANCE The rotavirus (RV) double-stranded RNA genome is replicated and packaged into virus progeny in cytoplasmic structures termed viroplasms. The nonstructural protein NSP5, which undergoes a complex hyperphosphorylation process during RV infection, is required for the formation of these virus-induced organelles. However, its roles in viroplasm formation and RV replication have never been directly assessed due to the lack of a fully tractable reverse-genetics (RG) system for rotaviruses. Here, we show a novel application of a recently developed RG system by establishing a stable trans-complementing NSP5-producing cell line required to rescue rotaviruses with mutations in NSP5. This approach allowed us to provide the first direct evidence of the pivotal role of this protein during RV replication. Furthermore, using recombinant RV mutants, we shed light on the molecular mechanism of NSP5 hyperphosphorylation during infection and its involvement in the assembly and maturation of replication-competent viroplasms. |
Acute respiratory distress syndrome (ARDS) is a devastating hypoxemic respiratory failure, characterized by disruption of the alveolar-capillary membrane barrier. Current management for ARDS remains supportive, including lung-protective ventilation and a conservative fluid strategy. Mesenchymal stem cells (MSCs) have emerged as a potentially attractive candidate for the management of ARDS through facilitating lung tissue regeneration and repair by releasing paracrine soluble factors. Over the last decade, a variety of strategies have emerged to optimize MSC-based therapy. Among these, the strategy using genetically modified MSCs has received increased attention recently due to its distinct advantage, in conferring incremental migratory capacity and, enhancing the anti-inflammatory, immunomodulatory, angiogenic, and antifibrotic effects of these cells in numerous preclinical ARDS models, which may in turn provide additional benefits in the management of ARDS. Here, we provide an overview of recent studies testing the efficacy of genetically modified MSCs using preclinical models of ARDS. |
The mortality rate of hemorrhagic African swine fever (ASF), which targets domestic pigs and wild boars is caused by African swine fever virus (ASFV), can reach 100%. Since the first confirmed ASF outbreak in China on 3 August 2018, 156 ASF outbreaks were detected in 32 provinces. About 1,170,000 pigs were culled in order to halt further spread. There is no effective treatment or vaccine for it and the present molecular diagnosis technologies have trade-offs in sensitivity, specificity, cost and speed, and none of them cater perfectly to ASF control. Thus, a technology that overcomes the need for laboratory facilities, is relatively low cost, and rapidly and sensitively detects ASFV would be highly valuable. Here, we describe an RAA-Cas12a-based system that combines recombinase aided amplification (RAA) and CRISPR/Cas12a for ASFV detection. The fluorescence intensity readout of this system detected ASFV p72 gene levels as low as 10 aM. For on-site ASFV detection, lateral-flow strip readout was introduced for the first time in the RAA-Cas12a based system (named CORDS, Cas12a-based On-site and Rapid Detection System). We used CORDS to detect target DNA highly specifically using the lateral-flow strip readout and the assay displayed no cross-reactivity to other 13 swine viruses including classical swine fever (CSF). CORDS could identify the ASFV DNA target at femtomolar sensitivity in an hour at 37°C, and only requires an incubator. For ease of use, the reagents of CORDS were lyophilized to three tubes and remained the same sensitivity when stored at 4°C for at least 7 days. Thus, CORDS provide a rapid, sensitive and easily operable method for ASFV on-site detection. Lyophilized CORDS can withstand long-term transportation and storage, and is ready for field-based applications. |
The generation of tissue-resident memory T cells (T(RM)) is an essential aspect of immunity at mucosal surfaces, and it has been suggested that preferential generation of T(RM) is one of the principal advantages of mucosally administered vaccines. We have previously shown that antigen-specific, IL-17-producing CD4(+) T cells can provide capsular antibody-independent protection against nasal carriage of Streptococcus pneumoniae; but whether pneumococcus-responsive T(RM) are localized within the nasal mucosa and are sufficient for protection from carriage has not been determined. Here we show that intranasal administration of live or killed pneumococci to mice generates pneumococcus-responsive IL-17A-producing CD4(+) mucosal T(RM). Furthermore, we show that these cells are sufficient to mediate long-lived, neutrophil-dependent protection against subsequent pneumococcal nasal challenge. Unexpectedly, and in contrast with the prevailing paradigm, we found that parenteral administration of killed pneumococci also generates protective IL-17A(+)CD4(+) T(RM) in the nasal mucosa. These results demonstrate a critical and sufficient role of T(RM) in prevention of pneumococcal colonization, and further that these cells can be generated by parenteral immunization. Our findings therefore have important implications regarding the generation of immune protection at mucosal surfaces by vaccination. |
The seasonal burden of influenza coupled with the pandemic outbreaks of more pathogenic strains underscore a critical need to understand the pathophysiology of influenza injury in the lung. Interleukin-22 (IL-22) is a promising cytokine that is critical in protecting the lung during infection. This cytokine is strongly regulated by the soluble receptor IL-22-binding protein (IL-22BP), which is constitutively expressed in the lungs where it inhibits IL-22 activity. The IL-22/IL-22BP axis is thought to prevent chronic exposure of epithelial cells to IL-22. However, the importance of this axis is not understood during an infection such as influenza. Here we demonstrate through the use of IL-22BP-knockout mice (il-22ra2(−/−)) that a pro-IL-22 environment reduces pulmonary inflammation during H1N1 (PR8/34 H1N1) infection and protects the lung by promoting tight junction formation. We confirmed these results in normal human bronchial epithelial cells in vitro demonstrating improved membrane resistance and induction of the tight junction proteins Cldn4, Tjp1, and Tjp2. Importantly, we show that administering recombinant IL-22 in vivo reduces inflammation and fluid leak into the lung. Taken together, our results demonstrate the IL-22/IL-22BP axis is a potential targetable pathway for reducing influenza-induced pneumonia. |
Illuminating the role of specific gene duplications within the human lineage can provide insights into human-specific adaptations. The so-called human core duplicon gene families have received particular attention in this respect, due to special features, such as expansion along single chromosomes, newly acquired protein domains and signatures of positive selection. Here, we summarize the data available for 10 such families and include some new analyses. A picture emerges that suggests broad functions for these protein families, possibly through modification of core cellular pathways. Still, more dedicated studies are required to elucidate the function of core-duplicons gene families and how they have shaped adaptations and evolution of humans. |
OBJECTIVE: To determine costs of hospitalization associated with bronchopulmonary dysplasia (BPD) during the first year in very low birth weight infants. STUDY DESIGN: Retrospective cohort study of California births from 2008–2011 linking birth certificate, discharge records, and clinical data from California Perinatal Quality Care Collaborative. Inclusion: birthweight 401–1500 grams, gestational age <30 weeks, inborn or transferred within 2 days, alive at 36 weeks corrected, and without major congenital anomalies. Outcomes included cost and length of stay of initial hospitalization and re-hospitalizations. RESULT: Out of 7,998 eligible infants, 2,696 (33.7%) developed BPD. Median hospitalization cost in the first year was $377,871 per infant with BPD compared to $175,836 per infant without BPD (adjusted cost ratio 1.54, 95% confidence interval 1.49–1.59). Infants with BPD also had longer length of stay and a higher likelihood of rehospitalization. CONCLUSION: BPD is associated with substantial resource utilization. Prevention strategies could help conserve healthcare resources. |
Zika virus (ZIKV) was first discovered in 1947 in Africa. Since then, sporadic ZIKV infections of humans have been reported in Africa and Asia. For a long time, this virus was mostly unnoticed due to its mild symptoms and low fatality rates. However, during the 2015–2016 epidemic in Central and South America, when millions of people were infected, it was discovered that ZIKV causes microcephaly in the babies of mothers infected during pregnancy. An examination of the M and C proteins of the ZIKV shell using the disorder predictor PONDR VLXT revealed that the M protein contains relatively high disorder levels comparable only to those of the yellow fever virus (YFV). On the other hand, the disorder levels in the C protein are relatively low, which can account for the low case fatality rate (CFR) of this virus in contrast to the more virulent YFV, which is characterized by high disorder in its C protein. A larger variation was found in the percentage of intrinsic disorder (PID) in the C protein of various ZIKV strains. Strains of African lineage are characterized by higher PIDs. Using both in vivo and in vitro experiments, laboratories have also previously shown that strains of African origin have a greater potential to inflict higher fetal morbidity than do strains of Asian lineage, with dengue-2 virus (DENV-2) having the least potential. Strong correlations were found between the potential to inflict fetal morbidity and shell disorder in ZIKV (r(2) = 0.9) and DENV-2 (DENV-2 + ZIKV, r(2) = 0.8). A strong correlation between CFR and PID was also observed when ZIKV was included in an analysis of sets of shell proteins from a variety of flaviviruses (r(2) = 0.8). These observations have potential implications for antiviral vaccine development and for the design of cancer therapeutics in terms of developing therapeutic viruses that penetrate hard-to-reach organs. |
BACKGROUND AND AIM: Bovine respiratory syncytial virus (BRSV) is one of the main causes of severe pneumonia, interstitial edema, and emphysema in cattle. The current study investigated the prevalence and risk factors of BRSV in cattle in the Nineveh Province, Iraq. MATERIALS AND METHODS: Between September 2017 and September 2018, 450 serum samples were collected from non-vaccinated cattle of different ages and breeds for BRSV testing. The epidemiological information of the animals was recorded. The prevalence of the disease was determined using an indirect enzyme-linked immunosorbent assay kit. RESULTS: The prevalence of BRSV was 83.11%, and it was significantly (p<0.05) higher in cattle aged greater than 7 months-1.5 years than in older animals; in imported cattle than in Native animals; and in animals originating from large herds (100 animals) than in those from smaller herds (40 animals). There was no significant difference between BRSV prevalence in male and female animals. When samples from different regions of the Nineveh Governorate were compared, the northern region was associated with the highest prevalence of the disease. Samples harvested in the winter displayed the highest BRSV titer, compared to those collected during the other seasons. CONCLUSION: BRSV is prevalent in cattle from the Nineveh Governorate. Risk factors such as animal age, origin, herd size, and the herd’s geographical location are associated with an increased prevalence of the disease in this region. Routine vaccination programs should be adopted to reduce the prevalence of BRSV. |
DNA, when folded into nanostructures with a specific shape, is capable of spacing and arranging binding sites into a complex geometric pattern with nanometre precision. Here we demonstrate a designer DNA nanostructure that can act as a template to display multiple binding motifs with precise spatial pattern-recognition properties, and that this approach can confer exceptional sensing and potent viral inhibitory capabilities. A star-shaped DNA architecture, carrying five molecular beacon-like motifs, was constructed to display ten dengue envelope protein domain III (ED3)-targeting aptamers into a two-dimensional pattern precisely matching the spatial arrangement of ED3 clusters on the dengue (DENV) viral surface. The resulting multivalent interactions provide high DENV-binding avidity. We show that this structure is a potent viral inhibitor and that it can act as a sensor by including a fluorescent output to report binding. Our molecular-platform design strategy could be adapted to detect and combat other disease-causing pathogens by generating the requisite ligand patterns on customized DNA nanoarchitectures. |
Anaplasma phagocytophilum is the agent of tick-borne fever, equine, canine and human granulocytic anaplasmosis. The common route of A. phagocytophilum transmission is through a tick bite, the main vector in Europe being Ixodes ricinus. Despite the apparently ubiquitous presence of the pathogen A. phagocytophilum in ticks and various wild and domestic animals from Europe, up to date published clinical cases of human granulocytic anaplasmosis (HGA) remain rare compared to the worldwide status. It is unclear if this reflects the epidemiological dynamics of the human infection in Europe or if the disease is underdiagnosed or underreported. Epidemiologic studies in Europe have suggested an increased occupational risk of infection for forestry workers, hunters, veterinarians, and farmers with a tick-bite history and living in endemic areas. Although the overall genetic diversity of A. phagocytophilum in Europe is higher than in the USA, the strains responsible for the human infections are related on both continents. However, the study of the genetic variability and assessment of the difference of pathogenicity and infectivity between strains to various hosts has been insufficiently explored to date. Most of the European HGA cases presented as a mild infection, common clinical signs being pyrexia, headache, myalgia and arthralgia. The diagnosis of HGA in the USA was recommended to be based on clinical signs and the patient’s history and later confirmed using specialized laboratory tests. However, in Europe since the majority of cases are presenting as mild infection, laboratory tests may be performed before the treatment in order to avoid antibiotic overuse. The drug of choice for HGA is doxycycline and because of potential for serious complication the treatment should be instituted on clinical suspicion alone. |
