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4,400 | Antimicrobial-associated harm in critical care: a narrative review | The belief that, for the individual patient, the benefit of prompt and continued use of antimicrobials outweighs any potential harm is a significant barrier to improved stewardship of these vital agents. Antimicrobial stewardship may be perceived as utilitarian rationing, seeking to preserve the availability of effective antimicrobials by limiting the development of resistance in a manner which could conflict with the immediate treatment of the patient in need. This view does not account for the growing evidence of antimicrobial-associated harm to individual patients. This review sets out the evidence for antimicrobial-associated harm and how this should be balanced with the need for prompt and appropriate therapy in infection. It describes the mechanisms by which antimicrobials may harm patients including: mitochondrial toxicity; immune cell toxicity; adverse drug reactions; selection of resistant organisms within a given patient; and disruption of the microbiome. Finally, the article indicates how the harms of antimicrobials may be mitigated and identifies areas for research and development in this field. |
4,401 | Impact of corticosteroid treatment on clinical outcomes of influenza-associated ARDS: a nationwide multicenter study | BACKGROUND: Corticosteroid treatment has been widely used in the treatment of septic shock, influenza, and ARDS, although some previous studies discourage its use in severe influenza patients. This multicenter retrospective cohort study conducted in the intensive care units (ICUs) of eight medical centers across Taiwan aims to determine the real-world status of corticosteroid treatment in patients with influenza-associated acute respiratory distress syndrome (ARDS) and its impact on clinical outcomes. Between October 2015 and March 2016, consecutive ICU patients with virology-proven influenza infections who fulfilled ARDS and received invasive mechanical ventilation were enrolled. The impact of early corticosteroid treatment (≥ 200 mg hydrocortisone equivalent dose within 3 days after ICU admission, determined by a sensitivity analysis) on hospital mortality (the primary outcome) was assessed by multivariable logistic regression analysis, and further confirmed in a propensity score-matched cohort. RESULTS: Among the 241 patients with influenza-associated ARDS, 85 (35.3%) patients receiving early corticosteroid treatment had similar baseline characteristics, but a significantly higher hospital mortality rate than those without early corticosteroid treatment [43.5% (37/85) vs. 19.2% (30/156), p < 0.001]. Early corticosteroid treatment was independently associated with increased hospital mortality in overall patients [adjusted odds ratio (95% CI) = 5.02 (2.39–10.54), p < 0.001] and in all subgroups. Earlier treatment and higher dosing were associated with higher hospital mortality. Early corticosteroid treatment was associated with a significantly increased odds of subsequent bacteremia [adjusted odds ratio (95% CI) = 2.37 (1.01–5.56)]. The analyses using a propensity score-matched cohort showed consistent results. CONCLUSIONS: Early corticosteroid treatment was associated with a significantly increased hospital mortality in adult patients with influenza-associated ARDS. Earlier treatment and higher dosing were associated with higher hospital mortality. Clinicians should be cautious while using corticosteroid treatment in this patient group. |
4,402 | Porcine circovirus type 2 exploits JNK-mediated disruption of tight junctions to facilitate Streptococcus suis translocation across the tracheal epithelium | Porcine circovirus type 2 (PCV2) is considered as the primary pathogen of porcine circovirus-associated disease (PCVAD), which results in significant economic losses worldwide. Clinically, PCV2 often causes disease through coinfection with other bacterial pathogens, including Streptococcus suis (S. suis), and especially the highly prevalent S. suis serotype 2 (SS2). The present study determined that continuous PCV2 infection in piglets down-regulates tight junction proteins (TJ) ZO-1 and occludin in the lungs. Swine tracheal epithelial cells (STEC) were used to explore the mechanisms and consequences of disruption of TJ, and an in vitro tracheal epithelial barrier model was established. Our results show that PCV2 infection in STEC decreases the expression levels of ZO-1 and occludin and increases the permeability of the tracheal epithelial barrier, resulting in easier translocation of SS2. Moreover, Western blot analysis indicates that PCV2 infection activates the JNK/MAPK pathway. The disruption of TJ in SETC and increased permeability of the epithelial barrier induced by PCV2 could be alleviated by inhibition of JNK phosphorylation, which indicates that the JNK/MAPK pathway regulates the expression of ZO-1 and occludin during PCV2 infection. This study allows us to better understand the mechanisms of PCV2 coinfection with bacterial pathogens and provides new insight into controlling the occurrence of PCVAD. |
4,403 | Impact of protocolized diuresis for de-resuscitation in the intensive care unit | OBJECTIVE: Administration of diuretics has been shown to assist fluid management and improve clinical outcomes in the critically ill post-shock resolution. Current guidelines have not yet included standardization or guidance for diuretic-based de-resuscitation in critically ill patients. This study aimed to evaluate the impact of a multi-disciplinary protocol for diuresis-guided de-resuscitation in the critically ill. METHODS: This was a pre-post single-center pilot study within the medical intensive care unit (ICU) of a large academic medical center. Adult patients admitted to the Medical ICU receiving mechanical ventilation with either (1) clinical signs of volume overload via chest radiography or physical exam or (2) any cumulative fluid balance ≥ 0 mL since hospital admission were eligible for inclusion. Patients received diuresis per clinician discretion for a 2-year period (historical control) followed by a diuresis protocol for 1 year (intervention). Patients within the intervention group were matched in a 1:3 ratio with those from the historical cohort who met the study inclusion and exclusion criteria. RESULTS: A total of 364 patients were included, 91 in the protocol group and 273 receiving standard care. Protocolized diuresis was associated with a significant decrease in 72-h post-shock cumulative fluid balance [median, IQR − 2257 (− 5676–920) mL vs 265 (− 2283–3025) mL; p < 0.0001]. In-hospital mortality in the intervention group was lower compared to the historical group (5.5% vs 16.1%; p = 0.008) and higher ICU-free days (p = 0.03). However, no statistically significant difference was found in ventilator-free days, and increased rates of hypernatremia and hypokalemia were demonstrated. CONCLUSIONS: This study showed that a protocol for diuresis for de-resuscitation can significantly improve 72-h post-shock fluid balance with potential benefit on clinical outcomes. |
4,404 | Structure of the host cell recognition and penetration machinery of a Staphylococcus aureus bacteriophage | Staphylococcus aureus is a common cause of infections in humans. The emergence of virulent, antibiotic-resistant strains of S. aureus is a significant public health concern. Most virulence and resistance factors in S. aureus are encoded by mobile genetic elements, and transduction by bacteriophages represents the main mechanism for horizontal gene transfer. The baseplate is a specialized structure at the tip of bacteriophage tails that plays key roles in host recognition, cell wall penetration, and DNA ejection. We have used high-resolution cryo-electron microscopy to determine the structure of the S. aureus bacteriophage 80α baseplate at 3.75 Å resolution, allowing atomic models to be built for most of the major tail and baseplate proteins, including two tail fibers, the receptor binding protein, and part of the tape measure protein. Our structure provides a structural basis for understanding host recognition, cell wall penetration and DNA ejection in viruses infecting Gram-positive bacteria. Comparison to other phages demonstrates the modular design of baseplate proteins, and the adaptations to the host that take place during the evolution of staphylococci and other pathogens. |
4,405 | Out of Pocket Expenditure for Sick Newborn Care in Referral Hospitals of Nepal | BACKGROUND: Almost all preventable neonatal deaths take place in low- and middle-income countries and affect the poorest who have the least access to high quality health services. Cost of health care is one of the factors preventing access to quality health services and universal health coverage. In Nepal, the majority of expenses related to newborn care are borne by the caregiver, regardless of socioeconomic status. We conducted a study to assess the out of pocket expenditure (OOPE) for sick newborn care in hospitals in Nepal. METHODS: This cross-sectional study of hospital care for newborns was conducted in 11 hospitals in Nepal and explored OOPE incurred by caregivers for sick newborn care. Data were collected from the caregivers of the sick newborn on the topics of cost of travel, accommodation, treatment (drugs, diagnosis) and documented on a sick newborn case record form. RESULTS: Data were collected from 814 caregivers. Cost of caregivers’ stay accounted for more than 40% of the OOPE for sick newborn care, followed by cost of travel, and the baby’s stay and treatment. The overall OOPE ranged from 13.6 to 226.1 US dollars (USD). The median OOPE was highest for preterm complications ($33.2 USD; CI 14.0–226.1), followed by hyperbilirubinemia ($31.9 USD; CI 14.0–60.7), respiratory distress syndrome ($26.9 USD; 15.3–121.5), neonatal sepsis ($ 25.8 USD; CI 13.6–139.8) and hypoxic ischemic encephalopathy ($23.4 USD; CI 13.6–97.7). DISCUSSION FOR PRACTICE: In Nepal, OOPE for sick newborn care in hospitals varied by neonatal morbidity and duration of stay. The largest proportion of OOPE were for accommodation and travel. Affordable and accessible health care will substantially reduce the OOPE for sick newborn care in hospitals. |
4,406 | Spatial epidemiological patterns suggest mechanisms of land-sea transmission for Sarcocystis neurona in a coastal marine mammal | Sarcocystis neurona was recognised as an important cause of mortality in southern sea otters (Enhydra lutris nereis) after an outbreak in April 2004 and has since been detected in many marine mammal species in the Northeast Pacific Ocean. Risk of S. neurona exposure in sea otters is associated with consumption of clams and soft-sediment prey and is temporally associated with runoff events. We examined the spatial distribution of S. neurona exposure risk based on serum antibody testing and assessed risk factors for exposure in animals from California, Washington, British Columbia and Alaska. Significant spatial clustering of seropositive animals was observed in California and Washington, compared with British Columbia and Alaska. Adult males were at greatest risk for exposure to S. neurona, and there were strong associations with terrestrial features (wetlands, cropland, high human housing-unit density). In California, habitats containing soft sediment exhibited greater risk than hard substrate or kelp beds. Consuming a diet rich in clams was also associated with increased exposure risk. These findings suggest a transmission pathway analogous to that described for Toxoplasma gondii, with infectious stages traveling in freshwater runoff and being concentrated in particular locations by marine habitat features, ocean physical processes, and invertebrate bioconcentration. |
4,407 | Surface Dielectric Barrier Discharge plasma: a suitable measure against fungal plant pathogens | Fungal diseases seriously affect agricultural production and the food industry. Crop protection is usually achieved by synthetic fungicides, therefore more sustainable and innovative technologies are increasingly required. The atmospheric pressure low-temperature plasma is a novel suitable measure. We report on the effect of plasma treatment on phytopathogenic fungi causing quantitative and qualitative losses of products both in the field and postharvest. We focus our attention on the in vitro direct inhibitory effect of non-contact Surface Dielectric Barrier Discharge on conidia germination of Botrytis cinerea, Monilinia fructicola, Aspergillus carbonarius and Alternaria alternata. A few minutes of treatment was required to completely inactivate the fungi on an artificial medium. Morphological analysis of spores by Scanning Electron Microscopy suggests that the main mechanism is plasma etching due to Reactive Oxygen Species or UV radiation. Spectroscopic analysis of plasma generated in humid air gives the hint that the rotational temperature of gas should not play a relevant role being very close to room temperature. In vivo experiments on artificially inoculated cherry fruits demonstrated that inactivation of fungal spores by the direct inhibitory effect of plasma extend their shelf life. Pre-treatment of fruits before inoculation improve the resistance to infections maybe by activating defense responses in plant tissues. |
4,408 | Labral calcification plays a key role in hip pain and symptoms in femoroacetabular impingement | BACKGROUND: Hip osteoarthritis (HOA) is the most common hip disorder and a major cause of disability in the adult population, with an estimated prevalence of end-stage disease and total hip replacement. Thus, the diagnosis, prevention, and treatment of the early stages of the disease in young adults are crucial to reduce the incidence of end-stage HOA. The purpose of this study was to determine whether (1) a relationship among the inflammatory status of labrum and synovium collected from patients with femoroacetabular impingement (FAI) would exist; and (2) to investigate the associations among the histopathological features of joint tissues, the pre-operative symptoms and the post-operative outcomes after arthroscopic surgery. METHODS: Joint tissues from 21 patients undergoing hip arthroscopy for FAI were collected and their histological and immunohistochemical features were correlated with clinical parameters. RESULTS: Synovial mononuclear cell infiltration was observed in 25% of FAI patients, inversely correlated with the hip disability and osteoarthritis outcome score (HOOS) pain and function subscales and with the absolute and relative change in total HOOS. All the labral samples showed some pattern of degeneration and 67% of the samples showed calcium deposits. The total labral score was associated with increased CD68 positive cells in the synovium. The presence of labral calcifications, along with the chondral damage worsened the HOOS post-op symptoms (adjusted R-square = 0.76 p = 0.0001). CONCLUSIONS: Our study reveals a relationship between the histologic labral features, the synovial inflammation, and the cartilage condition at the time of FAI. The presence of labral calcifications, along with the cartilage damage and the synovitis negatively affects the post-operative outcomes in patients with FAI. |
4,409 | Role of O-C2 angle in the development of dysphagia in patients with halo-vest fixation | BACKGROUND: Dysphagia is one of the most serious complications in patients treated with a halo-vest brace. However, the cause of dysphagia development by halo-vest fixation is not yet clear. We therefore investigated the incidence of dysphagia and cervical alignment as well as clinical data from medical charts in patients treated with a halo-vest brace. METHODS: We retrospectively reviewed clinical data from the medical charts of 49 patients who had undergone halo-vest fixation. Occipito (O)-C2 angle, C2-C6 angle, and pharyngeal inlet angle were assessed by lateral plain X-rays of the cervical spine. The impacts of these parameters on incidence and severity of dysphagia were analyzed. RESULTS: Thirteen patients (32%) suffered from dysphagia during halo-vest fixation, and age and length of intensive care unit (ICU) stay were greater in the dysphagia group (p = 0.044 and 0.013, respectively) than in those who did not develop dysphagia. O-C2 angle was smaller in the dysphagia group (p = 0.016). After multivariate logistic analysis, body mass index, ICU stay, and O-C2 angle remained as independent risk factors related to incidence of dysphagia. Spearman rank correlation showed a negative correlation between ICU stay and Food Intake Level Scale (FILS) (p = 0.026), and a positive correlation between O-C2 angle and FILS (p = 0.008). CONCLUSION: This study suggested that O-C2 angle is related to both incidence and severity of dysphagia due to halo-vest fixation. |