Tick-borne nairoviruses (order Bunyavirales) encode an ovarian tumor domain protease (OTU) that suppresses the innate immune response by reversing the post-translational modification of proteins by ubiquitin (Ub) and interferon-stimulated gene product 15 (ISG15). Ub is highly conserved across eukaryotes, whereas ISG15 is only present in vertebrates and shows substantial sequence diversity. Prior attempts to address the effect of ISG15 diversity on viral protein-ISG15 interactions have focused on only a single species’ ISG15 or a limited selection of nairovirus OTUs. To gain a more complete perspective of OTU-ISG15 interactions, we biochemically assessed the relative activities of 14 diverse nairovirus OTUs for 12 species’ ISG15 and found that ISG15 activity is predominantly restricted to particular nairovirus lineages reflecting, in general, known virus-host associations. To uncover the underlying molecular factors driving OTUs affinity for ISG15, X-ray crystal structures of Kupe virus and Ganjam virus OTUs bound to sheep ISG15 were solved and compared to complexes of Crimean-Congo hemorrhagic fever virus and Erve virus OTUs bound to human and mouse ISG15, respectively. Through mutational and structural analysis seven residues in ISG15 were identified that predominantly influence ISG15 species specificity among nairovirus OTUs. Additionally, OTU residues were identified that influence ISG15 preference, suggesting the potential for viral OTUs to adapt to different host ISG15s. These findings provide a foundation to further develop research methods to trace nairovirus-host relationships and delineate the full impact of ISG15 diversity on nairovirus infection. |
Failure to reproduce results from some scientific studies has raised awareness of the critical need for reproducibility in translational studies. Macroscopic and microscopic examination is a common approach to determine changes in tissues, but text descriptions and visual images have limitations for group comparisons. Semiquantitative scoring is a way of transforming qualitative tissue data into numerical data that allow more robust group comparisons. Semiquantitative scoring has broad uses in preclinical and clinical studies for evaluation of tissue lesions. Reproducibility can be improved by constraining bias through appropriate experimental design, randomization of tissues, effective use of multidisciplinary collaborations, and valid masking procedures. Scoring can be applied to tissue lesions (eg, size, distribution, characteristics) and also to tissues through evaluation of staining distribution and intensity. Semiquantitative scores should be validated to demonstrate relevance to biological data and to demonstrate observer reproducibility. Statistical analysis should make use of appropriate tests to give robust confidence in the results and interpretations. Following key principles of semiquantitative scoring will not only enhance descriptive tissue evaluation but also improve quality, reproducibility, and rigor of tissue studies. |
BACKGROUND: Herpesviridae reactivation among non-immunocompromised critically ill patients is associated with impaired prognosis, especially during acute respiratory distress syndrome (ARDS). However, little is known about herpes simplex virus (HSV) and Cytomegalovirus (CMV) reactivation occurring in patients with severe ARDS under veno-venous extracorporeal membrane oxygenation (ECMO). We tried to determine the frequency of Herpesviridae reactivation and its impact on patients’ prognosis during ECMO for severe ARDS. RESULTS: During a 5-year period, 123 non-immunocompromised patients with a severe ARDS requiring a veno-venous ECMO were included. Sixty-seven patients (54%) experienced HSV and/or CMV reactivation during ECMO course (20 viral co-infection, 40 HSV alone, and 7 CMV alone). HSV reactivation occurred earlier than CMV after the beginning of MV [(6–15) vs. 19 (13–29) days; p < 0.01] and after ECMO implementation [(2–8) vs. 14 (10–20) days; p < 0.01]. In univariate analysis, HSV/CMV reactivation was associated with a longer duration of mechanical ventilation [(22–52.5) vs. 17.5 (9–28) days; p < 0.01], a longer duration of ECMO [15 (10–22.5) vs. 9 (5–14) days; p < 0.01], and a prolonged ICU [29 (19.5–47.5) vs. 16 (9–30) days; p < 0.01] and hospital stay [44 (29–63.5) vs. 24 (11–43) days; p < 0.01] as compared to non-reactivated patients. However, in multivariate analysis, viral reactivation remained associated with prolonged MV only. When considered separately, both HSV and CMV reactivation were associated with a longer duration of MV as compared to non-reactivation patients [29 (19.5–41) and 28 (20.5–37), respectively, vs. 17.5 (9–28) days; p < 0.05]. Co-reactivation patients had a longer duration of MV [58.5 (38–72.3); p < 0.05] and ICU stay [51.5 (32.5–69) vs. 27.5 (17.75–35.5) and 29 (20–30.5), respectively] as compared to patients with HSV or CMV reactivation alone. In multivariate analysis, HSV reactivation remained independently associated with a longer duration of MV and hospital length of stay. CONCLUSIONS: Herpesviridae reactivation is frequent among patients with severe ARDS under veno-venous ECMO and is associated with a longer duration of mechanical ventilation. The direct causative link between HSV and CMV reactivation and respiratory function worsening under ECMO remains to be confirmed. |
Influenza is a major cause of morbidity and mortality worldwide, as well as in China. Knowledge of the spatial and temporal characteristics of influenza is important in evaluating and developing disease control programs. This study aims to describe an accurate spatiotemporal pattern of influenza at the prefecture level and explore the risk factors associated with influenza incidence risk in mainland China from 2005 to 2018. The incidence data of influenza were obtained from the Chinese Notifiable Infectious Disease Reporting System (CNIDRS). The Besag York Mollié (BYM) model was extended to include temporal and space-time interaction terms. The parameters for this extended Bayesian spatiotemporal model were estimated through integrated nested Laplace approximations (INLA) using the package R-INLA in R. A total of 702,226 influenza cases were reported in mainland China in CNIDRS from 2005–2018. The yearly reported incidence rate of influenza increased 15.6 times over the study period, from 3.51 in 2005 to 55.09 in 2008 per 100,000 populations. The temporal term in the spatiotemporal model showed that much of the increase occurred during the last 3 years of the study period. The risk factor analysis showed that the decreased number of influenza vaccines for sale, the new update of the influenza surveillance protocol, the increase in the rate of influenza A (H1N1)pdm09 among all processed specimens from influenza-like illness (ILI) patients, and the increase in the latitude and longitude of geographic location were associated with an increase in the influenza incidence risk. After the adjusting for fixed covariate effects and time random effects, the map of the spatial structured term shows that high-risk areas clustered in the central part of China and the lowest-risk areas in the east and west. Large space-time variations in influenza have been found since 2009. In conclusion, an increasing trend of influenza was observed from 2005 to 2018. The insufficient flu vaccine supplements, the newly emerging influenza A (H1N1)pdm09 and expansion of influenza surveillance efforts might be the major causes of the dramatic changes in outbreak and spatio-temporal epidemic patterns. Clusters of prefectures with high relative risks of influenza were identified in the central part of China. Future research with more risk factors at both national and local levels is necessary to explain the changing spatiotemporal patterns of influenza in China. |
Porcine epidemic diarrhea virus (PEDV) infection can induce intestinal dysfunction, resulting in severe diarrhea and even death, but the mode of action underlying these viral effects remains unclear. This study determined the effects of PEDV infection on intestinal absorption and the expression of genes for nutrient transporters via biochemical tests and microarray analysis. Sixteen 7-day-old healthy piglets fed a milk replacer were randomly allocated to one of two groups. After 5-day adaption, piglets (n = 8/group) were orally administrated with either sterile saline or PEDV (the strain from Yunnan province) at 10(4.5) TCID(50) (50% tissue culture infectious dose) per pig. All pigs were orally infused D-xylose (0.1 g/kg BW) on day 5 post PEDV or saline administration. One hour later, jugular vein blood samples as well as intestinal samples were collected for further analysis. In comparison with the control group, PEDV infection increased diarrhea incidence, blood diamine oxidase activity, and iFABP level, while reducing growth and plasma D-xylose concentration in piglets. Moreover, PEDV infection altered plasma and jejunal amino acid profiles, and decreased the expression of aquaporins and amino acid transporters (L-type amino acid transporter 1, sodium-independent amino acid transporter, B(°(,+))-type amino acid transport protein, sodium-dependent neutral amino acid transporter 1, sodium-dependent glutamate/aspartate transporter 3, and peptide transporter (1), lipid transport and metabolism-related genes (lipoprotein lipase, apolipoprotein A1, apolipoprotein A4, apolipoprotein C2, solute carrier family 27 member 2, solute carrier family 27 member 4, fatty acid synthase, and long-chain acyl-CoA synthetase (3), and glucose transport genes (glucose transporter-2 and insulin receptor) in the jejunum. However, PEDV administration increased mRNA levels for phosphoenolpyruvate carboxykinase 1, argininosuccinate synthase 1, sodium/glucose co-transporter-1, and cystic fibrosis transmembrane conductance regulator in the jejunum. Collectively, these comprehensive results indicate that PEDV infection induces intestinal injury and inhibits the expression of genes encoding for nutrient transporters. |
Chronic kidney disease is an epidemiologically identified risk factor for development of severe dengue in dengue-affected patients. However, available data on the immune pathogenesis in end stage renal disease (ESRD) patients affected by dengue is insufficient. We performed an in vitro study to evaluate the sequential immunological reactions and viral load in dengue virus type 2-infected mononuclear cells of patients with ESRD (n = 34) and in healthy controls (n = 30). The concentrations of interleukins (IL)-1 receptor antagonist (Ra), IL-2, IL-6, IL-8, IL-10, IL-12p40, granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1b (MIP-1b), vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF)-α and viral load cycle threshold (Ct) were measured in the dengue virus type 2-infected mononuclear cells at 6 h, 24 h, 48 h, and 72 h post-infection. We found in the ESRD group significantly higher GM-CSF and IL-2 levels at 6 h post-infection. However, IL-8, IL-10, IL-12p40, TNF-α, MCP-1, and MIP-1b levels were found significantly lower than in the control group. At 24 h, 48 h, and 72 h post-infection, significantly lower levels of IL-1Ra, IL-6, IL-8, IL-10, IL-12p40, TNF-α, MCP-1, and MIP-1b were detected in ESRD group. Concentration of VEGF at 24 h and 48 h, and of GM-CSF at 48 h and 72 h were also found to be lower in ESRD group than in control group. Compared with controls, the viral load Ct values were significantly lower in ESRD group at 6 h and 24 h post-infection No significant difference in viral load Ct values between two groups was found at 48 h and 72 h post-infection. Our study discloses that the expression of immune mediators of dengue-infected mononuclear cells is impaired in ESRD patients. |
PURPOSE: To compare early changes in autonomic nervous system (ANS) tone between newborns with complex congenital heart disease (CHD) and newborns without CHD. METHODS: We performed a case–control study of heart rate variability (HRV) in newborns with complex CHD [transposition of the great arteries (TGA) or hypoplastic left heart syndrome (HLHS)] and low-risk control newborns without CHD. Cases with CHD were admitted following birth to a pediatric cardiac intensive care unit and had archived continuous ECG data. Control infants were prospectively enrolled at birth. ECG data in cases and controls were analyzed for HRV in the time and frequency domains at 24 h of age. We analyzed the following HRV metrics: alpha short (α(s)), alpha long (α(L)), root mean square short and long (RMS(s) and RMS(L)), low-frequency (LF) power, normalized LF (nLF), high-frequency (HF) power, and normalized HF (nHF). We used ANOVA to compare HRV metrics between groups and to control for medication exposures. RESULTS: HRV data from 57 infants with CHD (TGA, n = 33 and HLHS, n = 24) and from 29 controls were analyzed. The HRV metrics α(S), RMS(L), LF, and nLF were significantly lower in infants with CHD than in the controls. Due to the effect of normalization, nHF was higher in CHD infants (P < 0.0001), although absolute HF was lower (P = 0.0461). After adjusting for medications, α(S) and nLF remained lower and nHF higher in newborns with CHD (P < 0.0005). CONCLUSIONS: Infants with complex CHD have depressed autonomic balance in the early postnatal period, which may complicate the fetal–neonatal transition. |
Aminopeptidase M (AMP) inhibition is of interest for several diseases, such as highly vascularized cancer types. AMP can be inhibited by linear pentapeptides isolated from Microcystis aeruginosa LTPNA08 (MG7XX). Porcine AMP inhibition—a model for human AMP—activity was spectrophotometrically measured by the formation of p-nitroanilide from L-leucine-p-nitroanilide substrate by AMP. AMP inhibition by MG770 exhibited comparable inhibition levels to amastatin (IC(50) values: 1.20 ± 0.1 μM and 0.98 ± 0.1 μM, respectively), while MG756 was slightly less potent (with IC(50) values of 3.26 ± 0.5 μM). Molecular modelling suggests a potential binding mode, based on the interaction with the Zn(2+) cofactor, where MG770′s extra methyl group contributes to the disturbance of the Zn(2+) cofactor complex and highlights the importance of hydrophobicity for the site. |
We present entry and exit screening outcomes on all persons passing through Freetown International Airport (FNA) in Sierra Leone during the period 1(st) September 2014 to 4(th) February 2016. A total of 166,242 persons underwent screening for Ebola Virus Disease (EVD) at FNA. Five persons were denied air travel from Sierra Leone after secondary screening. Laboratory testing revealed none were positive for EVD. No cases were identified through entry screening route. The public health value of airport screening for EVD is discussed. |
BACKGROUND: RNA pseudoknot structures play an important role in biological processes. However, existing RNA secondary structure prediction algorithms cannot predict the pseudoknot structure efficiently. Although random matching can improve the number of base pairs, these non-consecutive base pairs cannot make contributions to reduce the free energy. RESULT: In order to improve the efficiency of searching procedure, our algorithm take consecutive base pairs as the basic components. Firstly, our algorithm calculates and archive all the consecutive base pairs in triplet data structure, if the number of consecutive base pairs is greater than given minimum stem length. Secondly, the annealing schedule is adapted to select the optimal solution that has minimum free energy. Finally, the proposed algorithm is evaluated with the real instances in PseudoBase. CONCLUSION: The experimental results have been demonstrated to provide a competitive and oftentimes better performance when compared against some chosen state-of-the-art RNA structure prediction algorithms. |