4,410 | Molecular characterization of methicillin-resistant Staphylococcus aureus clinical strains from the endotracheal tubes of patients with nosocomial pneumonia | BACKGROUND: Among all cases of nosocomial pneumonia, Staphylococcus aureus is the second most prevalent pathogen (17.8%). In Europe, 29.9% of the isolates are oxacillin-resistant. The changing epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) nosocomial infections and the decreasing susceptibility to first-line antibiotics leave clinicians with few therapeutic options. The objective of our study was to determine the antimicrobial susceptibility, the associated molecular mechanisms of resistance and the epidemiological relatedness of MRSA strains isolated from the endotracheal tubes (ETT) of intubated critically ill patients in the intensive care unit (ICU) with nosocomial pneumonia caused by Staphylococcus aureus. METHODS: The antimicrobial susceptibility to vancomycin, linezolid, ciprofloxacin, clindamycin, erythromycin, chloramphenicol, fusidic acid, gentamicin, quinupristin-dalfopristin, rifampicin, sulfamethoxazole/trimethoprim, and tetracycline were measured. Resistance mechanisms were then analyzed by polymerase chain reaction and sequencing. Molecular epidemiology was carried out by multi-locus sequence typing. RESULTS: S. aureus isolates were resistant to ciprofloxacin, erythromycin, gentamicin, tetracycline, clindamycin, and fusidic acid. The most frequent mutations in quinolone-resistant S. aureus strains were S84L in the gyrA gene, V511A in the gyrB gene, S144P in the grlA gene, and K401R/E in the grlB gene. Strains resistant to erythromycin carried the ermC, ermA, and msrA genes; the same ermC and ermA genes were detected in strains resistant to clindamycin. The aac(6′)-aph(2″) gene was related to gentamicin resistance, while resistance to tetracycline was related to tetK (efflux pump). The fusB gene was detected in the strain resistant to fusidic acid. The most frequent sequence types were ST22, ST8, and ST217, which were distributed in four clonal complexes (CC5, CC22, CC45, and CC59). CONCLUSIONS: High levels of resistance to second-line antimicrobials threatens the treatment of nosocomial respiratory infections due to methicillin-resistant S. aureus with decreased susceptibility to linezolid and vancomycin. The wide genotypic diversity found reinforces the central role of ICU infection control in preventing nosocomial transmission. |
4,411 | Immunoinformatics and Vaccine Development: An Overview | The use of vaccines have resulted in a remarkable improvement in global health. It has saved several lives, reduced treatment costs and raised the quality of animal and human lives. Current traditional vaccines came empirically with either vague or completely no knowledge of how they modulate our immune system. Even at the face of potential vaccine design advance, immune-related concerns (as seen with specific vulnerable populations, cases of emerging/re-emerging infectious disease, pathogens with complex lifecycle and antigenic variability, need for personalized vaccinations, and concerns for vaccines' immunological safety -specifically vaccine likelihood to trigger non-antigen-specific responses that may cause autoimmunity and vaccine allergy) are being raised. And these concerns have driven immunologists toward research for a better approach to vaccine design that will consider these challenges. Currently, immunoinformatics has paved the way for a better understanding of some infectious disease pathogenesis, diagnosis, immune system response and computational vaccinology. The importance of this immunoinformatics in the study of infectious diseases is diverse in terms of computational approaches used, but is united by common qualities related to host–pathogen relationship. Bioinformatics methods are also used to assign functions to uncharacterized genes which can be targeted as a candidate in vaccine design and can be a better approach toward the inclusion of women that are pregnant into vaccine trials and programs. The essence of this review is to give insight into the need to focus on novel computational, experimental and computation-driven experimental approaches for studying of host–pathogen interactions and thus making a case for its use in vaccine development. |
4,412 | Klebsiella pneumoniae: an increasing threat to public health | OBJECTIVES: This review fills the paucity of information on K. pneumoniae as a nosocomial pathogen by providing pooled data on epidemiological risk factors, resistant trends and profiles and resistant and virulent genes of this organism in Asia. METHODS: Exhaustive search was conducted using PubMed, Web of Science, and Google scholar for most studies addressing the prevalence, risk factors, drug resistant-mediated genes and/or virulent factors of K. pneumoniae in Asia. Data extracted for meta-analysis were analyzed using comprehensive meta-analysis version 3. Trends data for the isolation rate and resistance rates were entered into Excel spread sheet and the results were presented in graphs. RESULTS: The prevalence rate of drug resistance in K. pneumoniae were; amikacin (40.8%) [95% CI 31.9–50.4], aztreonam (73.3%) [95% CI 59.9–83.4], ceftazidime (75.7%) [95% CI 65.4–83.6], ciprofloxacin (59.8%) [95% CI 48.6–70.1], colistin (2.9%) [95% CI 1.8–4.4], cefotaxime (79.2%) [95% CI 68.0–87.2], cefepime (72.6) [95% CI 57.7–83.8] and imipenem (65.6%) [95% CI 30.8–89.0]. TEM (39.5%) [95% CI 15.4–70.1], SHV-11 (41.8%) [95% CI 16.2–72.6] and KPC-2 (14.6%) [95% CI 6.0–31.4] were some of the resistance mediated genes observed in this study. The most virulent factors utilized by K. pneumoniae are; hypermucoviscous phenotype and mucoviscosity-related genes, genes for biosynthesis of lipopolysaccharide, iron uptake and transport genes and finally, adhesive genes. CONCLUSION: It can be concluded that, antimicrobial resistant in K. pneumoniae is a clear and present danger in Asia which needs strong surveillance to curb this menace. It is very important for public healthcare departments to monitor and report changes in antimicrobial-resistant isolates. |
4,413 | Addressing Minority Stress and Mental Health among Men Who Have Sex with Men (MSM) in China | PURPOSE OF REVIEW: Men who have sex with men (MSM) in China experience elevated risks of mental health issues in comparison to the general population in China, which contribute to vulnerability to HIV/STI risks and can comprise the effectiveness of HIV prevention efforts. A conceptual framework for understanding this mental health disparity is minority stress theory, which posits that experiences of external prejudice events (i.e., distal stressors) and internal stress processes such as internalized homophobia and concealment (i.e., proximal stressors) contribute to sexual minorities’ elevated risk of psychological distress. To deepen the understanding of mental health among Chinese MSM and explore the potential utility of minority stress theory in this population, this paper synthesizes research evidence regarding prevalent mental health issues as well as how minority stress may be linked to psychological health in Chinese MSM. RECENT FINDINGS: Results indicate that Chinese MSM experience a high prevalence of several mental health issues including depression, anxiety, suicidal behaviors, and alcohol dependence. SUMMARY: This review further reveals minority stress to be an important determinant of psychological distress among Chinese MSM, though evidence is mixed regarding the relationship between proximal minority stress and psychological health. Nonetheless, there is a lack of mental health services and interventions focusing on MSM in China. Culturally relevant, competent, and LGBT-affirmative mental health interventions are needed for Chinese MSM. To guide future intervention research, we provide considerations for reducing minority stress and promoting psychological health among Chinese MSM. |
4,414 | Transpulmonary thermodilution detects rapid and reversible increases in lung water induced by positive end-expiratory pressure in acute respiratory distress syndrome | PURPOSE: It has been suggested that, by recruiting lung regions and enlarging the distribution volume of the cold indicator, increasing the positive end-expiratory pressure (PEEP) may lead to an artefactual overestimation of extravascular lung water (EVLW) by transpulmonary thermodilution (TPTD). METHODS: In 60 ARDS patients, we measured EVLW (PiCCO2 device) at a PEEP level set to reach a plateau pressure of 30 cmH(2)O (HighPEEP(start)) and 15 and 45 min after decreasing PEEP to 5 cmH(2)O (LowPEEP(15′) and LowPEEP(45′), respectively). Then, we increased PEEP back to the baseline level (HighPEEP(end)). Between HighPEEP(start) and LowPEEP(15′), we estimated the degree of lung derecruitment either by measuring changes in the compliance of the respiratory system (Crs) in the whole population, or by measuring the lung derecruited volume in 30 patients. We defined patients with a large derecruitment from the other ones as patients in whom the Crs changes and the measured derecruited volume were larger than the median of these variables observed in the whole population. RESULTS: Reducing PEEP from HighPEEP(start) (14 ± 2 cmH(2)O) to LowPEEP(15′) significantly decreased EVLW from 20 ± 4 to 18 ± 4 mL/kg, central venous pressure (CVP) from 15 ± 4 to 12 ± 4 mmHg, the arterial oxygen tension over inspired oxygen fraction (PaO(2)/FiO(2)) ratio from 184 ± 76 to 150 ± 69 mmHg and lung volume by 144 [68–420] mL. The EVLW decrease was similar in “large derecruiters” and the other patients. When PEEP was re-increased to HighPEEP(end), CVP, PaO(2)/FiO(2) and EVLW significantly re-increased. At linear mixed effect model, EVLW changes were significantly determined only by changes in PEEP and CVP (p < 0.001 and p = 0.03, respectively, n = 60). When the same analysis was performed by estimating recruitment according to lung volume changes (n = 30), CVP remained significantly associated to the changes in EVLW (p < 0.001). CONCLUSIONS: In ARDS patients, changing the PEEP level induced parallel, small and reversible changes in EVLW. These changes were not due to an artefact of the TPTD technique and were likely due to the PEEP-induced changes in CVP, which is the backward pressure of the lung lymphatic drainage. Trial registration ID RCB: 2015-A01654-45. Registered 23 October 2015 |
4,415 | Yeast display platform technology to prepare oral vaccine against lethal H7N9 virus challenge in mice | BACKGROUND: Existing methods for preparing influenza vaccines pose the greatest challenge against highly pandemic avian influenza H7N9 outbreak in the poultry and humans. Exploring a new strategy for manufacturing and delivering a safe and effective H7N9 vaccine is needed urgently. RESULTS: An alternative approach is to develop an influenza H7N9 oral vaccine based on yeast display technology in a timely manner. Hemagglutinin (HA) of A/Anhui/1/2013 (AH-H7N9) is used as a model antigen and characterized its expression on the surface of Saccharomyces cerevisiae (S.cerevisiae) EBY 100. Mice administrated orally with S.cerevisiae EBY100/pYD5-HA produced significant titers of IgG antibody as well as significant amounts of cytokines IFN-γ and IL-4. Importantly, S.cerevisiae EBY100/pYD5-HA could provide effective immune protection against homologous A/Anhui/1/2013 (AH-H7N9) virus challenge. CONCLUSIONS: Our findings suggest that platform based on yeast surface technology provides an alternative approach to prepare a promising influenza H7N9 oral vaccine candidate that can significantly shorten the preparedness period and result in effective protection against influenza A pandemic. |
4,416 | Microarray analyses reveal strain-specific antibody responses to Plasmodium falciparum apical membrane antigen 1 variants following natural infection and vaccination | Vaccines based on Plasmodium falciparum apical membrane antigen 1 (AMA1) have failed due to extensive polymorphism in AMA1. To assess the strain-specificity of antibody responses to malaria infection and AMA1 vaccination, we designed protein and peptide microarrays representing hundreds of unique AMA1 variants. Following clinical malaria episodes, children had short-lived, sequence-independent increases in average whole-protein seroreactivity, as well as strain-specific responses to peptides representing diverse epitopes. Vaccination resulted in dramatically increased seroreactivity to all 263 AMA1 whole-protein variants. High-density peptide analysis revealed that vaccinated children had increases in seroreactivity to four distinct epitopes that exceeded responses to natural infection. A single amino acid change was critical to seroreactivity to peptides in a region of AMA1 associated with strain-specific vaccine efficacy. Antibody measurements using whole antigens may be biased towards conserved, immunodominant epitopes. Peptide microarrays may help to identify immunogenic epitopes, define correlates of vaccine protection, and measure strain-specific vaccine-induced antibodies. |
4,417 | Comparison between watchful waiting strategy and early initiation of renal replacement therapy in the critically ill acute kidney injury population: an updated systematic review and meta-analysis | BACKGROUND: The optimal timing of renal replacement therapy (RRT) initiation is debatable. Many articles in this field enrolled trials not based on acute kidney injury. The safety of the watchful waiting strategy has not been fully discussed, and late RRT initiation criteria vary across studies. The effect of early RRT initiation in the AKI population with high plasma neutrophil gelatinase-associated lipocalin (NGAL) has not been examined yet. METHODS: In accordance with PRISMA guidelines, the PubMed, Embase, and Cochrane databases were systemically searched for randomized controlled trials (RCTs). Trials not conducted in the AKI population were excluded. Data of study characteristics, primary outcome (all-cause mortality), and related secondary outcomes [mechanical ventilation (MV) days, length of hospital stay, RRT days, and length of ICU stay] were extracted. The outcomes were compared between early and late RRT groups by estimating the pooled odds ratio (OR) for binary outcomes and the weighted mean difference for continuous outcomes. Prospective trials were also examined and analyzed using the same method. RESULTS: Nine RCTs with 1938 patients were included. Early RRT did not provide a survival benefit (pooled OR, 0.88; 95% confidence interval [CI] 0.62–1.27). However, the early RRT group had significantly fewer MV days (pooled mean difference, − 3.98 days; 95% CI − 7.81 to − 0.15 days). Subgroup analysis showed that RCTs enrolling the surgical population (P = .001) and the AKI population with high plasma NGAL (P = .031) had favorable outcomes regarding RRT days in the early initiation group. Moreover, 6 of 9 RCTs were selected for examining the safety of the watchful waiting strategy, and no significant differences were found in primary and secondary outcomes between the early and late RRT groups. CONCLUSIONS: Overall, early RRT initiation did not provide a survival benefit, but a possible benefit of fewer MV days was detected. Early RRT might also provide the benefit of shorter MV or RRT support in the surgical population and in AKI patients with high plasma NGAL. Depending on the conventional indication for RRT initiation, the watchful waiting strategy is safe on the basis of all primary and secondary outcomes. |
4,418 | Associations of osteopontin and NT-proBNP with circulating miRNA levels in acute coronary syndrome | The genomic regulatory networks underlying the pathogenesis of non-ST-segment elevation acute coronary syndrome (NSTE-ACS) are incompletely understood. As intermediate traits, protein biomarkers report on underlying disease severity and prognosis in NSTE-ACS. We hypothesized that integration of dense microRNA (miRNA) profiling with biomarker measurements would highlight potential regulatory pathways that underlie the relationships between prognostic biomarkers, miRNAs, and cardiovascular phenotypes. We performed miRNA sequencing using whole blood from 186 patients from the TRILOGY-ACS trial. Seven circulating prognostic biomarkers were measured: NH(2)-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein, osteopontin (OPN), myeloperoxidase, growth differentiation factor 15, monocyte chemoattractant protein, and neopterin. We tested miRNAs for association with each biomarker with generalized linear models and controlled the false discovery rate at 0.05. Ten miRNAs, including known cardiac-related miRNAs 25-3p and 423-3p, were associated with NT-proBNP levels (min. P = 7.5 × 10(−4)) and 48 miRNAs, including cardiac-related miRNAs 378a-3p, 20b-5p and 320a, -b, and -d, were associated with OPN levels (min. P = 1.6 × 10(−6)). NT-proBNP and OPN were also associated with time to cardiovascular death, myocardial infarction (MI), or stroke in the sample. By integrating large-scale miRNA profiling with circulating biomarkers as intermediate traits, we identified associations of known cardiac-related and novel miRNAs with two prognostic biomarkers and identified potential genomic networks regulating these biomarkers. These results, highlighting plausible biological pathways connecting miRNAs with biomarkers and outcomes, may inform future studies seeking to delineate genomic pathways underlying NSTE-ACS outcomes. |
4,419 | Bilateral ureteral obstruction is rapidly accompanied by ER stress and activation of autophagic degradation of IMCD proteins, including AQP2 | After the release of bilateral ureteral obstruction (BUO), postobstructive diuresis from an impaired urine concentration mechanism is associated with reduced aquaporin 2 (AQP2) abundance in the inner medullary collecting duct (IMCD). However, the underlying molecular mechanism of this AQP2 reduction is incompletely understood. To elucidate the mechanisms responsible for this phenomenon, we studied molecular changes in IMCDs isolated from rats with 4-h BUO or sham operation at the early onset of AQP2 downregulation using mass spectrometry-based proteomic analysis. Two-hundred fifteen proteins had significant changes in abundances, with 65% of them downregulated in the IMCD of 4-h BUO rats compared with sham rats. Bioinformatic analysis revealed that significantly changed proteins were associated with functional Gene Ontology terms, including “cell-cell adhesion,” “cell-cell adherens junction,” “mitochondrial inner membrane,” “endoplasmic reticulum chaperone complex,” and the KEGG pathway of glycolysis/gluconeogenesis. Targeted liquid chromatography-tandem mass spectrometry or immunoblot analysis confirmed the changes in 19 proteins representative of each predominant cluster, including AQP2. Electron microscopy demonstrated disrupted tight junctions, disorganized adherens junctions, swollen mitochondria, enlargement of the endoplasmic reticulum lumen, and numerous autophagosomes/lysosomes in the IMCD of rats with 4-h BUO. AQP2 and seven proteins chosen as representative of the significantly altered clusters had a significant increase in immunofluorescence-based colocalization with autophagosomes/lysosomes. Immunogold electron microscopy confirmed colocalization of AQP2 with the autophagosome marker microtubule-associated protein 1A/1B-light chain 3 and the lysosomal marker cathepsin D in IMCD cells of rats with 4-h BUO. We conclude that enhanced autophagic degradation of AQP2 and other critical proteins, as well as endoplasmic reticulum stress in the IMCD, are initiated shortly after BUO. |
4,420 | Development of a model care pathway for the management of Hymenoptera venom allergy: evidence-based key interventions and indicators | BACKGROUND: Hymenoptera venom allergy (HVA) is an underestimated condition representing an important cause of morbidity and mortality worldwide. Preventing future allergic reactions in patients who have already developed a systemic reaction is based on the correct management of the acute phase of the reaction followed by a correct diagnosis and, where indicated, prescription of adrenaline autoinjectors and VIT. A possible strategy to optimize care processes and to improve outcomes is the implementation of a Diagnostic and Therapeutic Care Pathways, also known as Integrated Care Pathways or Clinical Pathways (CPWs). The aim of the care pathway is to enhance the quality of care by improving risk‐adjusted patient outcomes, promoting patient safety, increasing patient satisfaction, and optimizing the use of resources. To our knowledge, currently in Italy as well as in Europe, there is no CPWs codified for the management of HVA patients. This paper describes the development of the clinical content of a care pathway for the management of HVA. METHODS: The methodology applied is based on the eight step method to build the clinical content of an evidence-based care pathway suggested by Lodewijckx et al. RESULTS: Three hundred and seventeen different clinical activities were extracted from the selected literature. The expert panel was involved in their evaluation, expressing a judgment of relevance through the Delphi study. As a result, 126 clinical activities were appraised to be valid and feasible. The final recommendations (126) were translated into 123 key interventions. Six indicators were produced by the clinical activities. CONCLUSION: A set of 123 key interventions and of six process indicators were found to be appropriate for the development and standardization of the clinical content of the Hymenoptera venom allergy care pathway. |
4,421 | Intractable mechanical hemolytic anemia complicating mitral valve surgery: a case series study | BACKGROUND: Intractable, mechanical hemolytic anemia (IMHA) is a rare catastrophic complication following mitral valve surgery. We analyzed patient characteristics and IMHA management by reoperations after mitral valve surgery. METHODS: We collected medical records from mitral valve patients requiring reoperation due to IMHA. Inclusion criteria: hemoglobin < 100 g/L; positive hemolysis tests and echocardiography results; and exclusion of other hemolysis causes. RESULTS: Data from 25 IMHA cases included 10 (40%) early onset (1.3 (0.3,3.0) months) and 15 (60%) late onset (120 (24,204) months) cases. Early IMHA etiologies included surgical defects (6, 60%), uncontrolled infection (3, 30%) and Bechet’s disease (1, 10%). Late IMHA etiologies included degeneration (13, 87%), new infection (1, 7%) and trauma (1, 7%). There were more mechanical valves (15, 88%) than bio-valves (2, 12%); the main valvular dysfunction was paravalvular leak (16, 64%). IMHA manifestations included jaundice (18, 72%), dark urine (21, 84%), heart failure (16, 64%), acute kidney injury (11, 44%), hepatomegaly (15, 60%), splenomegaly (15, 60%) and pancreatitis (1, 4%). Laboratory results showed decreased hemoglobin (70 ± 14 g/L) and increased bilirubin (72 ± 57 μmol/L), lactate dehydrogenase (2607 ± 2142 IU/L) and creatinine (136 ± 101 μmol/L) levels. Creatinine level negatively correlated with hemoglobin level (B = -3.33, S.E. B = 1.31, Exp(B) = 368.15, P = 0.018). Preoperative medications included iron supplements (20, 80%), erythropoietin (16, 64%) and beta-blocker (22, 88%). Two patients died of cardiac causes before reoperation. The other 23 underwent reoperation with long surgical times (aortic cross clamp 124 ± 50 min, cardiopulmonary bypass 182 ± 69 min) and blood transfusions (red blood cells 6 (6, 8) units, plasma 600 (400,800) ml, platelet 1(0,2) units). Postoperative complications included cardiac dysfunction (5, 22%), arrhythmia (10, 43%), sepsis (6, 26%), pulmonary infection (5, 22%), gastrointestinal bleeding (3, 13%), cerebral hemorrhage (2, 9%), chronic renal dysfunction (1, 4%) and surgical hemorrhage (1, 4%). Five (33%) patients died after reoperation from cardiac dysfunction (3, 60%), septic shock (1, 20%) and self-discharge (1, 20%). CONCLUSIONS: IMHA induces severe multi-organ dysfunction, contributing to high mortality. Perioperative management should focus on etiological treatment, organ protection, and blood management. |
4,422 | Identification of a novel base J binding protein complex involved in RNA polymerase II transcription termination in trypanosomes | Base J, β-D-glucosyl-hydroxymethyluracil, is a modification of thymine DNA base involved in RNA Polymerase (Pol) II transcription termination in kinetoplastid protozoa. Little is understood regarding how specific thymine residues are targeted for J-modification or the mechanism of J regulated transcription termination. To identify proteins involved in J-synthesis, we expressed a tagged version of the J-glucosyltransferase (JGT) in Leishmania tarentolae, and identified four co-purified proteins by mass spectrometry: protein phosphatase (PP1), a homolog of Wdr82, a potential PP1 regulatory protein (PNUTS) and a protein containing a J-DNA binding domain (named JBP3). Gel shift studies indicate JBP3 is a J-DNA binding protein. Reciprocal tagging, co-IP and sucrose gradient analyses indicate PP1, JGT, JBP3, Wdr82 and PNUTS form a multimeric complex in kinetoplastids, similar to the mammalian PTW/PP1 complex involved in transcription termination via PP1 mediated dephosphorylation of Pol II. Using RNAi and analysis of Pol II termination by RNA-seq and RT-PCR, we demonstrate that ablation of PNUTS, JBP3 and Wdr82 lead to defects in Pol II termination at the 3’-end of polycistronic gene arrays in Trypanosoma brucei. Mutants also contain increased antisense RNA levels upstream of transcription start sites, suggesting an additional role of the complex in regulating termination of bi-directional transcription. In addition, PNUTS loss causes derepression of silent Variant Surface Glycoprotein genes involved in host immune evasion. Our results suggest a novel mechanistic link between base J and Pol II polycistronic transcription termination in kinetoplastids. |
4,423 | Effects of a national quality improvement program on ICUs in China: a controlled pre-post cohort study in 586 hospitals | INTRODUCTION: Patient safety and critical care quality remain a challenging issue in the ICU. However, the effects of the national quality improvement (QI) program remain unknown in China. METHODS: A national ICU QI program was implemented in a controlled cohort of 586 hospitals from 2016 to 2018. The effects of the QI program on critical care quality were comprehensively investigated. MAIN RESULTS: A total of 81,461,554 patients were enrolled in 586 hospitals, and 1,587,724 patients were admitted to the ICU over 3 years. In 2018, there was a significantly higher number of ICU beds (2016 vs. 2018: 10668 vs. 13,661, P = 0.0132) but a lower doctor-to-bed ratio (2016 vs. 2018: 0.64 (0.50, 0.83) vs. 0.60 (0.45, 0.75), P = 0.0016) and nurse-to-bed ratio (2016 vs. 2018: 2.00 (1.64, 2.50) vs. 2.00 (1.50, 2.40), P = 0.031) than in 2016. Continuous and significant improvements in the ventilator-associated pneumonia (VAP) incidence rate, microbiology detection rate before antibiotic use and deep vein thrombosis (DVT) prophylaxis rate were associated with the implementation of the QI program (VAP incidence rate (per 1000 ventilator-days), 2016 vs. 2017 vs. 2018: 11.06 (4.23, 22.70) vs. 10.20 (4.25, 23.94) vs. 8.05 (3.13, 17.37), P = 0.0002; microbiology detection rate before antibiotic use (%), 2016 vs. 2017 vs. 2018: 83.91 (49.75, 97.87) vs. 84.14 (60.46, 97.24) vs. 90.00 (69.62, 100), P < 0.0001; DVT prophylaxis rate, 2016 vs. 2017 vs. 2018: 74.19 (33.47, 96.16) vs. 71.70 (38.05, 96.28) vs. 83.27 (47.36, 97.77), P = 0.0093). Moreover, the 6-h SSC bundle compliance rates in 2018 were significantly higher than those in 2016 (6-h SSC bundle compliance rate, 2016 vs. 2018: 64.93 (33.55, 93.06) vs. 76.19 (46.88, 96.67)). A significant change trend was not found in the ICU mortality rate from 2016 to 2018 (ICU mortality rate (%), 2016 vs. 2017 vs. 2018: 8.49 (4.42, 14.82) vs. 8.95 (4.89, 15.70) vs. 9.05 (5.12, 15.80), P = 0.1075). CONCLUSIONS: The relationship between medical human resources and ICU overexpansion was mismatched during the past 3 years. The implementation of a national QI program improved ICU performance but did not reduce ICU mortality. |
4,424 | Therapeutic iloprost for the treatment of acute respiratory distress syndrome (ARDS) (the ThIlo trial): a prospective, randomized, multicenter phase II study | BACKGROUND: Acute respiratory distress syndrome (ARDS) is caused by rapid-onset (within hours) acute inflammatory processes in lung tissue, and it is a life-threatening condition with high mortality. The treatment of ARDS to date is focused on the prevention of further iatrogenic damage of the lung rather than the treatment of the initial inflammatory process. Several preclinical studies have revealed a beneficial effect of iloprost on the control of pulmonary inflammation, and in a small number of patients with ARDS, iloprost treatment resulted in improved oxygenation. Therefore, we plan to conduct a large multicenter trial to evaluate the effect of iloprost on ARDS. METHODS: The Therapeutic Iloprost during ARDS trial (ThIlo trial) is a multicenter, randomized, single blinded, clinical phase II trial assessing the efficacy of inhaled iloprost for the prevention of the development and progression of ARDS in critically ill patients. One hundred fifty critically ill patients suffering from acute ARDS will be treated either by nebulized iloprost or NaCl 0.9% for 5 days. Blood samples will be drawn at defined time points to elucidate the serum levels of iloprost and inflammatory markers during treatment. Mechanical ventilation will be standardized. In follow-up visits at days 28 and 90 as well as 6 months after enrollment, functional status according to the Barthel Index and a health care-related questionnaire, and frailty (Vulnerable Elders Survey) will be evaluated. The primary endpoint is the improvement of oxygenation, defined as the ratio of PaO(2)/FiO(2). Secondary endpoints include 90-day all-cause mortality, Sequential Organ Failure Assessment scores during the study period up to day 90, the duration of mechanical ventilation, the length of intensive care unit (ICU) stay, ventilator-associated pneumonia, delirium, ICU-acquired weakness, and discharge localization. The study will be conducted in three university ARDS centers in Germany. DISCUSSION: The results of the ThIlo trial will highlight the anti-inflammatory effect of iloprost on early inflammatory processes during ARDS, resulting in the improvement of outcome parameters in patients with ARDS. TRIAL REGISTRATION: EUDRA-CT: 2016-003168-37. Registered on 12 April 2017. ClinicalTrials.gov: NCT03111212. Registered on 4 June 2017. |
4,425 | Animal sources for zoonotic transmission of psittacosis: a systematic review | BACKGROUND: Human psittacosis, caused by Chlamydia (C.) psittaci, is likely underdiagnosed and underreported, since tests for C. psittaci are often not included in routine microbiological diagnostics. Source tracing traditionally focuses on psittacine pet birds, but recently other animal species have been gaining more attention as possible sources for human psittacosis. This review aims to provide an overview of all suspected animal sources of human psittacosis cases reported in the international literature. In addition, for each animal species the strength of evidence for zoonotic transmission was estimated. METHODS: A systematic literature search was conducted using four databases (Pubmed, Embase, Scopus and Proquest). Articles were included when there was mention of at least one human case of psittacosis and a possible animal source. Investigators independently extracted data from the included articles and estimated strength of evidence for zoonotic transmission, based on a self-developed scoring system taking into account number of human cases, epidemiological evidence and laboratory test results in human, animals, and the environment. RESULTS: Eighty articles were included, which provided information on 136 different situations of possible zoonotic transmission. The maximum score for zoonotic transmission was highest for turkeys, followed by ducks, owls, and the category ‘other poultry’. Articles reporting about zoonotic transmission from unspecified birds, psittaciformes and columbiformes provided a relatively low strength of evidence. A genotypical match between human and animal samples was reported twenty-eight times, including transmission from chickens, turkeys, guinea fowl, peafowl, pigeons, ducks, geese, songbirds, parrot-like birds and owls. CONCLUSIONS: Strong evidence exists for zoonotic transmission from turkeys, chickens and ducks, in addition to the more traditionally reported parrot-like animal sources. Based on our scoring system, the evidence was generally stronger for poultry than for parrot-like birds. Psittaciformes should not be disregarded as an important source of human psittacosis, still clinicians and public health officials should include poultry and birds species other than parrots in medical history and source tracing. |
4,426 | Efficacy, immunogenicity, and safety of IC43 recombinant Pseudomonas aeruginosa vaccine in mechanically ventilated intensive care patients—a randomized clinical trial | BACKGROUND: Pseudomonas aeruginosa infections are a serious threat in intensive care units (ICUs). The aim of this confirmatory, randomized, multicenter, placebo-controlled, double-blind, phase 2/3 study was to assess the efficacy, immunogenicity, and safety of IC43 recombinant Pseudomonas aeruginosa vaccine in non-surgical ICU patients. METHODS: Eight hundred patients aged 18 to 80 years admitted to the ICU with expected need for mechanical ventilation for ≥ 48 h were randomized 1:1 to either IC43 100 μg or saline placebo, given in two vaccinations 7 days apart. The primary efficacy endpoint was all-cause mortality in patients 28 days after the first vaccination. Immunogenicity and safety were also evaluated. FINDINGS: All-cause mortality rates at day 28 were 29.2% vs 27.7% in the IC43 and placebo groups, respectively (P = .67). Overall survival (Kaplan-Meier survival estimates, P = .46) and proportion of patients with ≥ one confirmed P. aeruginosa invasive infection or respiratory tract infection also did not differ significantly between both groups. The geometric mean fold increase in OprF/I titers was 1.5 after the first vaccination, 20 at day 28, after the second vaccination, and 2.9 at day 180. Significantly more patients in the placebo group (96.5%) had ≥ one adverse event (AE) versus the IC43 100 μg group (93.1%) (P = .04). The most frequently reported severe AEs in the IC43 and placebo groups were respiratory failure (6.9% vs 5.7%, respectively), septic shock (4.1% vs 6.5%), cardiac arrest (4.3% vs 5.7%), multiorgan failure (4.6% vs 5.5%), and sepsis (4.6% vs 4.2%). No related serious AEs were reported in the IC43 group. INTERPRETATION: The IC43 100 μg vaccine was well tolerated in this large population of medically ill, mechanically ventilated patients. The vaccine achieved high immunogenicity but provided no clinical benefit over placebo in terms of overall mortality. TRIAL REGISTRATION: https://clinicaltrials.gov (NCT01563263). Registration was sent to ClinicalTrials.gov on March 14, 2012, but posted by ClinicalTrials.gov on March 26, 2012. The first subject was included in the trial on March 22, 2012. |