BACKGROUND: Telocytes (TCs) are newly identified interstitial cells that participate in tissue protection and repair. The present study investigated the mechanisms underlying the protective effect of TCs in a mouse model of respiratory distress. METHODS: The mouse model of acute respiratory distress syndrome (ARDS) was established by intratracheal instillation of lipopolysaccharide (LPS). After instillation of TCs culture medium, lung injury was assessed, and angiogenesis markers, including CD31 and endothelial nitric oxide synthase (eNOS), were detected by immunofluorescence. Bioinformatics analysis was used to screen significantly differentially expressed microRNAs (miRNAs) in cultured TCs stimulated with LPS, and the regulation of downstream angiogenesis genes by these miRNAs was analysed and verified. PI3K subunits and pathways were evaluated by using a PI3K p110α inhibitor to study the involved mechanisms. RESULTS: In ARDS mice, instillation of TCs culture medium ameliorated LPS-induced inflammation and lung injury and increased the protein levels of CD31 and eNOS in the injured lungs. A total of 7 miRNAs and 1899 mRNAs were differentially regulated in TCs stimulated with LPS. Functional prediction analysis showed that the differentially expressed mRNAs were enriched in angiogenesis-related processes, which were highly correlated with miR-21a-3p. Culture medium from TCs with miR-21a-3p inhibition failed to promote angiogenesis in mouse models of LPS-induced ARDS. In cultured TCs, LPS stimulation upregulated the expression of miR-21a-3p, which further targeted the transcription factor E2F8 and decreased Notch2 protein expression. TCs culture medium enhanced hemangioendothelioma endothelial cells (EOMA cells) proliferation, which was blocked by the miR-21a-3p inhibitor. The PI3K p110α inhibitor decreased vascular endothelial growth factor levels in LPS-stimulated TCs and reversed the enhancing effect of TCs culture medium on EOMA cells proliferation. CONCLUSIONS: TCs exerted protective effects under inflammatory conditions by promoting angiogenesis via miR-21a-3p. The PI3K p110α subunit and transcriptional factor E2F8 could be involved in this process. |
We monitored the survival of human pathogenic bacteria [Escherichia coli (ATCC), extended-spectrum β-lactamase-producing E. coli (Clinical isolate), New Delhi metallo-β-lactamase-producing E. coli (clinical isolate), Staphylococcus aureus (ATCC)] on dry materials (vinyl chloride, aluminum, plastic, stainless steel) at distinct temperatures (room temperature or 15°C–37°C). These bacteria favored a lower temperature for their prolonged survival on the dry fomites, regardless of the material type. Interestingly, when mixed with S. aureus, E. coli survived for a longer time at a lower temperature. Cardiolipin, which can promote the survival of S. aureus in harsh environments, had no effect on maintaining the survival of E. coli. Although the trends remained unchanged, adjusting the humidity from 40% to 60% affected the survival of bacteria on dry surfaces. Scanning electron microscopic analysis revealed no morphological differences in these bacteria immediately before or after one day of dry conditions. In addition, ATP assessment, a method used to visualize high-touch surfaces in hospitals, was not effective at monitoring bacterial dynamics. A specialized handrail device fitted with a heater, which was maintained at normal human body core temperature, successfully prohibited the prolonged survival of bacteria [Enterococcus faecalis (ATCC), E. coli (ATCC), Pseudomonas aeruginosa (ATCC), S. aureus (ATCC), Acinetobacter baumannii (clinical isolate), and Serratia marcescens (clinical isolate)], with the exception of spore-forming Bacillus subtilis (from our laboratory collection) and the yeast-like fungus Candida albicans (from our laboratory collection)] on dry surfaces. Taken together, we concluded that the tested bacteria favor lower temperatures for their survival in dry environments. Therefore, the thermal control of dry fomites has the potential to control bacterial survival on high-touch surfaces in hospitals. |
During the Ebola virus disease (EVD) epidemic in Western Africa (2013‒2016), antimalarial treatment was administered to EVD patients due to the high coexisting malaria burden in accordance with World Health Organization guidelines. In an Ebola treatment center in Liberia, EVD patients receiving the combination antimalarial artesunate-amodiaquine had a lower risk of death compared to those treated with artemether-lumefantrine. As artemether and artesunate are derivatives of artemisinin, the beneficial anti-Ebola virus (EBOV) effect observed could possibly be attributed to the change from lumefantrine to amodiaquine. Amodiaquine is a widely used antimalarial in the countries that experience outbreaks of EVD and, therefore, holds promise as an approved drug that could be repurposed for treating EBOV infections. We investigated the potential anti-EBOV effect of amodiaquine in a well-characterized nonhuman primate model of EVD. Using a similar 3-day antimalarial dosing strategy as for human patients, plasma concentrations of amodiaquine in healthy animals were similar to those found in humans. However, the treatment regimen did not result in a survival benefit or decrease of disease signs in EBOV-infected animals. While amodiaquine on its own failed to demonstrate efficacy, we cannot exclude potential therapeutic value of amodiaquine when used in combination with artesunate or another antiviral. |
Zika virus (ZIKV) infection is currently one of the major concerns in human public health due to its association with neurological disorders. Intensive effort has been implemented for the treatment of ZIKV, however there are not currently approved vaccines or antivirals available to combat ZIKV infection. In this sense, the identification of virulence factors associated with changes in ZIKV virulence could help to develop safe and effective countermeasures to treat ZIKV or to prevent future outbreaks. Here, we have compared the virulence of two related ZIKV strains from the recent outbreak in Brazil (2015), Rio Grande do Norte Natal (RGN) and Paraiba. In spite of both viruses being identified in the same period of time and region, significant differences in virulence and replication were observed using a validated mouse model of ZIKV infection. While ZIKV-RGN has a 50% mouse lethal dose (MLD(50)) of ~10(5) focus forming units (FFUs), ZIKV-Paraiba infection resulted in 100% of lethality with less than 10 FFUs. Combining deep-sequencing analysis and our previously described infectious ZIKV-RGN cDNA clone, we identified a natural polymorphism in the non-structural protein 2 A (NS2A) that increase the virulence of ZIKV. Moreover, results demonstrate that the single amino acid alanine to valine substitution at position 117 (A117V) in the NS2A was sufficient to convert the attenuated rZIKV-RGN in a virulent Paraiba-like virus (MLD(50) < 10 FFU). The mechanism of action was also evaluated and data indicate that substitution A117V in ZIKV NS2A protein reduces host innate immune responses and viral-induced apoptosis in vitro. Therefore, amino acid substitution A117V in ZIKV NS2A could be used as a genetic risk-assessment marker for future ZIKV outbreaks. |
BACKGROUND: Telocytes (TCs) have the capacity of cell–cell communication with adjacent cells within the tissue, contributing to tissue repair and recovery from injury. The present study aims at investigating the molecular mechanisms by which the TGFβ1-ITGB1-PI3K signal pathways regulate TC cycle and proliferation. METHODS: Gene expression of integrin (ITG) family were measured in mouse primary TCs to compare with other cells. TC proliferation, movement, cell cycle, and PI3K isoform protein genes were assayed in ITGB1-negative or positive mouse lung TCs treated with the inhibition of PI3Kp110α, PI3Kα/δ, PKCβ, or GSK3, followed by TGFβ1 treatment. RESULTS: We found the characters and interactions of ITG or PKC family member networks in primary mouse lung TCs, different from other cells in the lung tissue. The deletion of ITGB1 changed TCs sensitivity to treatment with multifunctional cytokines or signal pathway inhibitors. The compensatory mechanisms occur among TGFβ1-induced PI3Kp110α, PI3Kα/δ, PKCβ, or GSK3 when ITGB1 gene was deleted, leading to alterations of TC cell cycle and proliferation. Of those PI3K isoform protein genes, mRNA expression of PIK3CG altered with ITGB1-negative TC cycle and proliferation. CONCLUSION: TCs have strong capacity of proliferation through the compensatory signaling mechanisms and contribute to the development of drug resistance due to alterations of TC sensitivity. |
Pre-emptive vaccination is regarded as one of the most protective measures to control influenza outbreak. There are mainly two types of influenza viruses—influenza A and B with several subtypes—that are commonly found to circulate among humans. The traditional trivalent (TIV) flu vaccine targets two strains of influenza A and one strain of influenza B. The quadrivalent (QIV) vaccine targets one extra B virus strain that ensures better protection against influenza; however, the use of QIV vaccine can be costly, hence impose an extra financial burden to society. This scenario might create a dilemma in choosing vaccine types at the individual level. This article endeavours to explain such a dilemma through the framework of a vaccination game, where individuals can opt for one of the three options: choose either of QIV or TIV vaccine or none. Our approach presumes a mean-field framework of a vaccination game in an infinite and well-mixed population, entangling the disease spreading process of influenza with the coevolution of two types of vaccination decision-making processes taking place before an epidemic season. We conduct a series of numerical simulations as an attempt to illustrate different scenarios. The framework has been validated by the so-called multi-agent simulation (MAS) approach. |
The dynamics of a spreadable disease are largely governed by four factors: proactive vaccination, retroactive treatment, individual decisions, and the prescribing behaviour of physicians. Under the imposed vaccination policy and antiviral treatment in society, complex factors (costs and expected effects of the vaccines and treatments, and fear of being infected) trigger an emulous situation in which individuals avoid infection by the pre-emptive or ex post provision. Aside from the established voluntary vaccination game, we propose a treatment game model associated with the resistance evolution of antiviral/antibiotic overuse. Moreover, the imperfectness of vaccinations has inevitably led to anti-vaccine behaviour, necessitating a proactive treatment policy. However, under the excessively heavy implementation of treatments such as antiviral medicine, resistant strains emerge. The model explicitly exhibits a dual social dilemma situation, in which the treatment behaviour changes on a local time scale, and the vaccination uptake later evolves on a global time scale. The impact of resistance evolution and the coexistence of dual dilemmas are investigated by the control reproduction number and the social efficiency deficit, respectively. Our investigation might elucidate the substantial impacts of both vaccination and treatment in the framework of epidemic dynamics, and hence suggest the appropriate use of antiviral treatment. |
BACKGROUND: Dexmedetomidine has been reported to improve organ dysfunction in critically ill patients. In a recent randomized controlled trial (Dexmedetomidine for Sepsis in Intensive Care Unit (ICU) Randomized Evolution [DESIRE]), we demonstrated that dexmedetomidine was associated with reduced mortality risk among patients with severe sepsis. We performed this exploratory sub-analysis to examine the mechanism underlying improved survival in patients sedated with dexmedetomidine. METHODS: The DESIRE trial compared a sedation strategy with and without dexmedetomidine among 201 mechanically ventilated adult patients with sepsis across eight ICUs in Japan. In the present study, we included 104 patients with Acute Physiology and Chronic Health Evaluation II (APACHE II) scores of ≥ 23 (54 in the dexmedetomidine [DEX] group and 50 in the non-dexmedetomidine [non-DEX] group). Initially, we compared the changes in the sequential organ failure assessment (SOFA) scores from the baseline within 6 days after randomization between groups. Subsequently, we evaluated the variables comprising the organ component of the SOFA score that showed relevant improvement in the initial comparison. RESULTS: The mean patient age was 71.0 ± 14.1 years. There was no difference in the median APACHE II score between the two groups (29 [interquartile range (IQR), 25–31] vs. 30 [IQR, 25–33]; p = 0.35). The median SOFA score at the baseline was lower in the DEX group (9 [IQR, 7–11] vs. 11 [IQR, 9–13]; p = 0.01). While the renal SOFA subscore at the baseline was similar for both groups, it significantly decreased in the DEX group on day 4 (p = 0.02). During the first 6 days, the urinary output was not significantly different (p = 0.09), but serum creatinine levels were significantly lower (p = 0.04) in the DEX group. The 28-day and in-hospital mortality rates were significantly lower in the DEX group (22% vs. 42%; p = 0.03, 28% vs. 52%; p = 0.01, respectively). CONCLUSION: A sedation strategy with dexmedetomidine is associated with improved renal function and decrease mortality rates among patients with severe sepsis. TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov (NCT01760967) on January 1, 2013. |
BACKGROUND: Global end-diastolic volume (GEDV) measured by transpulmonary thermodilution is regarded as indicator of cardiac preload. A bolus of cold saline injected in a central vein travels through the heart and lung, but also the aorta until detection in a femoral artery. While it is well accepted that injection in the inferior vena cava results in higher values, the impact of the aortic volume on GEDV is unknown. In this study, we hypothesized that a larger aortic volume directly translates to a numerically higher GEDV measurement. METHODS: We retrospectively analyzed data from 88 critically ill patients with thermodilution monitoring and who did require a contrast-enhanced thoraco-abdominal computed tomography scan. Aortic volumes derived from imaging were compared with GEDV measurements in temporal proximity. RESULTS: Median aortic volume was 194 ml (interquartile range 147 to 249 ml). Per milliliter increase of the aortic volume, we found a GEDV increase by 3.0 ml (95% CI 2.0 to 4.1 ml, p < 0.001). In case a femoral central venous line was used for saline bolus injection, GEDV raised additionally by 2.1 ml (95% CI 0.5 to 3.7 ml, p = 0.01) per ml volume of the vena cava inferior. Aortic volume explained 59.3% of the variance of thermodilution-derived GEDV. When aortic volume was included in multivariate regression, GEDV variance was unaffected by sex, age, body height, and weight. CONCLUSIONS: Our results suggest that the aortic volume is a substantial confounding variable for GEDV measurements performed with transpulmonary thermodilution. As the aorta is anatomically located after the heart, GEDV should not be considered to reflect cardiac preload. Guiding volume management by raw or indexed reference ranges of GEDV may be misleading. |
BACKGROUND: Human metapneumovirus (HMPV) is an important cause of acute respiratory illness in young children. Whole genome sequencing enables better identification of transmission events and outbreaks, which is not always possible with sub-genomic sequences. RESULTS: We report a 2-reaction amplicon-based next generation sequencing method to determine the complete genome sequences of five HMPV strains, representing three subgroups (A2, B1 and B2), directly from clinical samples. In addition to reporting five novel HMPV genomes from Africa we examined genetic diversity and sequence patterns of publicly available HMPV genomes. We found that the overall nucleotide sequence identity was 71.3 and 80% for HMPV group A and B, respectively, the diversity between HMPV groups was greater at amino acid level for SH and G surface protein genes, and multiple subgroups co-circulated in various countries. Comparison of sequences between HMPV groups revealed variability in G protein length (219 to 241 amino acids) due to changes in the stop codon position. Genome-wide phylogenetic analysis showed congruence with the individual gene sequence sets except for F and M2 genes. CONCLUSION: This is the first genomic characterization of HMPV genomes from African patients. |