4,427 | Quality indicators for patients with traumatic brain injury in European intensive care units: a CENTER-TBI study | BACKGROUND: The aim of this study is to validate a previously published consensus-based quality indicator set for the management of patients with traumatic brain injury (TBI) at intensive care units (ICUs) in Europe and to study its potential for quality measurement and improvement. METHODS: Our analysis was based on 2006 adult patients admitted to 54 ICUs between 2014 and 2018, enrolled in the CENTER-TBI study. Indicator scores were calculated as percentage adherence for structure and process indicators and as event rates or median scores for outcome indicators. Feasibility was quantified by the completeness of the variables. Discriminability was determined by the between-centre variation, estimated with a random effect regression model adjusted for case-mix severity and quantified by the median odds ratio (MOR). Statistical uncertainty of outcome indicators was determined by the median number of events per centre, using a cut-off of 10. RESULTS: A total of 26/42 indicators could be calculated from the CENTER-TBI database. Most quality indicators proved feasible to obtain with more than 70% completeness. Sub-optimal adherence was found for most quality indicators, ranging from 26 to 93% and 20 to 99% for structure and process indicators. Significant (p < 0.001) between-centre variation was found in seven process and five outcome indicators with MORs ranging from 1.51 to 4.14. Statistical uncertainty of outcome indicators was generally high; five out of seven had less than 10 events per centre. CONCLUSIONS: Overall, nine structures, five processes, but none of the outcome indicators showed potential for quality improvement purposes for TBI patients in the ICU. Future research should focus on implementation efforts and continuous reevaluation of quality indicators. TRIAL REGISTRATION: The core study was registered with ClinicalTrials.gov, number NCT02210221, registered on August 06, 2014, with Resource Identification Portal (RRID: SCR_015582). |
4,428 | Trends in microbial profile of burn patients following an event of dust explosion at a tertiary medical center | BACKGROUND: Microbial infection is the main cause of increased morbidity and mortality in burn patients, especially infections caused by multiple drug-resistant organisms (MDRO). The purpose of this study was to explore major microbial trends in burn patients. METHODS: This retrospective study was conducted at burn wards and intensive care units, where burn patients were admitted following an event of dust explosion. Data were collected for a number of variables including severity of burns, demographic and clinical characteristics, laboratory data, and therapeutic devices. RESULTS: A total of 1132 specimens were collected from 37 hospitalized burn patients with mean TBSA of 46.1%.The most commonly isolated species were Staphylococcus spp. (22.4%). The highest rate of antibiotic resistance was observed in carbapenem–resistant A. baumannii (14.6%), followed by methicillin-resistant S. aureus (11.3%). For each additional 10% TBSA, the isolation of MDRO increased 2.58–17.57 times (p < 0.05); for each additional 10% of the third-degree burn severity, the risk of MDRO significantly decreased by 47% (95% CI, 0.38–0.73, p < 0.001) by Cox model. CONCLUSIONS: The proportion of overall microbial isolates increased with the increase in TBSA and duration of time after burns. The extent of TBSA was the most important factor affecting MDRO. |
4,429 | Identification of Linear B-Cell Epitopes on Hemagglutinin Protein of Canine Distemper Virus Using Two Monoclonal Antibodies | Canine distemper virus (CDV) belongs to the Morbillivirus genus of the Paramyxoviridae family, which causes a threat to the domestic dog and fur-animal industry. Hemagglutinin protein is a major membrane protein of the vital molecular factor in CDV tropism, also known to induce hosts to produce neutralizing antibodies. In the current study, we prepared two monoclonal antibodies, 1A5 and 2B8, against the H protein of the CDV-PS strain. A series of partially overlapping synthetic peptides covering the hemagglutinin protein (amino acids 50–204) were screened to define the linear epitope identified by 1A5 and 2B8 mAbs. (120)QKTNFFNPNREFDFR(134) (F8) and (178)ARGDIFPPY(186) (F14-1) are minimal linear epitopes recognized by 1A5 and 2B8 mAbs, respectively. Further investigations revealed that F8 is conserved in different CDV strains; however, F14-1 contains mutant residues 178, 179, and 180. The epitopes F8 and F14-1 localized at the surface of hemagglutinin protein in a three-dimensional (3D) structure. CDV-infected dog serum can also recognize the identified B-cell epitopes. |
4,430 | Thoracic fluid content: a novel parameter for predicting failed weaning from mechanical ventilation | BACKGROUND: Weaning of patients from the mechanical ventilation remains one of the critical decisions in intensive care unit. This study aimed to evaluate the accuracy of thoracic fluid content (TFC) as a predictor of weaning outcome. METHODS: An observational cohort study included 64 critically ill surgical patients who were eligible for extubation. Before initiating the spontaneous breathing trial, the TFC was measured using the electrical cardiometry technology. Patients were followed up after extubation and divided into successful weaning group and failed weaning group. Both groups were compared according to respiratory and cardiovascular parameters. Receiver operating characteristic (ROC) curves were constructed to evaluate the ability of TFC to predict weaning outcome. RESULTS: The number of successfully weaned patients was 41/64 (64%). Twenty (31%) patients had impaired cardiac contractility, and of them, 13/20 (64%) patients were successfully extubated. Both groups, successful weaning group and failed weaning group, were comparable in most of baseline characteristics; however, the TFC was significantly higher in the failed weaning group compared to the successful weaning group. The area under the ROC curves (AUCs) showed moderate predictive ability for the TFC in predicting weaning failure (AUC [95% confidence interval] 0.69 [0.57–0.8], cutoff value > 50 kΩ(−1)), while the predictive ability of TFC was excellent in the subgroup of patients with ejection fraction < 40% (AUC [95% confidence interval 0.93 [0.72–1], cutoff value > 50 kΩ(−1)). CONCLUSIONS: Thoracic fluid content showed moderate ability for predicting weaning outcome in surgical critically ill patients. However, in the subgroup of patients with ejection fraction less than 40%, TFC above 50 kΩ(−1) has an excellent ability to predict weaning failure. |
4,431 | Public-private knowledge transfer and access to medicines: a systematic review and qualitative study of perceptions and roles of scientists involved in HPV vaccine research | BACKGROUND: Public research organizations and their interactions with industry partners play a crucial role for public health and access to medicines. The development and commercialization of the Human Papillomavirus (HPV) vaccines illustrate how licensing practices of public research organizations can contribute to high prices of the resulting product and affect accessibility to vulnerable populations. Efforts by the international community to improve access to medicines have recognised this issue and promote the public health-sensitive management of research conducted by public research organizations. This paper explores: how medical knowledge is exchanged between public and private actors; what role inventor scientists play in this process; and how they view the implementation of public health-sensitive knowledge exchange strategies. METHODS: We conducted a systematic qualitative literature review on medical knowledge exchange and qualitative interviews with a purposive sample of public sector scientists working on HPV vaccines. We explored the strategies by which knowledge is exchanged across institutional boundaries, how these strategies are negotiated, and the views of scientists regarding public health-sensitive knowledge exchange. RESULTS: We included 13 studies in the systematic review and conducted seven semi-structured interviews with high-ranking scientists. The main avenues of public-private medical knowledge exchange were publications, formal transfer of patented knowledge, problem-specific exchanges such as service agreements, informal exchanges and collaborative research. Scientists played a crucial role in these processes but appeared to be sceptical of public health-sensitive knowledge exchange strategies, as these were believed to deter corporate interest in the development of new medicines and thus risk the translation of the scientists’ research. CONCLUSION: Medical scientists at public research institutions play a key role in the exchange of knowledge they generate and are concerned about the accessibility of medicines resulting from their research. Their scepticism towards implementing public health-sensitive knowledge management strategies appears to be based on a biased understanding of the costs and risks involved in drug development and a perceived lack of alternatives to private engagement. Scientists could be encouraged to exchange knowledge in a public health-sensitive manner through not-for-profit drug development mechanisms, education on industry engagement, and stronger institutional and legal backing. |
4,432 | Application of the respiratory “critical care-sub-critical care-rehabilitation integrated management model” in severe stroke associated pneumonia | BACKGROUND: This study aimed to explore the feasibility of applying the respiratory “critical care-sub-critical care-rehabilitation integrated management model” in severe stroke-associated pneumonia and evaluate its effect. METHODS: From January to September 2018, 24 patients with severe stroke-associated pneumonia, who were admitted to the Respiratory Intensive Care Unit of the Respiratory and Critical Care Medicine Department of Henan Provincial People’s Hospital, were randomly divided into two groups: integrated management group and control group. According to the admission criteria of the respiratory “critical care-sub-critical care-rehabilitation integrated model” prescribed by the above-mentioned hospital, patients were grouped. The professional respiratory therapy team participated in the whole treatment. The acute physiology and chronic health evaluation II (APACHE II) score, clinical pulmonary infection score (CPIS) and oxygenation index of these two groups were dynamically observed, and the average hospital stay, 28-day mortality and patient satisfaction were investigated. RESULTS: Patients in the integrated management group and control group were similar before treatment (P > 0.05). After treatment, the main indicators, the APACHE II score, CPIS score and oxygenation index, were significantly different between the integration group and control group (P < 0.05). The secondary indicators, the average hospitalization days and patient/family member satisfaction scores, were also significantly different between the integration group and control group (P < 0.05). However, the 28-day mortality wasn’t significantly different (P > 0.05). CONCLUSIONS: For patients with severe stroke-associated pneumonia, it was feasible to implement the respiratory “critical care-sub-critical care-rehabilitation integrated management model”, which could significantly improve the treatment effect, shorten average hospitalization days and improve patient/family satisfaction. |
4,433 | A comprehensive and comparative phenotypic analysis of the collaborative founder strains identifies new and known phenotypes | The collaborative cross (CC) is a large panel of mouse-inbred lines derived from eight founder strains (NOD/ShiLtJ, NZO/HILtJ, A/J, C57BL/6J, 129S1/SvImJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ). Here, we performed a comprehensive and comparative phenotyping screening to identify phenotypic differences and similarities between the eight founder strains. In total, more than 300 parameters including allergy, behavior, cardiovascular, clinical blood chemistry, dysmorphology, bone and cartilage, energy metabolism, eye and vision, immunology, lung function, neurology, nociception, and pathology were analyzed; in most traits from sixteen females and sixteen males. We identified over 270 parameters that were significantly different between strains. This study highlights the value of the founder and CC strains for phenotype-genotype associations of many genetic traits that are highly relevant to human diseases. All data described here are publicly available from the mouse phenome database for analyses and downloads. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00335-020-09827-3) contains supplementary material, which is available to authorized users. |
4,434 | Optimal mean airway pressure during high-frequency oscillatory ventilation in an experimental model of acute respiratory distress syndrome: EIT-based method | BACKGROUND: High-frequency oscillatory ventilation (HFOV) may theoretically provide lung protective ventilation. The negative clinical results may be due to inadequate mean airway pressure (mPaw) settings in HFOV. Our objective was to evaluate the air distribution, ventilatory and hemodynamic effects of individual mPaw titration during HFOV in ARDS animal based on oxygenation and electrical impedance tomography (EIT). METHODS: ARDS was introduced with repeated bronchoalveolar lavage followed by injurious mechanical ventilation in ten healthy male pigs (51.2 ± 1.9 kg). Settings of HFOV were 9 Hz (respiratory frequency), 33% (inspiratory time) and 70 cmH(2)O (∆pressure). After lung recruitment, the mPaw was reduced in steps of 3 cmH(2)O every 6 min. Hemodynamics and blood gases were obtained in each step. Regional ventilation distribution was determined with EIT. RESULTS: PaO(2)/FiO(2) decreased significantly during the mPaw decremental phase (p < 0.001). Lung overdistended regions decreased, while recruitable regions increased as mPaw decreased. The optimal mPaw with respect to PaO(2)/FiO(2) was 21 (18.0–21.0) cmH(2)O, that is comparable to EIT-based center of ventilation (EIT-CoV) and EIT-collapse/over, 19.5 (15.0–21.0) and 19.5 (18.0–21.8), respectively (p = 0.07). EIT-CoV decreasing along with mPaw decrease revealed redistribution toward non-dependent regions. The individual mPaw titrated by EIT-based indices improved regional ventilation distribution with respect to overdistension and collapse (p = 0.035). CONCLUSION: Our data suggested personalized optimal mPaw titration by EIT-based indices improves regional ventilation distribution and lung homogeneity during high-frequency oscillatory ventilation. |
4,435 | Approaches to overcome flow cytometry limitations in the analysis of cells from veterinary relevant species | BACKGROUND: Flow cytometry is a powerful tool for the multiparameter analysis of leukocyte subsets on the single cell level. Recent advances have greatly increased the number of fluorochrome-labeled antibodies in flow cytometry. In particular, an increase in available fluorochromes with distinct excitation and emission spectra combined with novel multicolor flow cytometers with several lasers have enhanced the generation of multidimensional expression data for leukocytes and other cell types. However, these advances have mainly benefited the analysis of human or mouse cell samples given the lack of reagents for most animal species. The flow cytometric analysis of important veterinary, agricultural, wildlife, and other animal species is still hampered by several technical limitations, even though animal species other than the mouse can serve as more accurate models of specific human physiology and diseases. RESULTS: Here we present time-tested approaches that our laboratory regularly uses in the multiparameter flow cytometric analysis of ovine leukocytes. The discussed approaches will be applicable to the analysis of cells from most animal species and include direct modification of antibodies by covalent conjugation or Fc-directed labeling (Zenon™ technology), labeled secondary antibodies and other second step reagents, labeled receptor ligands, and antibodies with species cross-reactivity. CONCLUSIONS: Using refined technical approaches, the number of parameters analyzed by flow cytometry per cell sample can be greatly increased, enabling multidimensional analysis of rare samples and giving critical insight into veterinary and other less commonly analyzed species. By maximizing information from each cell sample, multicolor flow cytometry can reduce the required number of animals used in a study. |
4,436 | Predicting the microbial cause of community-acquired pneumonia: can physicians or a data-driven method differentiate viral from bacterial pneumonia at patient presentation? | BACKGROUND: Community-acquired pneumonia (CAP) requires urgent and specific antimicrobial therapy. However, the causal pathogen is typically unknown at the point when anti-infective therapeutics must be initiated. Physicians synthesize information from diverse data streams to make appropriate decisions. Artificial intelligence (AI) excels at finding complex relationships in large volumes of data. We aimed to evaluate the abilities of experienced physicians and AI to answer this question at patient admission: is it a viral or a bacterial pneumonia? METHODS: We included patients hospitalized for CAP and recorded all data available in the first 3-h period of care (clinical, biological and radiological information). For this proof-of-concept investigation, we decided to study only CAP caused by a singular and identified pathogen. We built a machine learning model prediction using all collected data. Finally, an independent validation set of samples was used to test the pathogen prediction performance of: (i) a panel of three experts and (ii) the AI algorithm. Both were blinded regarding the final microbial diagnosis. Positive likelihood ratio (LR) values > 10 and negative LR values < 0.1 were considered clinically relevant. RESULTS: We included 153 patients with CAP (70.6% men; 62 [51–73] years old; mean SAPSII, 37 [27–47]), 37% had viral pneumonia, 24% had bacterial pneumonia, 20% had a co-infection and 19% had no identified respiratory pathogen. We performed the analysis on 93 patients as co-pathogen and no-pathogen cases were excluded. The discriminant abilities of the AI approach were low to moderate (LR+ = 2.12 for viral and 6.29 for bacterial pneumonia), and the discriminant abilities of the experts were very low to low (LR+ = 3.81 for viral and 1.89 for bacterial pneumonia). CONCLUSION: Neither experts nor an AI algorithm can predict the microbial etiology of CAP within the first hours of hospitalization when there is an urgent need to define the anti-infective therapeutic strategy. |
4,437 | PPARγ and Its Agonists in Chronic Kidney Disease | Chronic kidney disease (CKD) has become a global healthcare issue. CKD can progress to irreversible end-stage renal diseases (ESRD) or renal failure. The major risk factors for CKD include obesity, diabetes, and cardiovascular diseases. Understanding the key process involved in the disease development may lead to novel interventive strategies, which is currently lagging behind. Peroxisome proliferator-activated receptor γ (PPARγ) is one of the ligand-activated transcription factor superfamily members and is globally expressed in human tissues. Its agonists such as thiazolidinediones (TZDs) have been applied as effective antidiabetic drugs as they control insulin sensitivity in multiple metabolic tissues. Besides, TZDs exert protective effects in multiple other CKD risk disease contexts. As PPARγ is abundantly expressed in major kidney cells, its physiological roles in those cells have been studied in both cell and animal models. The function of PPARγ in the kidney ranges from energy metabolism, cell proliferation to inflammatory suppression, although major renal side effects of existing agonists (including TZDs) have been reported, which limited their application in treating CKD. In the current review, we systemically assess the function of PPARγ in CKDs and the benefits and current limitations of its agonists in the clinical applications. |
4,438 | Yeast Infections after Esophagectomy: A Retrospective Analysis | Esophageal malignancy is a disease with poor prognosis. Curative therapy incorporates surgery and is burdensome with high rates of infection morbidity and mortality. The role of yeast as causative organisms of post-esophagectomy infections is poorly defined. Consequently, the benefits of specific antifungal prophylactic therapy in improving patient outcome are unclear. Therefore, this study aimed at investigating the incidence of yeast infections at the University Medical Center Groningen among 565 post-esophagectomy patients between 1991 and 2017. The results show that 7.3% of the patients developed a yeast infection after esophageal resection with significantly increased incidence among patients suffering from diabetes mellitus. For patients with yeast infections, higher Acute Physiology and Chronic Health Evaluation (APACHE) II scores, more frequent intensive care unit readmissions, prolonged hospital stays and higher mortality rates were observed. One-year survival was significantly lower for patients with a yeast infection, as well as diabetes mellitus and yeast-positive pleural effusion. We conclude that the incidence of yeast infections following esophagectomy is considerable, and that patients with diabetes mellitus are at increased risk. Furthermore, yeast infections are associated with higher complication rates and mortality. These observations encourage further prospective investigations on the possible benefits of antifungal prophylactic therapy for esophagectomy patients. |
4,439 | An ultralong CDRH2 in HCV neutralizing antibody demonstrates structural plasticity of antibodies against E2 glycoprotein | A vaccine protective against diverse HCV variants is needed to control the HCV epidemic. Structures of E2 complexes with front layer-specific broadly neutralizing antibodies (bNAbs) isolated from HCV-infected individuals, revealed a disulfide bond-containing CDRH3 that adopts straight (individuals who clear infection) or bent (individuals with chronic infection) conformation. To investigate whether a straight versus bent disulfide bond-containing CDRH3 is specific to particular HCV-infected individuals, we solved a crystal structure of the HCV E2 ectodomain in complex with AR3X, a bNAb with an unusually long CDRH2 that was isolated from the chronically-infected individual from whom the bent CDRH3 bNAbs were derived. The structure revealed that AR3X utilizes both its ultralong CDRH2 and a disulfide motif-containing straight CDRH3 to recognize the E2 front layer. These results demonstrate that both the straight and bent CDRH3 classes of HCV bNAb can be elicited in a single individual, revealing a structural plasticity of VH1-69-derived bNAbs. |
4,440 | Can Surgical Apgar Score (SAS) Predict Postoperative Complications in Patients Undergoing Gynecologic Oncological Surgery? | Surgeons constantly try to achieve optimal surgical outcome, number, or extent of postoperative complications being an important part of it. Oncological surgeries are conventionally more challenging and complex compared with most nononcological ones. Gawande et al. devised SAS in 2007 in Boston as a predictor tool for postoperative complications (J Am Coll Surg 204:201–208, 2007). A validation study was done by in another cohort of 100 patients; however, only 70% of them had pathologically confirmed malignancies (Ann Surg 240(2):205–213, 2004). We attempt to assess SAS as a tool to predict postoperative complications in a series of 100 gynecological oncological patients operated at tertiary care center. SAS score of 100 patients with gynecologic malignancies, undergoing surgery at a tertiary care center, was prospectively collected over 4 years. These patients were observed for development of any complications occurring up to 30 days postsurgery. The complication events were graded as per Clavien-Dindo classification (Indian J Gynecol Oncolog 15:49, 2017). The data obtained was statistically analyzed by chi-square test. Thirty complication events were recorded in these 100 patients over a period of 4 years. Majority of complication events were grade IIIa or less (22 out of 30); there was only one death on 8th postoperative day. Fifty percent of patients were with SAS score of 5 or less developed complications compared with just 22.9% in patients with a score of 6 or more. Lower SAS score might be associated with higher postoperative complications in patients undergoing gynecologic oncological surgeries. Thus, patients with lower scores may benefit from a triage to more intensive postoperative care. |
4,441 | Vaccine-Induced Th1-Type Response Protects against Invasive Group A Streptococcus Infection in the Absence of Opsonizing Antibodies | Recent global advocacy efforts have highlighted the importance of development of a vaccine against group A Streptococcus (GAS). Combo5 is a non-M protein-based vaccine that provides protection against GAS skin infection in mice and reduces the severity of pharyngitis in nonhuman primates. However, Combo5 with the addition of aluminum hydroxide (alum) as an adjuvant failed to protect against invasive GAS infection of mice. Here, we show that formulation of Combo5 with adjuvants containing saponin QS21 significantly improves protective efficacy, even though all 7 adjuvants tested generated high antigen-specific IgG antibody titers, including alum. Detailed characterization of Combo5 formulated with SMQ adjuvant, a squalene-in-water emulsion containing a TLR4 agonist and QS21, showed significant differences from the results obtained with alum in IgG subclasses generated following immunization, with an absence of GAS opsonizing antibodies. SMQ, but not alum, generated strong interleukin-6 (IL-6), gamma interferon (IFN-γ), and tumor necrosis alpha (TNF-α) responses. This work highlights the importance of adjuvant selection for non-M protein-based GAS vaccines to optimize immune responses and protective efficacy. |
4,442 | The Multifunctional Long-Distance Movement Protein of Pea Enation Mosaic Virus 2 Protects Viral and Host Transcripts from Nonsense-Mediated Decay | The nonsense-mediated decay (NMD) pathway presents a challenge for RNA viruses with termination codons that precede extended 3′ untranslated regions (UTRs). The umbravirus Pea enation mosaic virus 2 (PEMV2) is a nonsegmented, positive-sense RNA virus with an unusually long 3′ UTR that is susceptible to NMD. To establish a systemic infection, the PEMV2 long-distance movement protein p26 was previously shown to both stabilize viral RNAs and bind them for transport through the plant’s vascular system. The current study demonstrated that p26 protects both viral and nonviral messenger RNAs from NMD. Although p26 localizes to both the cytoplasm and nucleolus, p26 exerts its anti-NMD effects exclusively in the cytoplasm independently of long-distance movement. Using a transcriptome-wide approach in the model plant Nicotiana benthamiana, p26 protected a subset of cellular NMD target transcripts, particularly those containing long, structured, GC-rich 3′ UTRs. Furthermore, transcriptome sequencing (RNA-seq) revealed that the NMD pathway is highly dysfunctional during PEMV2 infection, with 1,820 (48%) of NMD targets increasing in abundance. Widespread changes in the host transcriptome are common during plant RNA virus infections, and these results suggest that, in at least some instances, virus-mediated NMD inhibition may be a major contributing factor. |
4,443 | Scalp eschar and neck lymphadenopathy after tick bite (SENLAT) caused by Bartonella henselae in Korea: a case report | BACKGROUND: Tick-borne lymphadenopathy (TIBOLA) is an infectious disease, mainly caused by species from the spotted fever group rickettsiae and is characterized by enlarged lymph nodes following a tick bite. Among cases of TIBOLA, a case of scalp eschar and neck lymphadenopathy after tick bite (SENLAT) is diagnosed when an eschar is present on the scalp, accompanied by peripheral lymphadenopathy (LAP). Only a few cases of SENLAT caused by Bartonella henselae have been reported. CASE PRESENTATION: A 58-year-old male sought medical advice while suffering from high fever and diarrhea. Three weeks before the visit, he had been hunting a water deer, and upon bringing the deer home discovered a tick on his scalp area. Symptoms occurred one week after hunting, and a lump was palpated on the right neck area 6 days after the onset of symptoms. Physical examination upon presentation confirmed an eschar-like lesion on the right scalp area, and cervical palpation revealed that the lymph nodes on the right side were non-painful and enlarged at 2.5 × 1.5 cm. Fine needle aspiration of the enlarged lymph nodes was performed, and results of nested PCR for the Bartonella internal transcribed spacer (ITS) confirmed B. henselae as the causative agent. CONCLUSION: With an isolated case of SENLAT and a confirmation of B. henselae in Korea, it is pertinent to raise awareness to physicians in other Asian countries that B. henselae could be a causative agent for SENLAT. |
4,444 | Status and gaps of research on respiratory disease pathogens of swine in Africa | Over the last two decades, the pig population in Africa has grown rapidly, reflecting the increased adoption of pig production as an important economic activity. Of all species, pigs are likely to constitute a greater share of the growth in the livestock subsector. However, constraints such as respiratory infectious diseases cause significant economic losses to the pig industry worldwide. Compared to industrialized countries, the occurrence and impacts of respiratory diseases on pig production in Africa is under-documented. Hence, knowledge on prevalence and incidence of economically important swine respiratory pathogens in pigs in Africa is necessary to guide interventions for prevention and control. The purpose of this review was to document the current status of research on five important respiratory pathogens of swine in Africa to inform future research and interventions. The pathogens included were porcine reproductive and respiratory syndrome virus (PPRSv), porcine circovirus 2 (PCV2), Mycoplasma hyopneumoniae (M. hyopneumoniae), Actinobacillus pleuropneumoniae (APP) and swine influenza A viruses (IAV). For this review, published articles were obtained using Harzing’s Publish or Perish software tool from GoogleScholar. Articles were also sourced from PubMed, ScienceDirect, FAO and OIE websites. The terms used for the search were Africa, swine or porcine, respiratory pathogens, M. hyopneumoniae, APP, PCV2, PPRSv, IAV, prevention and control. In all, 146 articles found were considered relevant, and upon further screening, only 85 articles were retained for the review. The search was limited to studies published from 2000 to 2019. Of all the studies that documented occurrence of the five respiratory pathogens, most were on IAV (48.4%, n = 15), followed by PCV2 (25.8%, n = 8), PPRSv (19.4%, n = 6), while only one study (3.2%, n = 1) reported APP and M. hyopneumoniae. This review highlights knowledge and information gaps on epidemiologic aspects as well as economic impacts of the various pathogens reported in swine in Africa, which calls for further studies. |
4,445 | Molecular characterization of Brazilian wild-type strains of bovine respiratory syncytial virus reveals genetic diversity and a putative new subgroup of the virus | Background: Bovine orthopneumovirus, formerly known as bovine respiratory syncytial virus (BRSV), is frequently associated with bovine respiratory disease (BRD). Aim: To perform the molecular characterization of the G and F proteins of Brazilian wild-type BRSV strains derived from bovine respiratory infections in both beef and dairy cattle. Materials and Methods: Ten BRSV strains derived from a dairy heifer rearing unit (n = 3) in 2011 and steers of three other feedlots (n = 7) in 2014 and 2015 were analyzed. For the BRSV G and F partial gene amplifications, RT-nested-PCR assays were performed with sequencing in both directions with forward and reverse primers used. Results: The G gene-based analysis revealed that two strains were highly similar to the BRSV sequences representative of subgroup III, including the Bayovac vaccine strain. However, the remaining seven Brazilian BRSV strains were diverse when compared with strains representative of the BRSV I to VIII subgroups. The central hydrophobic region of the Brazilian BRSV G gene showed the replacement of conserved cysteines and other residues of importance to antibody reactivity. The deduced F gene amino acid sequences from the Brazilian BRSV strains showed changes that were absent in the representative sequences of the known subgroups. Viral isolation on the nasopharyngeal swab suspensions failed to isolate BRSV. Conclusion: Results suggest that these strains represent a putative new subgroup of BRSV with mutations observed in the immunodominant region of the G protein. However, further studies on these Brazilian BRSV strains should be performed to establish their pathogenic potential. |