BACKGROUND: Antimicrobial resistance (AMR) compromises the treatment of patients with serious infections in intensive care units (ICUs), and intensive care physicians are increasingly facing patients with bacterial infections with limited or no adequate therapeutic options. A survey was conducted to assess the intensive care physicians’ perception of the AMR situation in the European Union/European Economic Area (EU/EEA). METHODS: Between May and July 2017, physicians working in European ICUs were invited to complete an online questionnaire hosted by the European Society of Intensive Care Medicine. The survey included 20 questions on hospital and ICU characteristics, frequency of infections with multidrug-resistant (MDR) bacteria and relevance of AMR in the respondent’s ICU, management of antimicrobial treatment as well as the use of last-line antibiotics in the six months preceding the survey. For the analysis of regional differences, EU/EEA countries were grouped into the four sub-regions of Eastern, Northern, Southern and Western Europe. RESULTS: Overall, 1062 responses from four European sub-regions were analysed. Infections with MDR bacteria in their ICU were rated as a major problem by 257 (24.2%), moderate problem by 360 (33.9%) and minor problem by 391 (36.8%) respondents. Third-generation cephalosporin-resistant Enterobacteriaceae were the most frequently encountered MDR bacteria followed by, in order of decreasing frequency, meticillin-resistant Staphylococcus aureus, carbapenem-resistant Enterobacteriaceae, carbapenem-resistant Pseudomonas aeruginosa and vancomycin-resistant enterococci. Perception of the relevance of the AMR problem and the frequency of specific MDR bacteria varied by European sub-region. Bacteria resistant to all or almost all available antibiotics were encountered by 132 (12.4%) respondents. Many physicians reported not having access to specific last-line antibiotics. CONCLUSIONS: The percentage of European ICU physicians perceiving AMR as a substantial problem in their ICU is high with variation by sub-region in line with epidemiological studies. The reports of bacteria resistant to almost all available antibiotics and the limited availability of last-line antibiotics in ICUs in the EU/EEA are of concern. |
Glycoconjugate vaccines based on bacterial capsular polysaccharides (CPS) have been extremely successful in preventing bacterial infections. The glycan antigens for the preparation of CPS based glycoconjugate vaccines are mainly obtained from bacterial fermentation, the quality and length of glycans are always inconsistent. Such kind of situation make the CMC of glycoconjugate vaccines are difficult to well control. Thanks to the advantage of synthetic methods for carbohydrates syntheses. The well controlled glycan antigens are more easily to obtain, and them are conjugated to carrier protein to from the so-call homogeneous fully synthetic glycoconjugate vaccines. Several fully glycoconjugate vaccines are in different phases of clinical trial for bacteria or cancers. The review will introduce the recent development of fully synthetic glycoconjugate vaccine. |
BACKGROUND: Acute kidney injury (AKI) is a common complication in burn patients admitted to the intensive care unit (ICU) associated with increased morbidity and mortality. Our primary aim was to review incidence, risk factors, and outcomes of AKI in burn patients admitted to the ICU. Secondary aims were to review the use of renal replacement therapy (RRT) and impact on health care costs. METHODS: We conducted a systematic search in PubMed, UpToDate, and NICE through 3 December 2018. All reviews in Cochrane Database of Systematic Reviews except protocols were added to the PubMed search. We searched for studies on AKI according to Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease (RIFLE); Acute Kidney Injury Network (AKIN); and/or Kidney Disease: Improving Global Outcomes (KDIGO) criteria in burn patients admitted to the ICU. We collected data on AKI incidence, risk factors, use of RRT, renal recovery, length of stay (LOS), mortality, and health care costs. RESULTS: We included 33 observational studies comprising 8200 patients. Overall study quality, scored according to the Newcastle-Ottawa scale, was moderate. Random effect model meta-analysis revealed that the incidence of AKI among burn patients in the ICU was 38 (30–46) %. Patients with AKI were almost evenly distributed in the mild, moderate, and severe AKI subgroups. RRT was used in 12 (8–16) % of all patients. Risk factors for AKI were high age, chronic hypertension, diabetes mellitus, high Total Body Surface Area percent burnt, high Abbreviated Burn Severity Index score, inhalation injury, rhabdomyolysis, surgery, high Acute Physiology and Chronic Health Evaluation II score, high Sequential Organ Failure Assessment score, sepsis, and mechanical ventilation. AKI patients had 8.6 (4.0–13.2) days longer ICU LOS and higher mortality than non-AKI patients, OR 11.3 (7.3–17.4). Few studies reported renal recovery, and no study reported health care costs. CONCLUSIONS: AKI occurred in 38% of burn patients admitted to the ICU, and 12% of all patients received RRT. Presence of AKI was associated with increased LOS and mortality. TRIAL REGISTRATION: PROSPERO (CRD42017060420) |
Mycobacterium tuberculosis (M.tb) is responsible for more deaths globally than any other pathogen. The only available vaccine, bacillus Calmette-Guérin (BCG), has variable efficacy throughout the world. A more effective vaccine is urgently needed. The immune response against tuberculosis relies, at least in part, on CD4(+) T cells. Protective vaccines require the induction of antigen-specific CD4(+) T cells via mycobacterial peptides presented by MHC class-II in infected macrophages. In order to identify mycobacterial antigens bound to MHC, we have immunoprecipitated MHC class-I and class-II complexes from THP-1 macrophages infected with BCG, purified MHC class-I and MHC class-II peptides and analysed them by liquid chromatography tandem mass spectrometry. We have successfully identified 94 mycobacterial peptides presented by MHC-II and 43 presented by MHC-I, from 76 and 41 antigens, respectively. These antigens were found to be highly expressed in infected macrophages. Gene ontology analysis suggests most of these antigens are associated with membranes and involved in lipid biosynthesis and transport. The sequences of selected peptides were confirmed by spectral match validation and immunogenicity evaluated by IFN-gamma ELISpot against peripheral blood mononuclear cell from volunteers vaccinated with BCG, M.tb latently infected subjects or patients with tuberculosis disease. Three antigens were expressed in viral vectors, and evaluated as vaccine candidates alone or in combination in a murine aerosol M.tb challenge model. When delivered in combination, the three candidate vaccines conferred significant protection in the lungs and spleen compared with BCG alone, demonstrating proof-of-concept for this unbiased approach to identifying new candidate antigens. |
A wide range of cancer immunotherapy approaches has been developed including non-specific immune-stimulants such as cytokines, cancer vaccines, immune checkpoint inhibitors (ICIs), and adoptive T cell therapy. Among them, ICIs are the most commonly used and intensively studied. Since 2011, these drugs have received marketing authorisation for melanoma, lung, bladder, renal, and head and neck cancers, with remarkable and long-lasting treatment response in some patients. The novel mechanism of action of ICIs, with immune and T cell activation, leads to unusual patterns of response on imaging, with the advent of so-called pseudoprogression being more pronounced and frequently observed when compared to other anticancer therapies. Pseudoprogression, described in about 2–10% of patients treated with ICIs, corresponds to an increase of tumour burden and/or the appearance of new lesions due to infiltration by activated T cells before the disease responds to therapy. To overcome the limitation of response evaluation criteria in solid tumors (RECIST) to assess these specific changes, new imaging criteria—so-called immune-related response criteria and then immune-related RECIST (irRECIST)—were proposed. The major modification involved the inclusion of the measurements of new target lesions into disease assessments and the need for a 4-week re-assessment to confirm or not confirm progression. The RECIST working group introduced the new concept of “unconfirmed progression”, into the irRECIST. This paper reviews current immunotherapeutic approaches and summarises radiologic criteria to evaluate new patterns of response to immunotherapy. Furthermore, imaging features of immunotherapy-related adverse events and available predictive biomarkers of response are presented. |
BACKGROUND: An efficient surface cleaning strategy would first target cleaning to surfaces that make large contributions to the risk of infections. METHODS: In this study, we used data from the literature about methicillin-resistant Staphylococcus aureus (MRSA) and developed an ordinary differential equations based mathematical model to quantify the impact of contact heterogeneity on MRSA transmission in a hypothetical 6-bed intensive care unit (ICU). The susceptible patients are divided into two types, these who are cared by the same nurse as the MRSA infected patient (Type 1) and these who are not (Type 2). RESULTS: The results showed that the mean MRSA concentration on three kinds of susceptible patient nearby surfaces was significantly linearly associated with the hand-touch frequency (p < 0.05). The noncompliance of daily cleaning on patient nearby high-touch surfaces (HTSs) had the most impact on MRSA transmission. If the HTSs were not cleaned, the MRSA exposure to Type 1 and 2 susceptible patients would increase 118.4% (standard deviation (SD): 33.0%) and 115.4% (SD: 30.5%) respectively. The communal surfaces (CSs) had the least impact, if CSs were not cleaned, the MRSA exposure to Type 1 susceptible patient would only increase 1.7% (SD: 1.3). The impact of clinical equipment (CE) differed largely for two types of susceptible patients. If the CE was not cleaned, the exposure to Type 1 patients would only increase 8.4% (SD: 3.0%), while for Type 2 patients, it can increase 70.4% (SD: 25.4%). CONCLUSIONS: This study provided a framework to study the pathogen concentration dynamics on environmental surfaces and quantitatively showed the importance of cleaning patient nearby HTSs on controlling the nosocomial infection transmission via contact route. |
BACKGROUND: General self-efficacy is considered one of the most influential parameters affecting the quality of clinical practice and nurses’ perceived professional benefits (NPPB). Perceived organizational support (POS) is regarded as being central in understanding job-related attitudes, and it is important to enhance POS for nurses to maintain their current employment. NPPB can further reduce nurses’ job burnout and turn-over intention. Many studies have explored the relationships among general self-efficacy, POS, nursing practice environment (NPE) and NPPB. However, a moderating effect of NPE has not been fully explored in nurses, especially among paediatric nurses. METHODS: A descriptive cross-sectional study was conducted from July to October 2018 with 300 paediatric nurses from 3 Class A tertiary hospitals in Jilin Province. The respondents completed the General Self-Efficacy Scale, Perceived Organizational Support Scale, Practice Environment Scale and Nurses’ Perceived Professional Benefits Scale. The data were analyzed using path analysis and SPSS (version 23.0, IBM). RESULTS: General self-efficacy and POS were significantly positively associated with NPPB, which showed that the model had a good fit to the data. NPE was found to play a partial mediating role between POS and NPPB and also had a complete mediating role between general self-efficacy and NPPB. CONCLUSIONS: The results suggest that general self-efficacy indirectly influences NPPB, and POS directly and indirectly influences NPPB by NPE. Effective measures should be taken to improve nurses’ practice environment in hospitals to raise nurses’ enthusiasm and confidence in their work. |
BACKGROUND: We aimed to compare the clinical characteristics of patients with community-acquired pneumonia (CAP), healthcare-associated pneumonia (HCAP), and hospital-acquired pneumonia (HAP) caused by Klebsiella pneumoniae and analyze the antimicrobial resistance and proportion of hypervirluent strains of the microbial isolates. METHODS: We conducted a retrospective study on patients with pneumonia caused by K. pneumoniae at the Taipei Veterans General Hospital in Taiwan between January 2014 and December 2016. To analyze the clinical characteristics of these patients, data was extracted from their medical records. K. pneumoniae strains were subjected to antimicrobial susceptibility testing, capsular genotyping and detection of the rmpA and rmpA2 genes to identify hypervirulent strains. RESULTS: We identified 276 patients with pneumonia caused by K. pneumoniae, of which 68 (24.6%), 74 (26.8%), and 134 (48.6%) presented with CAP, HCAP, and HAP, respectively. The 28-day mortality was highest in the HAP group (39.6%), followed by the HCAP (29.7%) and CAP (27.9%) groups. The HAP group also featured the highest proportion of multi-drug resistant strains (49.3%), followed by the HCAP (36.5%) and CAP groups (10.3%), while the CAP group had the highest proportion of hypervirulent strains (79.4%), followed by the HCAP (55.4%) and HAP groups (41.0%). CONCLUSION: Pneumonia caused by K. pneumoniae was associated with a high mortality. Importantly, multi-drug resistant strains were also detected in patients with CAP. Hypervirulent strains were prevalent in all 3 groups of pneumonia patients, even in those with HAP. |
OBJECTIVE: To describe the epidemiology of carbapenem-resistant Enterobacteriaceae (CRE) healthcare-associated infections (HAI) in Egyptian hospitals reporting to the national HAI surveillance system. METHODS: Design: Descriptive analysis of CRE HAIs and retrospective observational cohort study using national HAI surveillance data. Setting: Egyptian hospitals participating in the HAI surveillance system. The patient population included patients admitted to the intensive care unit (ICU) in participating hospitals. Enterobacteriaceae HAI cases were Klebsiella, Escherichia coli, and Enterobacter isolates from blood, urine, wound or respiratory specimen collected on or after day 3 of ICU admission. CRE HAI cases were those resistant to at least one carbapenem. For CRE HAI cases reported during 2011–2017, a hospital-level and patient-level analysis were conducted using only the first CRE isolate by pathogen and specimen type for each patient. For facility, microbiology, and clinical characteristics, frequencies and means were calculated among CRE HAI cases and compared with carbapenem-susceptible Enterobacteriaceae HAI cases through univariate and multivariate logistic regression using STATA 13. RESULTS: There were 1598 Enterobacteriaceae HAI cases, of which 871 (54.1%) were carbapenem resistant. The multivariate regression analysis demonstrated that carbapenem resistance was associated with specimen type, pathogen, location prior to admission, and length of ICU stay. Between 2011 and 2017, there was an increase in the proportion of Enterobacteriaceae HAI cases due to CRE (p-value = 0.003) and the incidence of CRE HAIs (p-value = 0.09). CONCLUSIONS: This analysis demonstrated a high and increasing burden of CRE in Egyptian hospitals, highlighting the importance of enhancing infection prevention and control (IPC) programs and antimicrobial stewardship activities and guiding the implementation of targeted IPC measures to contain CRE in Egyptian ICU’s . |
BACKGROUND: Although the prediction of renal prognosis in patients with IgA vasculitis with nephritis (IgAVN) is important, the association between gastrointestinal bleeding (GIB) and its renal prognosis is unknown. This study investigated the effect of GIB on the progression to end‐stage kidney disease (ESKD) in patients with IgAVN. METHODS: We compared the clinicopathological findings at diagnosis, therapy, and clinical outcomes between 10 patients with GIB and 20 patients without GIB in 30 patients with IgAVN aged ≥18 years at the renal biopsy. The primary outcome was the incidence of ESKD. Secondary outcomes included clinical remission and all‐cause mortality. The outcomes and factors affecting the progression to ESKD were evaluated using the Kaplan‐Meier method with log‐rank test and Cox proportional hazards models. RESULTS: End‐stage kidney disease, clinical remission, and deaths from any related cause occurred in 6, 17, and 2 patients, respectively. In Kaplan‐Meier analyses, the GIB group showed a higher incidence of ESKD (50% vs 5%, P = .003) and a lower incidence of clinical remission (20% vs 75%, P = .003). Although the numbers were not statistically significant, this group tended to have a greater number of deaths than the non‐GIB group (7% vs 0%, P = .07). In a multivariable Cox model adjusted for hypertension and urinary proteinuria, GIB could not demonstrate a significant association with ESKD (hazard ratio, 4.51; 95% confidence interval, 0.39‐52.7; P = .23). CONCLUSION: IgAVN with GIB has worse renal outcome, but GIB does not have a statistically significant association with progression to ESKD. |
Viruses have been infecting their host cells since the dawn of life, and this extremely long-term coevolution gave rise to some surprising consequences for the entire tree of life. It is hypothesised that viruses might have contributed to the formation of the first cellular life form, or that even the eukaryotic cell nucleus originates from an infection by a coated virus. The continuous struggle between viruses and their hosts to maintain at least a constant fitness level led to the development of an unceasing arms race, where weapons are often shuttled between the participants. In this literature review we try to give a short insight into some general consequences or traits of virus–host coevolution, and after this we zoom in to the viral clades of adenoviruses, herpesviruses, nucleo-cytoplasmic large DNA viruses, polyomaviruses and, finally, circoviruses. |
Mammalian asparagine endopeptidase (AEP) is a cysteine protease that cleaves its protein substrates on the C-terminal side of asparagine residues. Converging lines of evidence indicate that AEP may be involved in the pathogenesis of several neurological diseases, including Alzheimer’s disease, Parkinson’s disease, and frontotemporal dementia. AEP is activated in the aging brain, cleaves amyloid precursor protein (APP) and promotes the production of amyloid-β (Aβ). We renamed AEP to δ-secretase to emphasize its role in APP fragmentation and Aβ production. AEP also cleaves other substrates, such as tau, α-synuclein, SET, and TAR DNA-binding protein 43, generating neurotoxic fragments and disturbing their physiological functions. The activity of δ-secretase is tightly regulated at both the transcriptional and posttranslational levels. Here, we review the recent advances in the role of δ-secretase in neurodegenerative diseases, with a focus on its biochemical properties and the transcriptional and posttranslational regulation of its activity, and discuss the clinical implications of δ-secretase as a diagnostic biomarker and therapeutic target for neurodegenerative diseases. |
BACKGROUND: Influenza A viruses cause epidemics/severe pandemics that pose a great global health threat. Among eight viral RNA segments, the multiple functions of nucleoprotein (NP) play important roles in viral replication and transcription. METHODS: To understand how NP contributes to the virus evolution, we analyzed the NP gene of H3N2 viruses in Taiwan and 14,220 NP sequences collected from Influenza Research Database. The identified genetic variations were further analyzed by mini-genome assay, virus growth assay, viral RNA and protein expression as well as ferret model to analyze their impacts on viral replication properties. RESULTS: The NP genetic analysis by Taiwan and global sequences showed similar evolution pattern that the NP backbones changed through time accompanied with specific residue substitutions from 1999 to 2018. Other than the conserved residues, fifteen sporadic substitutions were observed in which the 31R, 377G and 450S showed higher frequency. We found 31R and 450S decreased polymerase activity while the dominant residues (31 K and 450G) had higher activity. The 31 K and 450G showed better viral translation and replication in vitro and in vivo. CONCLUSIONS: These findings indicated variations identified in evolution have roles in modulating viral replication in vitro and in vivo. This study demonstrates that the interaction between variations of NP during virus evolution deserves future attention. |
BACKGROUND: Heart failure (HF) has been recognized as a global pandemic with a high rate of hospitalization, morbidity, and mortality. Although numerous advances have been made, its representative molecular signatures remain largely unknown, especially the role of genes in HF progression. The aim of the present prospective follow-up study was to reveal potential biomarkers associated with the progression of heart failure. METHODS: We generated multi-level transcriptomic data from a cohort of left ventricular heart tissue collected from 21 HF patients and 9 healthy donors. By using Masson staining to calculate the fibrosis percentage for each sample, we applied lasso regression model to identify the genes associated with fibrosis as well as progression. The genes were further validated by immunohistochemistry (IHC) staining in the same cohort and qRT-PCR using another independent cohort (20 HF and 9 healthy donors). Enzyme-linked immunosorbent assay (ELISA) was used to measure the plasma level in a validation cohort (139 HF patients) for predicting HF progression. RESULTS: Based on the multi-level transcriptomic data, we examined differentially expressed genes [mRNAs, microRNAs, and long non-coding RNAs (lncRNAs)] in the study cohort. The follow-up functional annotation and regulatory network analyses revealed their potential roles in regulating extracellular matrix. We further identified several genes that were associated with fibrosis. By using the survival time before transplantation, COL1A1 was identified as a potential biomarker for HF progression and its upregulation was confirmed by both IHC and qRT-PCR. Furthermore, COL1A1 content ≥ 256.5 ng/ml in plasma was found to be associated with poor survival within 1 year of heart transplantation from heart failure [hazard ratio (HR) 7.4, 95% confidence interval (CI) 3.5 to 15.8, Log-rank p value < 1.0 × 10(− 4)]. CONCLUSIONS: Our results suggested that COL1A1 might be a plasma biomarker of HF and associated with HF progression, especially to predict the 1-year survival from HF onset to transplantation. |
Modern societies are exposed to a myriad of risks ranging from disease to natural hazards and technological disruptions. Exploring how the awareness of risk spreads and how it triggers a diffusion of coping strategies is prominent in the research agenda of various domains. It requires a deep understanding of how individuals perceive risks and communicate about the effectiveness of protective measures, highlighting learning and social interaction as the core mechanisms driving such processes. Methodological approaches that range from purely physics-based diffusion models to data-driven environmental methods rely on agent-based modeling to accommodate context-dependent learning and social interactions in a diffusion process. Mixing agent-based modeling with data-driven machine learning has become popularity. However, little attention has been paid to the role of intelligent learning in risk appraisal and protective decisions, whether used in an individual or a collective process. The differences between collective learning and individual learning have not been sufficiently explored in diffusion modeling in general and in agent-based models of socio-environmental systems in particular. To address this research gap, we explored the implications of intelligent learning on the gradient from individual to collective learning, using an agent-based model enhanced by machine learning. Our simulation experiments showed that individual intelligent judgement about risks and the selection of coping strategies by groups with majority votes were outperformed by leader-based groups and even individuals deciding alone. Social interactions appeared essential for both individual learning and group learning. The choice of how to represent social learning in an agent-based model could be driven by existing cultural and social norms prevalent in a modeled society. |
Mortality in acute respiratory distress syndrome (ARDS) remains unacceptably high at approximately 39%. One of the only treatments is supportive: mechanical ventilation. However, improperly set mechanical ventilation can further increase the risk of death in patients with ARDS. Recent studies suggest that ventilation-induced lung injury (VILI) is caused by exaggerated regional lung strain, particularly in areas of alveolar instability subject to tidal recruitment/derecruitment and stress-multiplication. Thus, it is reasonable to expect that if a ventilation strategy can maintain stable lung inflation and homogeneity, regional dynamic strain would be reduced and VILI attenuated. A time-controlled adaptive ventilation (TCAV) method was developed to minimize dynamic alveolar strain by adjusting the delivered breath according to the mechanical characteristics of the lung. The goal of this review is to describe how the TCAV method impacts pathophysiology and protects lungs with, or at high risk of, acute lung injury. We present work from our group and others that identifies novel mechanisms of VILI in the alveolar microenvironment and demonstrates that the TCAV method can reduce VILI in translational animal ARDS models and mortality in surgical/trauma patients. Our TCAV method utilizes the airway pressure release ventilation (APRV) mode and is based on opening and collapsing time constants, which reflect the viscoelastic properties of the terminal airspaces. Time-controlled adaptive ventilation uses inspiratory and expiratory time to (1) gradually “nudge” alveoli and alveolar ducts open with an extended inspiratory duration and (2) prevent alveolar collapse using a brief (sub-second) expiratory duration that does not allow time for alveolar collapse. The new paradigm in TCAV is configuring each breath guided by the previous one, which achieves real-time titration of ventilator settings and minimizes instability induced tissue damage. This novel methodology changes the current approach to mechanical ventilation, from arbitrary to personalized and adaptive. The outcome of this approach is an open and stable lung with reduced regional strain and greater lung protection. |
BACKGROUND: There have been no systematic studies of microbiological differences before and after antibiotics treatment. The aim of this study was to evaluate the effect of prior receipt of antibiotics on the microorganism distribution. METHODS: A retrospective, observational cohort study was conducted in a 3200-bed tertiary, referral, teaching hospital in eastern China. During a 2-year period, all hospitalized patients treated with antimicrobial agents were enrolled in this study. Among 48,692 patients evaluated, the 27,792 (57.1%) who were sampled within 2 days before or after administration of the first dose of antimicrobial agents were included. Distribution of clinical specimens and the microorganism were compared between before and after antibiotic drug treatment groups. RESULTS: Compared to specimens taken after antibiotics exposure, specimens taken before antibiotics exposure had a higher proportion of blood and urine specimens and a higher culture positive rate (all P < 0.001). Higher percentages of Staphylococcus aureus (9.9% vs. 8.5%, P = 0.041), non-fermenting bacteria (27.7% vs. 19.9%, P < 0.001), and fungi (8.4% vs. 4.0%, P < 0.001) were isolated from the group after antibiotics exposure, while the percentages of Streptococcus spp. (4.8% vs. 2.7%, P < 0.001), Haemophilus influenzae (2.3% vs. 0.8%, P < 0.001), and Moraxella catarrhalis (0.7% vs. 0.1%, P < 0.001) were higher in the group before antibiotics exposure. Further analysis found significant differences of microbes derived from respiratory secretions, blood or urine samples. We found, after antibiotics exposure, the separation rate of non-fermenting bacteria was significantly increased (all P < 0.05), and the separation rate of Candida spp. was higher, with statistical significance in airway secretion and urine samples (both P < 0.05), but the separation rate of Staphylococcus aureus among the three groups was not affected by antibiotics. In addition, the isolation rate of Streptococcus spp. in blood and urine samples decreased significantly (both P < 0.05) after antibiotics exposure. Interestingly, no statistical difference was found for microbes isolated from body fluid specimens between the two groups. CONCLUSIONS: The outcome revealed that antibiotic-insensitive organisms such as non-fermentative bacteria and fungi were more frequently isolated after antibiotics exposure. However, this trend might be specimen dependent and was not obvious in body fluid specimens. |
BACKGROUND: In pediatric cardiac anesthesiology, there is increased focus on minimizing morbidity, ensuring optimal functional status, and using health care resources sparingly. One aspect of care that has potential to affect all of the above is postoperative mechanical ventilation. Historically, postoperative ventilation was considered a must for maintaining patient stability. Ironically, it is recognized that mechanical ventilation may increase risk of adverse outcomes in the postoperative period. Hence, many institutions have advocated for immediate extubation or early extubation after many congenital heart surgeries which was first reported decades ago. METHODS: 637 consecutive patient charts were reviewed for pediatric patients undergoing cardiac surgery with cardiopulmonary bypass. Patients were placed into three groups. Those that were extubated in the operating room (OR) at the conclusion of surgery (Immediate Extubation or IE), those that were extubated within six hours of admission to the ICU (Early Extubation or EE) and those that were extubated sometime after six hours (Delayed Extubation or DE). Multiple variables were then recorded to see which factors correlated with successful Immediate or Early Extubation. RESULTS: Overall, 338 patients (53.1%) had IE), 273 (42.8%) had DE while only 26 patients (4.1%) had EE. The median age was 1174 days for the IE patients, 39 days for the DE patients, whereas 194 days for EE patients (p < 0.001). Weight and length were also significantly different in at least one extubation group from the other two (p < 0.001). The median ICU LOS was 3 and 4 days for IE and EE patients respectively, whereas it was 9.5 days for DE patients (p < 0.001). DE group had a significant longer median anesthesia time and cardiopulmonary bypass time than the other two extubation groups (p > 63,826.88 < 0.001). Regional low flow perfusion, deep hypothermia, deep hypothermic circulatory arrest, redo sternotomy, use of other sedatives, furosemide, epinephrine, vasopressin, open chest, cardiopulmonary support, pulmonary edema, syndrome, as well as difficult intubation were significantly associated with delayed extubation (IE, EE or DE). CONCLUSIONS: Immediate and early extubation was significantly associated with several factors, including patient age and size, duration of CPB, use of certain anesthetic drugs, and the amount of blood loss and blood replacement. IE can be successfully accomplished in a majority of pediatric patients undergoing surgery for congenital heart disease, including in a minority of infants. |