4,446 | The impact of news exposure on collective attention in the United States during the 2016 Zika epidemic | In recent years, many studies have drawn attention to the important role of collective awareness and human behaviour during epidemic outbreaks. A number of modelling efforts have investigated the interaction between the disease transmission dynamics and human behaviour change mediated by news coverage and by information spreading in the population. Yet, given the scarcity of data on public awareness during an epidemic, few studies have relied on empirical data. Here, we use fine-grained, geo-referenced data from three online sources—Wikipedia, the GDELT Project and the Internet Archive—to quantify population-scale information seeking about the 2016 Zika virus epidemic in the U.S., explicitly linking such behavioural signal to epidemiological data. Geo-localized Wikipedia pageview data reveal that visiting patterns of Zika-related pages in Wikipedia were highly synchronized across the United States and largely explained by exposure to national television broadcast. Contrary to the assumption of some theoretical epidemic models, news volume and Wikipedia visiting patterns were not significantly correlated with the magnitude or the extent of the epidemic. Attention to Zika, in terms of Zika-related Wikipedia pageviews, was high at the beginning of the outbreak, when public health agencies raised an international alert and triggered media coverage, but subsequently exhibited an activity profile that suggests nonlinear dependencies and memory effects in the relation between information seeking, media pressure, and disease dynamics. This calls for a new and more general modelling framework to describe the interaction between media exposure, public awareness and disease dynamics during epidemic outbreaks. |
4,447 | The influence of time to adrenaline administration in the Paramedic 2 randomised controlled trial | PURPOSE: To examine the time to drug administration in patients with a witnessed cardiac arrest enrolled in the Pre-Hospital Assessment of the Role of Adrenaline: Measuring the Effectiveness of Drug Administration in Cardiac Arrest (PARAMEDIC2) randomised controlled trial. METHODS: The PARAMEDIC2 trial was undertaken across 5 NHS ambulance services in England and Wales with randomisation between December 2014 and October 2017. Patients with an out-of-hospital cardiac arrest who were unresponsive to initial resuscitation attempts were randomly assigned to 1 mg intravenous adrenaline or matching placebo according to treatment packs that were identical apart from treatment number. Participants and study staff were masked to treatment allocation. RESULTS: 8016 patients were enrolled, 4902 sustained a witnessed cardiac arrest of whom 2437 received placebo and 2465 received adrenaline. The odds of return of spontaneous circulation decreased in both groups over time but at a greater rate in the placebo arm odds ratio (OR) 0.93 (95% CI 0.92–0.95) compared with the adrenaline arm OR 0.96 (95% CI 0.95–0.97); interaction OR: 1.03, 95% CI 1.01–1.05, p = 0.005. By contrast, although the rate of survival and favourable neurological outcome decreased as time to treatment increased, the rates did not differ between the adrenaline and placebo groups. CONCLUSION: The rate of return of spontaneous circulation, survival and favourable neurological outcomes decrease over time. As time to drug treatment increases, adrenaline increases the chances of return of spontaneous circulation. Longer term outcomes were not affected by the time to adrenaline administration. (ISRCTN73485024). ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00134-019-05836-2) contains supplementary material, which is available to authorized users. |
4,448 | Acid ceramidase of macrophages traps herpes simplex virus in multivesicular bodies and protects from severe disease | Macrophages have important protective functions during infection with herpes simplex virus type 1 (HSV-1). However, molecular mechanisms that restrict viral propagation and protect from severe disease are unclear. Here we show that macrophages take up HSV-1 via endocytosis and transport the virions into multivesicular bodies (MVBs). In MVBs, acid ceramidase (aCDase) converts ceramide into sphingosine and increases the formation of sphingosine-rich intraluminal vesicles (ILVs). Once HSV-1 particles reach MVBs, sphingosine-rich ILVs bind to HSV-1 particles, which restricts fusion with the limiting endosomal membrane and prevents cellular infection. Lack of aCDase in macrophage cultures or in Asah1(−/−) mice results in replication of HSV-1 and Asah1(−/−) mice die soon after systemic or intravaginal inoculation. The treatment of macrophages with sphingosine enhancing compounds blocks HSV-1 propagation, suggesting a therapeutic potential of this pathway. In conclusion, aCDase loads ILVs with sphingosine, which prevents HSV-1 capsids from penetrating into the cytosol. |
4,449 | Mechanical ventilation weaning issues can be counted on the fingers of just one hand: part 1 | Although mechanical ventilation may be a patient’s vital ally during acute illness, it can quickly transform into an enemy during chronic conditions. The weaning process is the fundamental phase that enables the resumption of physiological respiratory function; however, it is also associated with a number of life-threatening complications, and a large percentage of critically ill patients never achieve airway device removal or require the resumption of mechanical ventilation just a few days post-weaning. Indeed, the weaning process is, at present, more of an art than a science. As such, there is urgent need for novel contributions from the scientific literature to abate the growing rates of morbidity and mortality associated with weaning failure. The physician attempting to wean a patient must integrate clinical parameters and common-sense criteria. Numerous studies have striven to identify single predictive factors of weaning failure and sought to standardize the weaning process, but the results are characterized by remarkable heterogeneity. Despite the lack of benchmarks, it is clear that the analysis of respiratory function must include a detailed overview of the five situations described below rather than a single aspect. The purpose of this two-part review is to provide a comprehensive description of these situations to clarify the “arena” physicians are entering when weaning critically ill patients from mechanical ventilation. |
4,450 | Mechanical ventilation weaning issues can be counted on the fingers of just one hand: part 2 | Assessing heart and diaphragm function constitutes only one of the steps to consider along the weaning path. In this second part of the review, we will deal with the more systematic evaluation of the pulmonary parenchyma—often implicated in the genesis of respiratory failure. We will also consider the other possible causes of weaning failure that lie beyond the cardio-pulmonary-diaphragmatic system. Finally, we will take a moment to consider the remaining unsolved problems arising from mechanical ventilation and describe the so-called protective approach to parenchyma and diaphragm ventilation. |
4,451 | Infection Spread and High-Resolution Detection of Close Contact Behaviors | Knowledge of human behaviors is important for improving indoor-environment design, building-energy efficiency, and productivity, and for studies of infection spread. However, such data are lacking. In this study, we designed a device for detecting and recording, second by second, the 3D indoor positioning and head and body motions of each graduate student in an office. From more than 400 person hours of data. Students spent 92.2%, 4.1%, 2.9%, and 0.8% of their time in their own office cubicles, other office cubicles, aisles, and areas near public facilities, respectively. They spent 9.7% of time in close contact, and each student averagely had 4.0 close contacts/h. Students spent long time on close contact in the office which may lead to high infection risk. The average interpersonal distance during close contact was 0.81 m. When sitting, students preferred small relative face orientation angle. Pairs of standing students preferred a face-to-face orientation during close contact which means this pattern had a lower infection risk via close contact. Probability of close contact decreased exponentially with the increasing distance between two students’ cubicles. Data on human behaviour during close contact is helpful for infection risk analysis and infection control and prevention. |
4,452 | Awareness, Knowledge, Attitude and Preventive Practice of Leptospirosis Among Healthy Malaysian and Non-Malaysian Wet Market Workers in Selected Urban Areas in Selangor, Malaysia | Leptospirosis has been reported as an endemic in most tropical countries. Among high risk occupations, leptospirosis includes workers in agriculture and domestic animal industries. Environmental hygiene in the wet market has established a link between the presence of rodents with probability of leptospirosis infection. This study was aimed to compare the level of knowledge, attitude and preventive practice against leptospirosis between healthy Malaysian and non-Malaysian wet market workers in selected wet markets in urban areas of Selangor. A cross-sectional study in the determined area was conducted with the participation of 147 respondents. The respondents were randomly chosen from the list provided by the state agency that regulates these markets. A self-administered bilingual validated questionnaire (English and Bahasa Melayu) was distributed to the selected respondents. There were 68 (48.3%) Malaysian respondents and 79 (53.7%) non-Malaysian respondents. The majority of them were males, who attained formal education and were less than 40 years old. Meanwhile, the respondents earned less than RM3000. Among the Malaysian respondents, 80.9% were aware of leptospirosis as compared to 17.7% of the non-Malaysian colleagues (p < 0.05). All items of knowledge showed that the Malaysian respondents scored higher as compared to non-Malaysian respondents. On attitude towards infection prevention, most Malaysian respondents had a positive attitude, while most non-Malaysian respondents had undecided perception on the majority of crucial attitude items. In practicing preventive measures, there was a marked significant difference in proportion between Malaysian and non-Malaysian respondents for items on “Specific Protection and Isolation at Source.” There was a significant gap on knowledge, attitude and preventive practice among Malaysian workers as compared to non-Malaysian workers. Therefore, it was highly recommended the health promotion implementation should also provide specific focus on non-Malaysian workers. |
4,453 | Case report: Mycobacterium monacense isolated from the blood culture of a patient with pulmonary infection | BACKGROUND: The poorly known mycobacterial species Mycobacterium monacense is a rapidly growing non-tuberculous mycobacterium that was first described in 2006 (Reischl et al., Int J Syst Evol Microbiol 56:2575-8, 2006); it has been reported that its isolation is usually associated with skin and lung infections, especially in immunosuppressed patients (Hogardt et al., Jpn J Infect Dis 61:77-8, 2008; Taieb et al., J Hand Surg Am 33:94-6, 2008; Therese et al., Lung India 28:124-6, 2011; Shojaei et al., Ann Lab Med 32:87-90, 2012; Romero et al., New Microbes New Infect 10:112-5, 2016 ). The clinical significance of Mycobacterium monacense is not yet fully understood. Here, we report the first isolation of Mycobacterium monacense from the blood culture of a patient in China with severe pneumonia. CASE PRESENTATION: On June 26, 2018, a 38-year-old man was admitted to the intensive care unit with breathing difficulty. One day prior, he was discovered with his face immersed in a small pond (non-chlorinated water) and with limb convulsions. He had undergone craniocerebral surgery after trauma 5 years earlier, which left him with epilepsy as a sequela. Bilateral diffuse ground-glass opacity was found in the lungs on chest X ray and chest CT image at admission. The result of the HIV serology test of the patient was negative. The patient was diagnosed with severe pneumonia. Drug-susceptible Klebsiella pneumoniae and Candida glabrata were isolated in the BALF, and yellow-pigmented colonies were isolated from blood cultures of the patient. The strain isolated from blood was identified by 16S rDNA sequencing as Mycobacteria monacense, which is a rapidly growing mycobacterium (RGM). The patient was treated with a combination of cefoperazone sulbactam, linezolid and voriconazole for 10 days, and the symptoms improved. During the one-year follow-up time, the patient did not relapse. CONCLUSIONS: We report the first case of M. monacense isolated from blood cultures in a patient with severe pneumonia, which provided evidence that the environmental microorganism possessed pathogenic characteristics. |
4,454 | Effects of Pidotimod on recurrent respiratory infections in children with Down syndrome: a retrospective Italian study | BACKGROUND: Children with Down syndrome (DS) show a high susceptibility to recurrent infections (RI), caused by immune defects and abnormalities of the airways. Our goal was to investigate the effects of Pidotimod on RI prevention in children with DS, comparing immune and clinical parameters before (T0) and after (T1) the treatment with Pidotimod. METHODS: The study was conducted at the Down syndrome outpatient Center of Bambino Gesù Children’s Hospital, in Rome. We reviewed the medical records of all children with a positive history for RI and who received oral prophylaxis of Pidotimod from September 2016 to February 2017. RESULTS: Thirty-three children met the inclusion criteria (males: 51.5%; average age: 6 years ±SD: 3). We found a significant decrease in the number of children with upper respiratory infections (82% at T0 vs 24% at T1; p = 0,0001) and with lower respiratory infections (36% at T0 vs 9% at T1; p = 0.003) after treatment with Pidotimod. We also demonstrated a significant decrease in the number of children hospitalized for respiratory infections (18% at T0 vs 3% at T1; p = 0.03). We measured T and B cells in the peripheral blood and B cell function in vitro at T0 and T1. We found that the response to CpG improved at T1. A significant increase of B cell frequency (p = 0.0009), B cell proliferation (p = 0.0278) and IgM secretion (p = 0.0478) were observed in children with DS after treatment. CONCLUSIONS: Our results provided evidence that Pidotimod may be able to prevent RI in children with Down syndrome. |
4,455 | The challenge of safe anesthesia in developing countries: defining the problems in a medical center in Cambodia | BACKGROUND: The International Standards for a Safe Practice of Anesthesia (ISSPA) were developed on behalf of the World Federation of Societies of Anaesthesiologists and the World Health Organization. It has been recommend as an assessment tool that allows anesthetic providers in developing countries to assess their compliance and needs. This study was performed to describe the anesthesia service in one main public hospital during an 8-month medical mission in Cambodia and evaluate its anesthetic safety issues according to the ISSPA. METHODS: We conduct a retrospective study involving 1953 patients at the Preah Ket Mealea hospital. Patient demographics, anesthetic techniques, and complications were reviewed according to the registers of the anesthetic services and questionnaires. The inadequacies in personnel, facilities, equipment, medications, and conduct of anesthesia drugs were recorded using a checklist based on the ISSPA. RESULTS: A total of 1792 patients received general and regional anesthesia in the operating room, while 161 patients receiving sedation for gastroscopy. The patients’ mean age was 45.0 ± 16.6 years (range, 17–87 years). The three most common surgical procedures were abdominal (52.0%; confidence interval [CI], 49.3–54.7), orthopedic (27.6%; CI, 25.2–29.9), and urological surgery (14.7%; CI, 12.8–16.6). General anesthesia, spinal anesthesia, and brachial plexus block were performed in 54.3% (CI, 51.7–56.8), 28.2% (CI, 25.9–30.5), and 9.4% (CI, 7.9–10.9) of patients, respectively. One death occurred. Twenty-six items related to professional aspects, monitoring, and conduct of anesthesia did not meet the ISSPA-recommended standards. A lack of commonly used drugs and monitoring equipment was noted, posing major threats to the safety of anesthesia practice, especially in emergency situations. CONCLUSIONS: This study adds to the scarce literature on anesthesia practice in low- and middle-income countries such as Cambodia. Future medical assistance should help to strengthen these countries’ inadequacies, allowing for the adoption of international standards for the safe practice of anesthesia. |