BACKGROUND: Vaccines are the most reliable alternative to elicit sterile immunity against malaria but their development has been hindered by polymorphisms and strain-specificity in previously studied antigens. New vaccine candidates are therefore urgently needed. Highly conserved Plasmodium falciparum reticulocyte-binding protein homologue-5 (PfRH5) has been identified as a potential candidate for anti-disease vaccine development. PfRH5 is essential for erythrocyte invasion by merozoites and crucial for parasite survival. However, there is paucity of data on the extent of genetic variations on PfRH5 in field isolates of Plasmodium falciparum. This study described genetic polymorphisms at the high affinity binding polypeptides (HABPs) 36718, 36727, 36728 of PfRH5 in Nigerian isolates of P. falciparum. This study tested the hypothesis that only specific conserved B and T cell epitopes on PfRH5 HABPs are crucial for vaccine development. METHODS: One hundred and ninety-five microscopically confirmed P. falciparum samples collected in a prospective cross-sectional study of three different populations in Lagos, Nigeria. Genetic diversity and haplotype construct of Pfrh5 gene were determined using bi-directional sequencing approach. Tajima’s D and the ratio of nonsynonymous vs synonymous mutations were utilized to estimate the extent of balancing and directional selection in the pfrh5 gene. RESULTS: Sequence analysis revealed three haplotypes of PfRH5 with negative Tajima’s D and dN/dS value of − 1.717 and 0.011 ± 0.020, respectively. A single nucleotide polymorphism, SNP (G → A) at position 608 was observed, which resulted in a change of the amino acid cysteine at position 203 to tyrosine. Haplotype and nucleotide diversities were 0.318 ± 0.016 and 0.0046 ± 0.0001 while inter-population genetic differentiation ranged from 0.007 to 0.037. Five polypeptide variants were identified, the most frequent being KTKYH with a frequency of 51.3%. One B-cell epitope, 151 major histocompatibility complex (MHC) class II T-cell epitopes, four intrinsically unstructured regions (IURs) and six MHC class I T-cell epitopes were observed in the study. Phylogenetic analysis of the sequences showed clustering and evidence of evolutionary relationship with 3D7, PAS-2 and FCB-2 RH5 sequences. CONCLUSIONS: This study has revealed low level of genetic polymorphisms in PfRH5 antigen with B- and T-cell epitopes in intrinsically unstructured regions along the PfRH5 gene in Lagos, Nigeria. A broader investigation is however required in other parts of the country to support the possible inclusion of PfRH5 in a cross-protective multi-component vaccine. |
The brainstem conveys sensory and motor inputs between the spinal cord and the brain, and contains nuclei of the cranial nerves. It controls the sleep-wake cycle and vital functions via the ascending reticular activating system and the autonomic nuclei, respectively. Brainstem dysfunction may lead to sensory and motor deficits, cranial nerve palsies, impairment of consciousness, dysautonomia, and respiratory failure. The brainstem is prone to various primary and secondary insults, resulting in acute or chronic dysfunction. Of particular importance for characterizing brainstem dysfunction and identifying the underlying etiology are a detailed clinical examination, MRI, neurophysiologic tests such as brainstem auditory evoked potentials, and an analysis of the cerebrospinal fluid. Detection of brainstem dysfunction is challenging but of utmost importance in comatose and deeply sedated patients both to guide therapy and to support outcome prediction. In the present review, we summarize the neuroanatomy, clinical syndromes, and diagnostic techniques of critical illness-associated brainstem dysfunction for the critical care setting. |
BACKGROUND: Growth hormone inducible transmembrane protein (GHITM) is a highly conserved transmembrane protein. This study was conducted to investigate the role of GHITM gene in the apoptosis and growth of the golden apple snail Pomacea canaliculate. RESULTS: The complete cDNA of this gene was cloned using the rapid amplification of cDNA ends (RACE) method and subjected to bioinformatics analysis. The full-length cDNA was 2242 bp, including an open reading frame of 1021 bp that encoded a protein of 342 amino acid residues. The mRNA expression profiles of GHITM gene in different tissues (liver, kidney, gonad and foot) and different growth phases (6-months old and 2-years old) showed that it was expressed in various tissues and different growth phases. Silencing of the GHITM gene by RNAi (RNA interference) experiments revealed that the GHITM gene possibly plays a role in inhibiting apoptosis through detecting the Caspase (Cysteine-requiring Aspartate Protease)-3 activity. In addition, the aperture width and body whorl length of the snail was significantly affected by RNAi, suggesting that this gene plays a significant role in promoting the growth of the organism. CONCLUSIONS: These results demonstrated that the GHITM gene was involved in apoptosis and growth in golden apple snail. |
OBJECTIVE: To examine the extent to which acute care hospitals in the Netherlands have adopted recommended practices to prevent catheter-associated urinary tract infection (CAUTI), central line-associated bloodstream infection (CLABSI), ventilator-associated pneumonia (VAP), and Clostridioides difficile infection (CDI). METHODS: Between 18 July 2017 and 31 October 2017, we surveyed the infection prevention teams of all acute care hospitals in the Netherlands. The survey instrument was based on the ‘Translating Healthcare-Associated Infection Prevention Research into Practice’ (TRIP) questionnaire and adapted to the Dutch context. Descriptive statistics were used to examine the reported regular use of CAUTI, CLABSI, VAP, and CDI prevention practices as well as the hospital characteristics. RESULTS: Out of 72 eligible hospitals, 47 (65.3%) responded. Surveillance systems for monitoring CAUTI, CLABSI, VAP, and CDI were present in 17.8, 95.4, 26.2, and 77.3% of hospitals, respectively. Antimicrobial stewardship programs have been established in 91.5% of participating hospitals. For CAUTI, the majority of hospitals regularly used aseptic technique during catheter insertion (95%) and portable bladder ultrasound scanners (86.1%). Intermittent catheterization and catheter stop-orders were regularly used by 65.8 and 62.2% of hospitals. For CLABSI, all hospitals regularly used maximum sterile barrier precautions and chlorhexidine gluconate for insertion site antisepsis. Avoidance of the femoral site for central line insertions was regularly used by 65.9% of hospitals. Urinary catheters and central-lines impregnated with antibiotics or antiseptics were rarely used (≤ 5%). Selective decontamination strategies for preventing VAP were used in 84% of hospitals. With the exception of disposable thermometers (31.8%), all prevention practices to prevent CDI were regularly used by more than 80% of hospitals. CONCLUSIONS: Most Dutch hospitals report regular use of recommended practices for preventing CLABSI and CDI. Several specific practices to prevent CAUTI and VAP were less frequently used, however, providing an opportunity for improvement. |
In a recent study, we proposed a novel method to evaluate hypoxic ischemic encephalopathy (HIE) by assessing propofol-induced changes in the 19-channel electroencephalogram (EEG). The study suggested that patients with HIE are unable to generate EEG slow waves during propofol anesthesia 48 h after cardiac arrest (CA). Since a low number of electrodes would make the method clinically more practical, we now investigated whether our results received with a full EEG cap could be reproduced using only forehead electrodes. Experimental data from comatose post-CA patients (N = 10) were used. EEG was recorded approximately 48 h after CA using 19-channel EEG cap during a controlled propofol exposure. The slow wave activity was calculated separately for all electrodes and four forehead electrodes (Fp1, Fp2, F7, and F8) by determining the low-frequency (< 1 Hz) power of the EEG. HIE was defined by following the patients’ recovery for six months. In patients without HIE (N = 6), propofol substantially increased (244 ± 91%, mean ± SD) the slow wave activity in forehead electrodes, whereas the patients with HIE (N = 4) were unable to produce such activity. The results received with forehead electrodes were similar to those of the full EEG cap. With the experimental pilot study data, the forehead electrodes were as capable as the full EEG cap in capturing the effect of HIE on propofol-induced slow wave activity. The finding offers potential in developing a clinically practical method for the early detection of HIE. |
The study described poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) accumulation in Bacillus aryabhattai PHB10 for the first time and evaluated the polymer induced cytotoxicity in-vitro with PHBV/poly(ethylene glycol) (PEG) blends. The B. aryabhattai strain produced 2.8 g/L PHBV, equivalent to 71.15% of cell dry mass in a medium supplemented with propionic acid, after 48 h incubation. The optimum temperature and pH for the copolymer accumulation was 31 °C and 7, respectively. The gas chromatography–mass spectrometry and nuclear magnetic resonance analyses confirmed the polymer obtained as PHBV. The differential scanning calorimetry analysis revealed that the melting point of the material as 90 °C and its thermal stability up to 220 °C. The average molecular weight (Mn) and polydispersity index of the sample was estimated by gel permeation chromatography analysis and observed as 128.508 kDa and 2.82, respectively. The PHBV showed tensile strength of 10.3 MPa and elongation at break of 13.3%. The PHBV and their blends with PEG were tested for cytotoxicity on human keratinocytes (HaCaT cells) and the cells incubated with PHBV/PEG2kDa blends were 99% viable, whereas with the PHBV alone showed comparatively higher cytotoxicity. The significant improvement in the cell viability of PHBV/PEG2kDa blends indicates its potential as a candidate for skin graft applications. |
PCV3 capsid protein (Cap) is an important antigen for diagnosis and vaccine development. To achieve high-level expression of recombinant PCV3 Cap in Escherichia coli (E. coli), the gene of wild-type entire Cap (wt-eCap) was amplified from clinical samples, and three optimized entire Cap (opti-eCap) and one optimized Cap deleted nuclear location signal (NLS) (opti-dCap) gene fragments encoding the same amino acid sequence with wt-eCap were synthesized based on the codon bias of E. coli. Those gene fragments were inserted into the pET30a expression vector. One recombinant strain with the highest expressed soluble eCap from four entire Cap (one wt-eCap and three opti-eCap) and one recombinant strain expressed opti-dCap were selected for further purification. The purified eCap and dCap were identified by transmission electron microscopy (TEM), a large number of round hollow particles with a diameter of 10 nm virus-like particles (VLPs) were observed in eCap, whereas irregular aggregation of proteins observed in dCap. After formation the VLPs were applied as a coating antigen to establish an indirect ELISA (I-ELISA) for detection of PCV3-specific antibody in swine serum. 373 clinical swine serum samples from China collected in 2019 were tested utilizing the VLP-based I-ELISA method under optimized conditions. To the best of our knowledge, this is the first report of self-assembly into VLPs of PCV3 recombinant Cap. Our results demonstrated that the VLP-based I-ELISA will be a valuable tool for detecting the presence of PCV3 antibodies in serum samples and will facilitate screening of large numbers of swine serum for clinical purposes. |
BACKGROUND AND AIMS: Nonalcoholic steatohepatitis (NASH) is a common inflammatory liver condition that may lead to cirrhosis and hepatocellular carcinoma (HCC). Risk factors for NASH include a saturated fat diet, altered lipid metabolism, and genetic and epigenetic factors, including microRNAs. Serum levels of cholecystokinin (CCK) are elevated in mice and humans that consume a high-saturated fat diet. CCK receptors (CCK-Rs) have been reported on fibroblasts which when activated can induce fibrosis; however, their role in hepatic fibrosis remains unknown. We hypothesized that elevated levels of CCK acting on the CCK-Rs play a role in the development of NASH and in NASH-associated HCC. METHODS: We performed a NASH Prevention study and Reversal study in mice fed a saturated fat 75% choline-deficient–ethionine-supplemented (CDE) diet for 12 or 18 weeks. In each study, half of the mice received untreated drinking water, while the other half received water supplemented with the CCK-R antagonist proglumide. CCK-R expression was evaluated in mouse liver and murine HCC cells. RESULTS: CCK receptor antagonist treatment not only prevented NASH but also reversed hepatic inflammation, fibrosis, and steatosis and normalized hepatic transaminases after NASH was established. Thirty-five percent of the mice on the CDE diet developed HCC compared with none in the proglumide-treated group. We found that CCK-BR expression was markedly upregulated in mouse CDE liver and HCC cells compared with normal hepatic parenchymal cells, and this expression was epigenetically regulated by microRNA-148a. CONCLUSION: These results support the novel role of CCK receptors in the pathogenesis of NASH and HCC. |
Using the RNA-dependent RNA polymerase (RdRp) from poliovirus (PV) as our model system, we have shown that Lys-359 in motif-D functions as a general acid in the mechanism of nucleotidyl transfer. A K359H (KH) RdRp derivative is slow and faithful relative to wild-type enzyme. In the context of the KH virus, RdRp-coding sequence evolves, selecting for the following substitutions: I331F (IF, motif-C) and P356S (PS, motif-D). We have evaluated IF-KH, PS-KH, and IF-PS-KH viruses and enzymes. The speed and fidelity of each double mutant are equivalent. Each exhibits a unique recombination phenotype, with IF-KH being competent for copy-choice recombination and PS-KH being competent for forced-copy-choice recombination. Although the IF-PS-KH RdRp exhibits biochemical properties within twofold of wild type, the virus is impaired substantially for recombination in cells. We conclude that there are biochemical properties of the RdRp in addition to speed and fidelity that determine the mechanism and efficiency of recombination. The interwoven nature of speed, fidelity, the undefined property suggested here, and recombination makes it impossible to attribute a single property of the RdRp to fitness. However, the derivatives described here may permit elucidation of the importance of recombination on the fitness of the viral population in a background of constant polymerase speed and fidelity. |