4,456 | Assisted mechanical ventilation promotes recovery of diaphragmatic thickness in critically ill patients: a prospective observational study | BACKGROUND: Diaphragm atrophy and dysfunction are consequences of mechanical ventilation and are determinants of clinical outcomes. We hypothesize that partial preservation of diaphragm function, such as during assisted modes of ventilation, will restore diaphragm thickness. We also aim to correlate the changes in diaphragm thickness and function to outcomes and clinical factors. METHODS: This is a prospective, multicentre, observational study. Patients mechanically ventilated for more than 48 h in controlled mode and eventually switched to assisted ventilation were enrolled. Diaphragm ultrasound and clinical data collection were performed every 48 h until discharge or death. A threshold of 10% was used to define thinning during controlled and recovery of thickness during assisted ventilation. Patients were also classified based on the level of diaphragm activity during assisted ventilation. We evaluated the association between changes in diaphragm thickness and activity and clinical outcomes and data, such as ventilation parameters. RESULTS: Sixty-two patients ventilated in controlled mode and then switched to the assisted mode of ventilation were enrolled. Diaphragm thickness significantly decreased during controlled ventilation (1.84 ± 0.44 to 1.49 ± 0.37 mm, p < 0.001) and was partially restored during assisted ventilation (1.49 ± 0.37 to 1.75 ± 0.43 mm, p < 0.001). A diaphragm thinning of more than 10% was associated with longer duration of controlled ventilation (10 [5, 15] versus 5 [4, 8.5] days, p = 0.004) and higher PEEP levels (12.6 ± 4 versus 10.4 ± 4 cmH(2)O, p = 0.034). An increase in diaphragm thickness of more than 10% during assisted ventilation was not associated with any clinical outcome but with lower respiratory rate (16.7 ± 3.2 versus 19.2 ± 4 bpm, p = 0.019) and Rapid Shallow Breathing Index (37 ± 11 versus 44 ± 13, p = 0.029) and with higher Pressure Muscle Index (2 [0.5, 3] versus 0.4 [0, 1.9], p = 0.024). Change in diaphragm thickness was not related to diaphragm function expressed as diaphragm thickening fraction. CONCLUSION: Mode of ventilation affects diaphragm thickness, and preservation of diaphragmatic contraction, as during assisted modes, can partially reverse the muscle atrophy process. Avoiding a strenuous inspiratory work, as measured by Rapid Shallow Breathing Index and Pressure Muscle Index, may help diaphragm thickness restoration. |
4,457 | Validation of END-of-life ScorING-system to identify the dying patient: a prospective analysis | BACKGROUND: The “END-of-Life ScorING-System” (ENDING-S) was previously developed to identify patients at high-risk of dying in the ICU and to facilitate a practical integration between palliative and intensive care. The aim of this study is to prospectively validate ENDING-S in a cohort of long-term critical care patients. MATERIALS AND METHODS: Adult long-term ICU patients (with a length-of-stay> 4 days) were considered for this prospective multicenter observational study. ENDING-S and SOFA score were calculated daily and evaluated against the patient’s ICU outcome. The predictive properties were evaluated through a receiver operating characteristic (ROC) analysis. RESULTS: Two hundred twenty patients were enrolled for this study. Among these, 21.46% died during the ICU stay. ENDING-S correctly predicted the ICU outcome in 71.4% of patients. Sensitivity, specificity, positive and negative predictive values associated with the previously identified ENDING-S cut-off of 11.5 were 68.1, 72.3, 60 and 89.3%, respectively. ROC-AUC for outcome prediction was 0.79 for ENDING-S and 0.88 for SOFA in this cohort. CONCLUSIONS: ENDING-S, while not as accurately as in the pilot study, demonstrated acceptable discrimination properties in identifying long-term ICU patients at very high-risk of dying. ENDING-S may be a useful tool aimed at facilitating a practical integration between palliative, end-of-life and intensive care. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT02875912; First registration August 4, 2016. |
4,458 | Diagnostic accuracy and utility of three dengue diagnostic tests for the diagnosis of acute dengue infection in Malaysia | BACKGROUND: Dengue is an emerging infectious disease that infects up to 390 million people yearly. The growing demand of dengue diagnostics especially in low-resource settings gave rise to many rapid diagnostic tests (RDT). This study evaluated the accuracy and utility of ViroTrack Dengue Acute - a new biosensors-based dengue NS1 RDT, SD Bioline Dengue Duo NS1/IgM/IgG combo - a commercially available RDT, and SD Dengue NS1 Ag enzyme-linked immunosorbent assay (ELISA), for the diagnosis of acute dengue infection. METHODS: This prospective cross-sectional study consecutively recruited 494 patients with suspected dengue from a health clinic in Malaysia. Both RDTs were performed onsite. The evaluated ELISA and reference tests were performed in a virology laboratory. The reference tests comprised of a reverse transcription-polymerase chain reaction and three ELISAs for the detection of dengue NS1 antigen, IgM and IgG antibodies, respectively. The diagnostic performance of evaluated tests was computed using STATA version 12. RESULTS: The sensitivity and specificity of ViroTrack were 62.3% (95%CI 55.6–68.7) and 95.0% (95%CI 91.7–97.3), versus 66.5% (95%CI 60.0–72.6) and 95.4% (95%CI 92.1–97.6) for SD NS1 ELISA, and 52.4% (95%CI 45.7–59.1) and 97.7% (95%CI 95.1–99.2) for NS1 component of SD Bioline, respectively. The combination of the latter with its IgM and IgG components were able to increase test sensitivity to 82.4% (95%CI 76.8–87.1) with corresponding decrease in specificity to 87.4% (95%CI 82.8–91.2). Although a positive test on any of the NS1 assays would increase the probability of dengue to above 90% in a patient, a negative result would only reduce this probability to 23.0–29.3%. In contrast, this probability of false negative diagnosis would be further reduced to 14.7% (95%CI 11.4–18.6) if SD Bioline NS1/IgM/IgG combo was negative. CONCLUSIONS: The performance of ViroTrack Dengue Acute was comparable to SD Dengue NS1 Ag ELISA. Addition of serology components to SD Bioline Dengue Duo significantly improved its sensitivity and reduced its false negative rate such that it missed the fewest dengue patients, making it a better point-of-care diagnostic tool. New RDT like ViroTrack Dengue Acute may be a potential alternative to existing RDT if its combination with serology components is proven better in future studies. |
4,459 | Impact of blunt chest trauma on outcome after traumatic brain injury– a matched-pair analysis of the TraumaRegister DGU® | BACKGROUND: Traumatic brain injury (TBI) is associated with high rates of long-term disability and mortality. Our aim was to investigate the effects of thoracic trauma on the in-hospital course and outcome of patients with TBI. METHODS: We performed a matched pair analysis of the multicenter trauma database TraumaRegisterDGU® (TR-DGU) in the 5-year period from 2012 to 2016. We included adult patients (≥18 years of age) with moderate to severe TBI (abbreviated injury scale (AIS)= 3–5). Patients with isolated TBI (group 1) were compared to patients with TBI and varying degrees of additional blunt thoracic trauma (AIS(Thorax)= 2–5) (group 2). Matching criteria were gender, age, severity of TBI, initial GCS and presence/absence of shock. The χ(2)-test was used for comparing categorical variables and the Mann-Whitney-U-test was chosen for continuous parameters. Statistical significance was defined by a p-value < 0.05. RESULTS: A total of 5414 matched pairs (10,828 patients) were included. The presence of additional thoracic injuries in patients with TBI was associated with a longer duration of mechanical ventilation and a prolonged ICU and hospital length of stay. Additional thoracic trauma was also associated with higher mortality rates. These effects were most pronounced in thoracic AIS subgroups 4 and 5. Additional thoracic trauma, regardless of its severity (AIS(Thorax) ≥2) was associated with significantly decreased rates of good neurologic recovery (GOS = 5) after TBI. CONCLUSIONS: Chest trauma in general, regardless of its initial severity (AIS(Thorax)= 2–5), is associated with decreased chance of good neurologic recovery after TBI. Affected patients should be considered “at risk” and vigilance for the maintenance of optimal neuro-protective measures should be high. |
4,460 | Challenges and opportunities for China entering global research and development for emerging infectious diseases: a case study from Ebola experience | BACKGROUND: China has emerged as a powerful platform for global pharmaceutical research and development (R&D) amid the 2014 Ebola outbreak. The research and development impact of developing countries on prevention and control of infectious disease outbreaks has long been underestimated, particularly for emerging economies like China. Here, we studied its research and development progress and government support in response to Ebola outbreak by timeline, input, and output at each research and development stage. This study will contribute to a deeper understanding of the research and development gaps and challenges faced by China, as well as providing evidence-based suggestions on how to accelerate the drug development process to meet urgent needs during future outbreaks. METHODS: Data were obtained from the National Nature Science Foundation of China database, PubMed database, Patent Search System of the State Intellectual Property Office of China, National Medical Products Administration, national policy reports and literature between Jan 1st, 2006 and Dec 31st, 2017. An overview of research funding, research output, pharmaceutical product patent, and product licensed was described and analyzed by Microsoft Excel. A descriptive analysis with a visualization of plotting charts and graphs was conducted by reporting the mean ± standard deviation. RESULTS: China has successfully completed the research and development of the Ebola Ad5-EBOV vaccine within 26 months, while the preparation and implementation of clinical trials took relative long time. The National Nature Science Foundation of China funded CNY 44.05 million (USD 6.27 million) for Ebola-related researches and committed strongly to the phase of basic research (87.8%). A proliferation of literature arose between 2014 and 2015, with a 1.7-fold increase in drug research and a 2.5-fold increase in diagnostic research within 1 year. Three years on from the Ebola outbreak, six Ebola-related products in China were approved by the National Medical Products Administration. CONCLUSIONS: China has started to emphasize the importance of medical product innovation as one of the solutions for tackling emerging infectious diseases. Continuing research on the development of regulatory and market incentives, as well as a multilateral collaboration mechanism that unifies cross-channel supports, would advance the process for China to enter global R&D market more effectively. |
4,461 | Comment on Early versus delayed mobilization for in-hospital mortality and health-related quality of life among critically ill patients: a systematic review and meta-analysis (Okada et al., Journal of Intensive Care 2019) | Critical comment on the review by Okada et al. on the effect of early versus delayed mobilization because of their definition of early mobilization as mobilization within a week of ICU admission in contrast to current evidence. |
4,462 | Engineered immunogen binding to alum adjuvant enhances humoral immunity | Adjuvants are central to the efficacy of subunit vaccines. Aluminum hydroxide (alum) is the most commonly used vaccine adjuvant, yet its adjuvanticity is often weak and mechanisms of triggering antibody responses remain poorly understood. We demonstrate that site-specific modification of immunogens with short peptides composed of repeating phosphoserine (pSer) residues enhances binding to alum and prolongs immunogen bioavailability. The pSer-modified immunogens formulated in alum elicited greatly increased germinal center, antibody, neutralizing antibody, memory and long-lived plasma cell responses compared to conventional alum-adsorbed immunogens. Mechanistically, pSer-immunogen:alum complexes form nanoparticles that traffic to lymph nodes and trigger B cell activation through multivalent and oriented antigen display. Direct uptake of antigen-decorated alum particles by B cells upregulated antigen processing and presentation pathways, further enhancing B cell activation. These data provide insights into mechanisms of action of alum and introduce a readily translatable approach to significantly improve humoral immunity to subunit vaccines using a clinical adjuvant. |
4,463 | Amyloidogenic Peptides in Human Neuro-Degenerative Diseases and in Microorganisms: A Sorrow Shared Is a Sorrow Halved? | The term “amyloid” refers to proteinaceous deposits of peptides that might be generated from larger precursor proteins e.g., by proteolysis. Common to these peptides is a stable cross-β dominated secondary structure which allows self-assembly, leading to insoluble oligomers and lastly to fibrils. These highly ordered protein aggregates have been, for a long time, mainly associated with human neurodegenerative diseases such as Alzheimer’s disease (Amyloid-β peptides). However, they also exert physiological functions such as in release of deposited hormones in human beings. In the light of the rediscovery of our microbial commensals as important companions in health and disease, the fact that microbes also possess amyloidogenic peptides is intriguing. Transmission of amyloids by iatrogenic means or by consumption of contaminated meat from diseased animals is a well-known fact. What if also our microbial commensals might drive human amyloidosis or suffer from our aggregated amyloids? Moreover, as the microbial amyloids are evolutionarily older, we might learn from these organisms how to cope with the sword of Damocles forged of endogenous, potentially toxic peptides. This review summarizes knowledge about the interplay between human amyloids involved in neurodegenerative diseases and microbial amyloids. |
4,464 | Twenty-five-year research progress in hookworm excretory/secretory products | Hookworm infection is a major public health problem that threatens about 500 million people throughout tropical areas of the world. Adult hookworms survive for many years in the host intestine, where they suck blood, causing iron deficiency anemia and malnutrition. Numerous molecules, named excretory/secretory (ES) products, are secreted by hookworm adults and/or larvae to aid in parasite survival and pathobiology. Although the molecular cloning and characterization of hookworm ES products began 25 years ago, the biological role and molecular nature of many of them are still unclear. Hookworm ES products, with distinct structures and functions, have been linked to many essential events in the disease pathogenesis. These events include host invasion and tissue migration, parasite nourishment and reproduction, and immune modulation. Several of these products represent promising vaccine targets for controlling hookworm disease and therapeutic targets for many inflammatory diseases. This review aims to summarize our present knowledge about hookworm ES products, including their role in parasite biology, host-parasite interactions, and as vaccine and pharmaceutical targets and to identify research gaps and future research directions in this field. [Image: see text] |
4,465 | Quality of intrapartum care: direct observations in a low-resource tertiary hospital | BACKGROUND: The majority of the world’s perinatal deaths occur in low- and middle-income countries. A substantial proportion occurs intrapartum and is avoidable with better care. At a low-resource tertiary hospital, this study assessed the quality of intrapartum care and adherence to locally-tailored clinical guidelines. METHODS: A non-participatory, structured, direct observation study was held at Mnazi Mmoja Hospital, Zanzibar, Tanzania, between October and November 2016. Women in active labour were followed and structure, processes of labour care and outcomes of care systematically recorded. Descriptive analyses were performed on the labour observations and compared to local guidelines and supplemented by qualitative findings. A Poisson regression analysis assessed factors affecting foetal heart rate monitoring (FHRM) guidelines adherence. RESULTS: 161 labouring women were observed. The nurse/midwife-to-labouring-women ratio of 1:4, resulted in doctors providing a significant part of intrapartum monitoring. Care during labour and two-thirds of deliveries was provided in a one-room labour ward with shared beds. Screening for privacy and communication of examination findings were done in 50 and 34%, respectively. For the majority, there was delayed recognition of labour progress and insufficient support in second stage of labour. While FHRM was generally performed suboptimally with a median interval of 105 (interquartile range 57–160) minutes, occurrence of an intrapartum risk event (non-reassuring FHR, oxytocin use or poor progress) increased assessment frequency significantly (rate ratio 1.32 (CI 1.09–1.58)). CONCLUSIONS: Neither international nor locally-adapted standards of intrapartum routine care were optimally achieved. This was most likely due to a grossly inadequate capacity of birth attendants; without whom innovative interventions at birth are unlikely to succeed. This calls for international and local stakeholders to address the root causes of unsafe intrafacility care in low-resource settings, including the number of skilled birth attendants required for safe and respectful births. |