Objective: The goal was to develop a pediatric airway stent for treating tracheobronchomalacia that could be used as an alternative to positive pressure ventilation. The design goals were for the stent to allow mucus flow and to resist migration inside the airways, while also enabling easy insertion and removal. Methods: A helical stent design, together with insertion and removal tools, is presented. A mechanics model of stent compression is derived to assist in selecting stent design parameters (pitch and wire diameter) that provide the desired amount of tracheal support, while introducing the minimal amount of foreign material into the airway. Worst-case airway area reduction with stent support is investigated experimentally using a pressurized tracheal phantom matched to porcine tracheal tissue properties. The stent design is then evaluated in a porcine in vivo experiment. Results: Phantom testing validated the mechanics model of stent compression. In vivo testing demonstrated that the stent was well tolerated by the animal. Since the helical design covers only a small portion of the epithelium, mucus transport through the stented region was minimally impeded. Furthermore, the screw-like stent resisted migration, while also providing for atraumatic removal through the use of an unscrewing motion during removal. Conclusion: The proposed stent design and tools represent a promising approach to prevent airway collapse in children with tracheobronchomalacia. Significance: The proposed technology overcomes the limitations of existing airway stents and may provide an alternative to maintaining children on a ventilator. |
BACKGROUND: Randomised controlled trials (RCTs) provide the most reliable information to inform clinical practice and patient care. We aimed to map global clinical research publication activity through RCT-related articles in high-impact-factor medical journals over the past five decades. METHODS: We conducted a cross-sectional analysis of articles published in the highest ranked medical journals with an impact factor > 10 (according to Journal Citation Reports published in 2017). We searched PubMed/MEDLINE (from inception to December 31, 2017) for all RCT-related articles (e.g. primary RCTs, secondary analyses and methodology papers) published in high-impact-factor medical journals. For each included article, raw metadata were abstracted from the Web of Science. A process of standardization was conducted to unify the different terms and grammatical variants and to remove typographical, transcription and/or indexing errors. Descriptive analyses were conducted (including the number of articles, citations, most prolific authors, countries, journals, funding sources and keywords). Network analyses of collaborations between countries and co-words are presented. RESULTS: We included 39,305 articles (for the period 1965–2017) published in forty journals. The Lancet (n = 3593; 9.1%), the Journal of Clinical Oncology (n = 3343; 8.5%) and The New England Journal of Medicine (n = 3275 articles; 8.3%) published the largest number of RCTs. A total of 154 countries were involved in the production of articles. The global productivity ranking was led by the United States (n = 18,393 articles), followed by the United Kingdom (n = 8028 articles), Canada (n = 4548 articles) and Germany (n = 4415 articles). Seventeen authors who had published 100 or more articles were identified; the most prolific authors were affiliated with Duke University (United States), Harvard University (United States) and McMaster University (Canada). The main funding institutions were the National Institutes of Health (United States), Hoffmann-La Roche (Switzerland), Pfizer (United States), Merck Sharp & Dohme (United States) and Novartis (Switzerland). The 100 most cited RCTs were published in nine journals, led by The New England Journal of Medicine (n = 78 articles), The Lancet (n = 9 articles) and JAMA (n = 7 articles). These landmark contributions focused on novel methodological approaches (e.g. the “Bland-Altman method”) and trials on the management of chronic conditions (e.g. diabetes control, hormone replacement therapy in postmenopausal women, multiple therapies for diverse cancers, cardiovascular therapies such as lipid-lowering statins, antihypertensive medications, and antiplatelet and antithrombotic therapy). CONCLUSIONS: Our analysis identified authors, countries, funding institutions, landmark contributions and high-impact-factor medical journals publishing RCTs. Over the last 50 years, publication production in leading medical journals has increased, with Western countries leading in research but with low- and middle-income countries showing very limited representation. |
BACKGROUND: Professional caregivers working in child and youth welfare institutions are frequently faced with the complex mental health issues, emotional needs and challenging coping strategies of clients with cumulated traumatic experiences, leaving them prone to developing high levels of stress, burn-out and compassion fatigue. Trauma-informed care (TIC) is a milieu-therapeutic approach that aims to promote the self-efficacy and self-care of youth welfare staff by guiding them to a better understanding of their own and their clients’ stress symptoms and countertransference. Despite increasing efforts to implement TIC practices, and more widespread recognition of their value in youth welfare systems, there is a lack of studies evaluating the effectiveness of this approach. The aim of this study was to assess the effects of TIC practices in youth welfare institutions on both the physiological stress of staff members and clients’ physical aggression towards their caregivers. . METHODS: Data was obtained from a longitudinal study investigating the effectiveness of TIC in 14 residential youth welfare institutions. Our sample consisted of 47 youth welfare employees (66.0% female) aged from 23 to 60 years (M = 37.4, SD = 10.4 years). Hair cortisol concentration (HCC) and occurrences of client physical aggression were assessed at four annual measurement time points (T1 to T4). RESULTS: Participants in five institutions employing TIC practices (intervention group) showed significantly lower HCC at T4 than staff members from institutions who did not receive training in TIC (control group), indicating reduced physiological stress levels. At T4, the intervention group reported significantly less physical aggression than the control group. CONCLUSIONS: TIC might be a promising approach for reducing the emotional burden of employees and institutions should invest in training their staff in TIC practices. More research is necessary, to investigate the benefits and efficacy of TIC, both to youths and staff members, and to foster a better understanding of which specific factors may contribute to stress reduction. |
BACKGROUND: Catheter-related bloodstream infections (CR-BSI) cause high neonatal mortality and are related to inadequate aseptic technique during the care and maintenance of a catheter. The incidence of CR-BSI among neonates in Hung Vuong Hospital was higher than that of other neonatal care centres in Vietnam. METHODS: An 18-month pre- and post-intervention study was conducted over three 6-month periods to evaluate the effectiveness of the intervention for CR-BSI and to identify risk factors associated with CR-BSI. During the intervention period, we trained all nurses in the Department of Neonatology on BSI preventive practices, provided auditing and feedback about aseptic technique during catheter care and maintenance, and reorganised preparation of total parenteral nutrition. All neonates with intravenous catheter insertion ≥48 h in the pre- and post-intervention period were enrolled. A standardised questionnaire was used to collect data. Blood samples were collected for cultures. We used Poisson regression to calculate rate ratio (RR) and 95% confidence interval (CI) for CR-BSI incidence rates and logistic regression to identify risk factors associated with CR-BSI. RESULTS: Of 2225 neonates enrolled, 1027 were enrolled in the pre-intervention period, of which 53 CR-BSI cases occurred in 8399 catheter-days, and 1198 were enrolled in the post-intervention period, of which 32 CR-BSI cases occurred in 8324 catheter-days. Incidence rates of CR-BSI significantly decreased after the intervention (RR = 0.61, 95% CI 0.39–0.94). Days of hospitalisation, episodes of non-catheter–related hospital-acquired infections, and the proportion of deaths significantly decreased after the intervention (p < 0.01). The CR-BSI was associated with days of intravenous catheter (odds ratio [OR] = 1.05, 95% CI 1.03–1.08), use of endotracheal intubation (OR = 2.27, 95% CI 1.27–4.06), and intravenous injection (OR = 8.50, 95% CI 1.14–63.4). CONCLUSIONS: The interventions significantly decreased the incidence rate of CR-BSI. Regular refresher training and auditing and feedback about aseptic technique during care and maintenance of catheters are critical to reducing CR-BSI. |
BACKGROUND: Pneumonia is a frequent complication in patients undergoing heart transplantation (HTx) that increases morbidity and mortality in this population. Nevertheless, the risk factors for postoperative pneumonia (POP) are still unknown. The aim of this study was to investigate the predictive risk factors for POP in HTx recipients. METHODS: In this retrospective study, all patients undergoing HTx between January 2014 and December 2015 were included. All cases of POP occurring until hospital discharge were investigated. The study aimed to determine risk factors using univariate and multivariate Cox regression models. Data are expressed in Odds Ratio [95% CI]. P < 0.05 was necessary to reject the null hypothesis. RESULTS: A total of 175 patients were included without any patients being lost to follow-up, and 89 instances of POP were diagnosed in 59 (34%) patients. Enterobacteriaceae and Pseudomonas aeruginosa were the most common pathogens. In the multivariate analysis, the risk factors were preoperative mechanical ventilation (OR 1.42 [1.12–1.80], P < 0.01) and perioperative blood transfusion (OR 1.42 [95% CI: 1.20–1.70], P < 0.01). POP significantly impacted mortality at 30 days (OR: 4 [1.3–12.4], P = 0.01) and 1 year (OR: 6.8 [2.5–8.4], P < 0.01) and was associated with a longer duration of mechanical ventilation, time to weaning from venoarterial extracorporeal membrane oxygenation and stay in an intensive care unit. Plasma exchanges and intravenous administration of immunoglobulins did not increase the risk of POP. CONCLUSION: After HTx, preoperative mechanical ventilation and blood transfusion were risk factors for POP and were associated with increased mortality. Enterobacteriaceae and Pseudomonas aeruginosa are the most common pathogens of POP. |
BACKGROUND: Immunization with attenuated malaria sporozoites protects humans from experimental malaria challenge by mosquito bite. Protection in humans is strongly correlated with the production of T cells targeting a heterogeneous population of pre-erythrocyte antigen proteoforms, including liver stage antigens. Currently, few T cell epitopes derived from Plasmodium falciparum, the major aetiologic agent of malaria in humans are known. METHODS: In this study both in vitro and in vivo malaria liver stage models were used to sequence host and pathogen proteoforms. Proteoforms from these diverse models were subjected to mild acid elution (of soluble forms), multi-dimensional fractionation, tandem mass spectrometry, and top-down bioinformatics analysis to identify proteoforms in their intact state. RESULTS: These results identify a group of host and malaria liver stage proteoforms that meet a 5% false discovery rate threshold. CONCLUSIONS: This work provides proof-of-concept for the validity of this mass spectrometry/bioinformatic approach for future studies seeking to reveal malaria liver stage antigens towards vaccine development. |
BACKGROUND: Toxocariasis is a worldwide zoonotic parasitic disease caused by species of Toxocara and Toxascaris, common in dogs and cats. Herein, a meta-analysis was contrived to assess the prevalence of Toxocara/Toxascaris in carnivore and human hosts in different regions of Iran from April 1969 to June 2019. METHODS: The available online articles of English (PubMed, Science Direct, Scopus, and Ovid) and Persian (SID, Iran Medex, Magiran, and Iran Doc) databases and also the articles that presented in held parasitology congresses of Iran were involved. RESULTS: The weighted prevalence of Toxocara/Toxascaris in dogs (Canis familiaris) and cats (Felis catus) was 24.2% (95% CI: 18.0–31.0%) and 32.6% (95% CI: 22.6–43.4%), respectively. Also, pooled prevalence in jackal (Canis aureus) and red fox (Vulpes vulpes) was 23.3% (95% CI: 7.7–43.2%) and 69.4% (95% CI: 60.3–77.8%), correspondingly. Weighted mean prevalence of human cases with overall 28 records was 9.3% (95% CI: 6.3–13.1%). The weighted prevalence of Toxocara canis, Toxocara cati, and Toxascaris leonina was represented as 13.8% (95% CI: 9.8–18.3%), 28.5% (95% CI: 20–37.7%) and 14.3% (95% CI: 8.1–22.0%), respectively. CONCLUSION: Our meta-analysis results illustrate a considerable prevalence rate of Toxocara/Toxascaris, particularly in cats and dogs of northern parts of Iran. The presence of suitable animal hosts, optimum climate and close contact of humans and animals would have been the reason for higher seroprevalence rates of human cases in our region. Given the significance clinical outcomes of human Toxocara/Toxascaris, necessary measures should be taken. |
Despite the availability of highly effective direct-acting antiviral (DAA) regimens for the treatment of hepatitis C virus (HCV) infections, sustained viral response (SVR) rates remain suboptimal for difficult-to-treat patient populations such as those with HCV genotype 3, cirrhosis or prior treatment experience, warranting development of more potent HCV replication antivirals. AT-527 is the hemi-sulfate salt of AT-511, a novel phosphoramidate prodrug of 2’-fluoro-2’-C-methylguanosine-5'-monophosphate that has potent in vitro activity against HCV. The EC(50) of AT-511, determined using HCV laboratory strains and clinical isolates with genotypes 1–5, ranged from 5–28 nM. The active 5'-triphosphate metabolite, AT-9010, specifically inhibited the HCV RNA-dependent RNA polymerase. AT-511 did not inhibit the replication of other selected RNA or DNA viruses in vitro. AT-511 was approximately 10-fold more active than sofosbuvir (SOF) against a panel of laboratory strains and clinical isolates of HCV genotypes 1–5 and remained fully active against S282T resistance-associated variants, with up to 58-fold more potency than SOF. In vitro, AT-511 did not inhibit human DNA polymerases or elicit cytotoxicity or mitochondrial toxicity at concentrations up to 100 μM. Unlike the other potent guanosine analogs PSI-938 and PSI-661, no mutagenic O(6)-alkylguanine bases were formed when incubated with cytochrome P450 (CYP) 3A4, and AT-511 had IC(50) values ≥25 μM against a panel of CYP enzymes. In hepatocytes from multiple species, the active triphosphate was the predominant metabolite produced from the prodrug, with a half-life of 10 h in human hepatocytes. When given orally to rats and monkeys, AT-527 preferentially delivered high levels of AT-9010 in the liver in vivo. These favorable preclinical attributes support the ongoing clinical development of AT-527 and suggest that, when used in combination with an HCV DAA from a different class, AT-527 may increase SVR rates, especially for difficult-to-treat patient populations, and could potentially shorten treatment duration for all patients. |
This retrospective cohort study investigated the association between in-hospital survival and two-dimensional (2D) echocardiography within 24 hours after the return of spontaneous circulation (ROSC) in patients who underwent in-hospital cardiopulmonary resuscitation (ICPR) after in-hospital cardiopulmonary arrest (IHCA). The 2D-echo and non-2D-echo groups comprised eligible patients who underwent transthoracic 2D echocardiography performed by the cardiology team within 24 hours after ROSC and those who did not, respectively. After propensity score (PS) matching, 142 and 284 patients in the 2D-echo and non-2D-echo groups, respectively, were included. A logistic regression analysis showed that the likelihood of in-hospital survival was 2.35-fold higher in the 2D-echo group than in the non-2D-echo group (P < 0.001). Regarding IHCA aetiology, in-hospital survival after cardiac arrest of a cardiac cause was 2.51-fold more likely in the 2D-echo group than in the non-2D-echo group (P < 0.001), with no significant inter-group difference in survival after cardiac arrest of a non-cardiac cause (P = 0.120). In this study, 2D echocardiography performed within 24 hours after ROSC was associated with better in-hospital survival outcomes for patients who underwent ICPR for IHCA with a cardiac aetiology. Thus, 2D echocardiography may be performed within 24 hours after ROSC in patients experiencing IHCA to enable better treatment. |
Porcine circovirus type 3 (PCV3) contains two major open reading frames (ORFs) and the ORF2 gene encodes the major structural capsid protein. In this study, nuclear localization of ORF2 was demonstrated by fluorescence observation and subcellular fractionation assays in ORF2-transfected PK-15 cells. The subcellular localization of truncated ORF2 indicated that the 38 N-terminal amino acids were responsible for the nuclear localization of ORF2. The truncated and site-directed mutagenesis of this domain were constructed, and the results demonstrated that the basic amino acid residues at positions 8–32 were essential for the strict nuclear localization. The basic motifs (8)RRR-R-RRR(16) and (16)RRRHRRR(22) were further shown to be the key functional nucleolar localization signals that guide PCV3 ORF2 into nucleoli. Furthermore, sequence analysis showed that the amino acids of PCV3 nuclear localization signals were highly conserved. Overall, this study provides insight into the biological and functional characteristics of the PCV3 ORF2 protein. |
The QX-type avian infectious bronchitis virus (IBV) is still a prevalent genotype in Southwestern China. To analyze the antigenicity and pathogenicity characteristics of the dominant genotype strains (QX-type), S1 gene sequence analysis, virus cross-neutralization tests, and pathogenicity test of eight QX-type IBV isolates were conducted. Sequence analysis showed that the nucleotide homology between the eight strains was high, but distantly related to H120 and 4/91 vaccine strains. Cross-neutralization tests showed that all eight strains isolated from 2015 and 2017 belonged to the same serotype, but exhibited antigenic variations over time. The pathogenicity test of the five QX-type IBV isolates showed that only three strains, CK/CH/SC/DYW/16, CK/CH/SC/MS/17, and CK/CH/SC/GH/15, had a high mortality rate with strong respiratory and renal pathogenicity, whereas CK/CH/SC/PZ/17 and CK/CH/SC/DYYJ/17 caused only mild clinical symptoms and tissue lesions. Our results indicate that the prevalent QX-type IBVs displayed antigenic variations and pathogenicity difference. These findings may provide reference for research on the evolution of IBV and vaccine preparation of infectious bronchitis (IB). |
BACKGROUND: Prostaglandins (PG) are lipid mediators derived from arachidonic acid metabolism. They are involved in cellular processes such as inflammation and tissue homeostasis. PG production is not restricted to multicellular organisms. Trypanosomatids also synthesize several metabolites of arachidonic acid. Nevertheless, their biological role in these early-branching parasites and their role in host-parasite interaction are not well elucidated. Prostaglandin F(2α) synthase (PGF2S) has been observed in the Leishmania braziliensis secreted proteome and in L. donovani extracellular vesicles. Furthermore, we previously reported a positive correlation between L. braziliensis PGF2S (LbrPGF2S) expression and pathogenicity in mice. METHODS: LbrPGF2S gene expression and PGF2α synthesis in promastigotes were detected and quantified by western blotting and EIA assay kit, respectively. To investigate LbrPGF2S localization in amastigotes during bone marrow-derived macrophage infection, parasites expressing mCherry-LbrPGF2S were generated and followed by time-lapse imaging for 48 h post-infection. PGF2S homolog sequences from Leishmania and humans were analyzed in silico using ClustalW on Geneious v6 and EMBOSS Needle. RESULTS: Leishmania braziliensis promastigotes synthesize prostaglandin F(2α) in the presence of arachidonic acid, with peak production in the stationary growth phase under heat stress. LbrPGF2S is a cytoplasmic protein enriched in the secretory site of the parasite cell body, the flagellar pocket. It is an enzyme constitutively expressed throughout promastigote development, but overexpression of LbrPGF2S leads to an increase of infectivity in vitro. The data suggest that LbrPGF2S may be released from intracellular amastigotes into the cytoplasm of bone marrow-derived macrophages over a 48-hour infection period, using time-lapse microscopy and mCherry-PGF2S (mChPGF2S)-expressing parasites. CONCLUSIONS: LbrPGF2S, a parasite-derived protein, is targeted to the host cell cytoplasm. The putative transfer of this enzyme, involved in pro-inflammatory lipid mediator synthesis, to the host cell suggests a potential role in host-parasite interaction and may partially explain the increased pathogenicity associated with overexpression of LbrPGF2S in L. braziliensis. Our data provide valuable insights to help understand the importance of parasite-derived lipid mediators in pathogenesis. [Image: see text] |
BACKGROUND: Plasmodium falciparum (Pf) whole-organism sporozoite vaccines have been shown to provide significant protection against controlled human malaria infection (CHMI) in clinical trials. Initial CHMI studies showed significantly higher durable protection against homologous than heterologous strains, suggesting the presence of strain-specific vaccine-induced protection. However, interpretation of these results and understanding of their relevance to vaccine efficacy have been hampered by the lack of knowledge on genetic differences between vaccine and CHMI strains, and how these strains are related to parasites in malaria endemic regions. METHODS: Whole genome sequencing using long-read (Pacific Biosciences) and short-read (Illumina) sequencing platforms was conducted to generate de novo genome assemblies for the vaccine strain, NF54, and for strains used in heterologous CHMI (7G8 from Brazil, NF166.C8 from Guinea, and NF135.C10 from Cambodia). The assemblies were used to characterize sequences in each strain relative to the reference 3D7 (a clone of NF54) genome. Strains were compared to each other and to a collection of clinical isolates (sequenced as part of this study or from public repositories) from South America, sub-Saharan Africa, and Southeast Asia. RESULTS: While few variants were detected between 3D7 and NF54, we identified tens of thousands of variants between NF54 and the three heterologous strains. These variants include SNPs, indels, and small structural variants that fall in regulatory and immunologically important regions, including transcription factors (such as PfAP2-L and PfAP2-G) and pre-erythrocytic antigens that may be key for sporozoite vaccine-induced protection. Additionally, these variants directly contributed to diversity in immunologically important regions of the genomes as detected through in silico CD8(+) T cell epitope predictions. Of all heterologous strains, NF135.C10 had the highest number of unique predicted epitope sequences when compared to NF54. Comparison to global clinical isolates revealed that these four strains are representative of their geographic origin despite long-term culture adaptation; of note, NF135.C10 is from an admixed population, and not part of recently formed subpopulations resistant to artemisinin-based therapies present in the Greater Mekong Sub-region. CONCLUSIONS: These results will assist in the interpretation of vaccine efficacy of whole-organism vaccines against homologous and heterologous CHMI. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13073-019-0708-9) contains supplementary material, which is available to authorized users. |
BACKGROUND: Knowledge about parasitic infections is crucial information for animal health, particularly of free-ranging species that might come into contact with livestock and humans. METHODS: We investigated the seroprevalence of three tissue-cyst-forming apicomplexan parasites (Toxoplasma gondii, Neospora caninum and Besnoitia besnoiti) in 506 individuals of 12 wildlife species in Namibia using in-house enzyme linked immunosorbent assays (indirect ELISAs applying purified antigens) for screening and immunoblots as confirmatory tests. We included six species of the suborder Feliformia, four species of the suborder Caniformia and two species of the suborder Ruminantia. For the two species for which we had most samples and life-history information, i.e. cheetahs (Acinonyx jubatus, n = 250) and leopards (Panthera pardus, n = 58), we investigated T. gondii seroprevalence in relation to age class, sex, sociality (solitary, mother-offspring group, independent sibling group, coalition group) and site (natural habitat vs farmland). RESULTS: All but one carnivore species (bat-eared fox Otocyon megalotis, n = 4) were seropositive to T. gondii, with a seroprevalence ranging from 52.4% (131/250) in cheetahs to 93.2% (55/59) in African lions (Panthera leo). We also detected antibodies to T. gondii in 10.0% (2/20) of blue wildebeest (Connochaetes taurinus). Adult cheetahs and leopards were more likely to be seropositive to T. gondii than subadult conspecifics, whereas seroprevalence did not vary with sex, sociality and site. Furthermore, we measured antibodies to N. caninum in 15.4% (2/13) of brown hyenas (Hyaena brunnea) and 2.6% (1/39) of black-backed jackals (Canis mesomelas). Antibodies to B. besnoiti were detected in 3.4% (2/59) of African lions and 20.0% (4/20) of blue wildebeest. CONCLUSIONS: Our results demonstrate that Namibian wildlife species were exposed to apicomplexan parasites at different prevalences, depending on parasite and host species. In addition to serological work, molecular work is also needed to better understand the sylvatic cycle and the clear role of wildlife in the epidemiology of these parasites in southern Africa. |
The simultaneous electrochemical determination of myricetin and rutin remains a challenge due to their indistinguishable potentials. To solve this problem, we constructed a ternary platinum nanoparticle, reduced graphene oxide, multi-walled carbon nanotubes (Pt@r-GO@MWCNTs) nanocomposite via a facile one-pot synthetic method. Under the optimized conditions, the ternary Pt@r-GO@MWCNTs nanocomposite exhibited good electrocatalytic activity toward myricetin and rutin via solid phase extraction and excellent performance for the simultaneous determination of myricetin and rutin. The oxidation peak current of myricetin was proportional to its concentrations in the range of 0.05–50 μM with a detection limit of 0.01 μM (S/N = 3). The linear range for rutin was 0.05–50 μM with a detection limit of 0.005 μM (S/N = 3). The ternary nanocomposite sensor also exhibited good reproducibility and stability, and was successfully used for the simultaneous determination of myricetin and rutin in real orange juice samples with recoveries ranging between 100.57% and 108.46%. |
Plasmacytoid dendritic cells (pDCs) are sensor cells with diverse immune functions, from type I interferon (IFN-I) production to antigen presentation, T cell activation, and tolerance. Regulation of these functions remains poorly understood but could be mediated by functionally specialized pDC subpopulations. We address pDC diversity using a high-dimensional single-cell approach: mass cytometry (CyTOF). Our analysis uncovers a murine pDC-like population that specializes in antigen presentation with limited capacity for IFN-I production. Using a multifaceted cross-species comparison, we show that this pDC-like population is the definitive murine equivalent of the recently described human AXL(+) DCs, which we unify under the name transitional DCs (tDCs) given their continuum of pDC and cDC2 characteristics. tDCs share developmental traits with pDCs, as well as recruitment dynamics during viral infection. Altogether, we provide a framework for deciphering the function of pDCs and tDCs during diseases, which has the potential to open new avenues for therapeutic design. |
Freya Shearer and co-authors discuss the use of decision analysis in planning for infectious disease pandemics. |
During HIV infection, cell-to-cell transmission results in endosomal uptake of the virus by target CD4+ T cells and potential exposure of the viral ssRNA genome to endosomal Toll-like receptors (TLRs). TLRs are instrumental in activating inflammatory responses in innate immune cells, but their function in adaptive immune cells is less well understood. Here we show that synthetic ligands of TLR8 boosted T cell receptor signaling, resulting in increased cytokine production and upregulation of surface activation markers. Adjuvant TLR8 stimulation, but not TLR7 or TLR9, further promoted T helper cell differentiation towards Th1 and Th17. In addition, we found that endosomal HIV induced cytokine secretion from CD4+ T cells in a TLR8-specific manner. TLR8 engagement also enhanced HIV-1 replication and potentiated the reversal of latency in patient-derived T cells. The adjuvant TLR8 activity in T cells can contribute to viral dissemination in the lymph node and low-grade inflammation in HIV patients. In addition, it can potentially be exploited for therapeutic targeting and vaccine development. |
The role of laparoscopic surgery for left-sided colon cancer has been supported by the results of randomized controlled trials. However, its benefits and disadvantages in the real world setting should be further assessed with population-based studies.The hospitalization data of patients undergoing open or laparoscopic surgery for left-sided colon cancer were sourced from the Taiwan National Health Insurance Research Database. Patient and hospital characteristics and perioperative outcomes including length of hospital stay, operation time, opioid use, blood transfusion, intensive care unit (ICU) admission, and use of mechanical ventilation were compared. The overall survival was also assessed. Patients undergoing laparoscopic surgery had shorter hospital stay (p < 0.0001) and less demand for opioid analgesia (p = 0.0005). Further logistic regression revealed that patients undergoing open surgery were 1.70, 2.89, and 3.00 times more likely to have blood transfusion, to be admitted to ICU, and to use mechanical ventilation than patients undergoing laparoscopic surgery. Operations performed in medical centers were also associated with less adverse events. The overall survival was comparable between the 2 groups.With adequate hospital quality and volume, laparoscopic surgery for left-sided colon cancer was associated with improved perioperative outcomes. The long-term survival was not compromised. |
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