4,466 | Brown marmorated stink bug, Halyomorpha halys (Stål), genome: putative underpinnings of polyphagy, insecticide resistance potential and biology of a top worldwide pest | BACKGROUND: Halyomorpha halys (Stål), the brown marmorated stink bug, is a highly invasive insect species due in part to its exceptionally high levels of polyphagy. This species is also a nuisance due to overwintering in human-made structures. It has caused significant agricultural losses in recent years along the Atlantic seaboard of North America and in continental Europe. Genomic resources will assist with determining the molecular basis for this species’ feeding and habitat traits, defining potential targets for pest management strategies. RESULTS: Analysis of the 1.15-Gb draft genome assembly has identified a wide variety of genetic elements underpinning the biological characteristics of this formidable pest species, encompassing the roles of sensory functions, digestion, immunity, detoxification and development, all of which likely support H. halys’ capacity for invasiveness. Many of the genes identified herein have potential for biomolecular pesticide applications. CONCLUSIONS: Availability of the H. halys genome sequence will be useful for the development of environmentally friendly biomolecular pesticides to be applied in concert with more traditional, synthetic chemical-based controls. |
4,467 | Economic evaluation of meningococcal vaccines: considerations for the future | In 2018, a panel of health economics and meningococcal disease experts convened to review methodologies, frameworks, and decision-making processes for economic evaluations of vaccines, with a focus on evaluation of vaccines targeting invasive meningococcal disease (IMD). The panel discussed vaccine evaluation methods across countries; IMD prevention benefits that are well quantified using current methods, not well quantified, or missing in current cost-effectiveness methodologies; and development of recommendations for future evaluation methods. Consensus was reached on a number of points and further consideration was deemed necessary for some topics. Experts agreed that the unpredictability of IMD complicates an accurate evaluation of meningococcal vaccine benefits and that vaccine cost-effectiveness evaluations should encompass indirect benefits, both for meningococcal vaccines and vaccines in general. In addition, the panel agreed that transparency in the vaccine decision-making process is beneficial and should be implemented when possible. Further discussion is required to ascertain: how enhancing consistency of frameworks for evaluating outcomes of vaccine introduction can be improved; reviews of existing tools used to capture quality of life; how indirect costs are considered within models; and whether and how the weighting of quality-adjusted life-years (QALY), application of QALY adjustment factors, or use of altered cost-effectiveness thresholds should be used in the economic evaluation of vaccines. |
4,468 | COMP Report: A survey of radiation safety regulations for medical imaging x‐ray equipment in Canada | X‐ray regulations and room design methodology vary widely across Canada. The Canadian Organization of Medical Physicists (COMP) conducted a survey in 2016/2017 to provide a useful snapshot of existing variations in rules and methodologies for human patient medical imaging facilities. Some jurisdictions no longer have radiation safety regulatory requirements and COMP is concerned that lack of regulatory oversight might erode safe practices. Harmonized standards will facilitate oversight that will ensure continued attention is given to public safety and to control workplace exposure. COMP encourages all Canadian jurisdictions to adopt the dose limits and constraints outlined in Health Canada Safety Code 35 with the codicil that the design standards be updated to those outlined in NCRP 147 and BIR 2012. |
4,469 | Single-Virus Tracking: From Imaging Methodologies to Virological Applications | [Image: see text] Uncovering the mechanisms of virus infection and assembly is crucial for preventing the spread of viruses and treating viral disease. The technique of single-virus tracking (SVT), also known as single-virus tracing, allows one to follow individual viruses at different parts of their life cycle and thereby provides dynamic insights into fundamental processes of viruses occurring in live cells. SVT is typically based on fluorescence imaging and reveals insights into previously unreported infection mechanisms. In this review article, we provide the readers a broad overview of the SVT technique. We first summarize recent advances in SVT, from the choice of fluorescent labels and labeling strategies to imaging implementation and analytical methodologies. We then describe representative applications in detail to elucidate how SVT serves as a valuable tool in virological research. Finally, we present our perspectives regarding the future possibilities and challenges of SVT. |
4,470 | Role of plasmid carrying bla(NDM) in mediating antibiotic resistance among Acinetobacter baumannii clinical isolates from Egypt | We investigated antibiotic resistance levels among bla(NDM)-positive (n = 9) and -negative (n = 65) A. baumannii clinical isolates collected in 2010 and 2015 from Alexandria Main University Hospital, Egypt using disc diffusion and minimum inhibitory concentration (MIC) determination. Plasmids from bla(NDM)-positive isolates were transformed into a carbapenem-susceptible A. baumannii (CS-AB) isolate to assess the role of plasmid transfer in mediating carbapenem resistance. Imipenem, meropenem, and ertapenem MIC90 values against bla(NDM)-positive isolates were 128, > 256, and 256 µg/mL, respectively. Plasmid isolation and polymerase chain reaction revealed that bla(NDM) was plasmid mediated. The plasmids were electroporated into the cells of a CS-AB isolate at an efficiency of 1.3 × 10(–8) to 2.6 × 10(–7), transforming them to bla(NDM)-positive carbapenem-resistant cells with an imipenem MIC increase of 256-fold. In addition to carbapenem resistance, the bla(NDM)-positive isolates also exhibited higher levels of cephalosporins, tetracycline, aminoglycosides, fluoroquinolones, and colistin resistance than the bla(NDM)-negative isolates. Acquisition of bla(NDM)-carrying plasmids dramatically increased imipenem resistance among A. baumannii isolates. Intriguingly, bla(NDM)-positive isolates also showed a high degree of resistance to antibiotics of different classes. The potential co-existence of different resistance determinants on A. baumannii plasmids and their possible transfer owing to the natural competence of the pathogen are especially alarming. More effective infection control and antibiotic stewardship programs are needed to curb the spread and treat such infections in both hospital and community settings. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13205-020-2157-y) contains supplementary material, which is available to authorized users. |
4,471 | Nanomaterials Designed for Antiviral Drug Delivery Transport across Biological Barriers | Viral infections are a major global health problem, representing a significant cause of mortality with an unfavorable continuously amplified socio-economic impact. The increased drug resistance and constant viral replication have been the trigger for important studies regarding the use of nanotechnology in antiviral therapies. Nanomaterials offer unique physico-chemical properties that have linked benefits for drug delivery as ideal tools for viral treatment. Currently, different types of nanomaterials namely nanoparticles, liposomes, nanospheres, nanogels, nanosuspensions and nanoemulsions were studied either in vitro or in vivo for drug delivery of antiviral agents with prospects to be translated in clinical practice. This review highlights the drug delivery nanosystems incorporating the major antiviral classes and their transport across specific barriers at cellular and intracellular level. Important reflections on nanomedicines currently approved or undergoing investigations for the treatment of viral infections are also discussed. Finally, the authors present an overview on the requirements for the design of antiviral nanotherapeutics. |
4,472 | Indirubin, a small molecular deriving from connectivity map (CMAP) screening, ameliorates obesity-induced metabolic dysfunction by enhancing brown adipose thermogenesis and white adipose browning | BACKGROUND: Obesity occurs when the body’s energy intake is constantly greater than its energy consumption and the pharmacological enhancing the activity of brown adipose tissue (BAT) and (or) browning of white adipose tissue (WAT) has been considered promising strategies to treat obesity. METHODS: In this study, we took a multi-pronged approach to screen UCP1 activators, including in silico predictions, in vitro assays, as well as in vivo experiments. RESULTS: Base on Connectivity MAP (CMAP) screening, we obtained multiple drugs that possess a remarkably correlating gene expression pattern to that of enhancing activity in BAT and (or) sWAT signature. Particularly, we focused on a previously unreported drug-indirubin, a compound obtained from the Indigo plant, which is now mainly used for the treatment of chronic myelogenous leukemia (CML). In the current study, our results shown that indirubin could enhance the BAT activity, as evidenced by up-regulated Ucp1 expression and enhanced mitochondrial respiratory function in vitro cellular model. Furthermore, indirubin treatment restrained high-fat diet (HFD)-induced body weight gain, improved glucose homeostasis and ameliorated hepatic steatosis which were associated with the increase of energy expenditure in the mice model. Moreover, we revealed that indirubin treatment increased BAT activity by promoting thermogenesis and mitochondrial biogenesis in BAT and induced browning of subcutaneous inguinal white adipose tissue (sWAT) of mice under HFD. Besides, our results indicated that indirubin induced UCP1 expression in brown adipocytes, at least in part, via activation of PKA and p38MAPK signaling pathways. CONCLUSIONS: Our results clearly show that as an effective BAT (as well as beige cells) activator, indirubin may have a protective effect on the prevention and treatment of obesity and its complications. |
4,473 | Effects of respiratory rate on venous-to-arterial CO(2) tension difference in septic shock patients undergoing volume mechanical ventilation | BACKGROUND: To explore the effects of the respiratory rate (RR) on the venous-to-arterial CO(2) tension difference (gapCO(2)) in septic shock patients undergoing volume mechanical ventilation. METHODS: Adult patients with septic shock underwent volume mechanical ventilation between October 2015 and October 2016. RR was started at 10 breaths/min, and 2 breaths/min were added every 60 min until 16 breaths/min was reached. At every point, central venous and arterial blood gas measurements were obtained simultaneously. RESULTS: In this study, gapCO(2) induced by hyperventilation significantly increased, while the central venous carbon dioxide pressure (PvCO(2)) and the partial pressure of CO(2) (PaCO(2)) in arteries decreased. The decreasing trend of the PaCO(2) was more obvious than that of the PvCO(2). HCO(3)(−) and ctCO(2) were markedly decreased, when the RR was increased (P < 0.05). Central venous oxygen saturation (S(cv)O(2)) had a decreasing trend between 14 (77.1 ± 8.3%) and 16 (75.2 ± 8.7%) breaths/min; however, the difference was not significant. CONCLUSIONS: In septic patients undergoing ventilation, respiratory alkalosis induced by hyperventilation caused an increase in the gapCO(2). Clinicians should cautiously interpret the gapCO(2) in hemodynamically stable ventilated septic shock patients and its relationship with low cardiac output and inadequate perfusion. |
4,474 | Replication Compartments of DNA Viruses in the Nucleus: Location, Location, Location | DNA viruses that replicate in the nucleus encompass a range of ubiquitous and clinically important viruses, from acute pathogens to persistent tumor viruses. These viruses must co-opt nuclear processes for the benefit of the virus, whilst evading host processes that would otherwise attenuate viral replication. Accordingly, DNA viruses induce the formation of membraneless assemblies termed viral replication compartments (VRCs). These compartments facilitate the spatial organization of viral processes and regulate virus–host interactions. Here, we review advances in our understanding of VRCs. We cover their initiation and formation, their function as the sites of viral processes, and aspects of their composition and organization. In doing so, we highlight ongoing and emerging areas of research highly pertinent to our understanding of nuclear-replicating DNA viruses. |
4,475 | Nanoscale Structure Determination of Murray Valley Encephalitis and Powassan Virus Non-Coding RNAs | Viral infections are responsible for numerous deaths worldwide. Flaviviruses, which contain RNA as their genetic material, are one of the most pathogenic families of viruses. There is an increasing amount of evidence suggesting that their 5’ and 3’ non-coding terminal regions are critical for their survival. Information on their structural features is essential to gain detailed insights into their functions and interactions with host proteins. In this study, the 5’ and 3’ terminal regions of Murray Valley encephalitis virus and Powassan virus were examined using biophysical and computational modeling methods. First, we used size exclusion chromatography and analytical ultracentrifuge methods to investigate the purity of in-vitro transcribed RNAs. Next, we employed small-angle X-ray scattering techniques to study solution conformation and low-resolution structures of these RNAs, which suggest that the 3’ terminal regions are highly extended as compared to the 5’ terminal regions for both viruses. Using computational modeling tools, we reconstructed 3-dimensional structures of each RNA fragment and compared them with derived small-angle X-ray scattering low-resolution structures. This approach allowed us to reinforce that the 5’ terminal regions adopt more dynamic structures compared to the mainly double-stranded structures of the 3’ terminal regions. |
4,476 | TRIM41-Mediated Ubiquitination of Nucleoprotein Limits Vesicular Stomatitis Virus Infection | Vesicular stomatitis virus (VSV) is a zoonotic, negative-stranded RNA virus of the family Rhabdoviridae. The nucleoprotein (N) of VSV protects the viral genomic RNA and plays an essential role in viral transcription and replication, which makes the nucleoprotein an ideal target of host defense. However, whether and how host innate/intrinsic immunity limits VSV infection by targeting the N protein are unknown. In this study, we found that the N protein of VSV (VSV-N) interacted with a ubiquitin E3 ligase, tripartite motif protein 41 (TRIM41). Overexpression of TRIM41 inhibited VSV infection. Conversely, the depletion of TRIM41 increased host susceptibility to VSV. Furthermore, the E3 ligase defective mutant of TRIM41 failed to limit VSV infection, suggesting the requirement of the E3 ligase activity of TRIM41 in viral restriction. Indeed, TRIM41 ubiquitinated VSV-N in cells and in vitro. TRIM41-mediated ubiquitination leads to the degradation of VSV-N through proteasome, thereby limiting VSV infection. Taken together, our study identifies TRIM41 as a new intrinsic immune factor against VSV by targeting the viral nucleoprotein for ubiquitination and subsequent protein degradation. |
4,477 | Letea Virus: Comparative Genomics and Phylogenetic Analysis of a Novel Reassortant Orbivirus Discovered in Grass Snakes (Natrix natrix) | The discovery and characterization of novel arthropod-borne viruses provide valuable information on their genetic diversity, ecology, evolution and potential to threaten animal or public health. Arbovirus surveillance is not conducted regularly in Romania, being particularly very scarce in the remote and diverse areas like the Danube Delta. Here we describe the detection and genetic characterization of a novel orbivirus (Reoviridae: Orbivirus) designated as Letea virus, which was found in grass snakes (Natrix natrix) during a metagenomic and metatranscriptomic survey conducted between 2014 and 2017. This virus is the first orbivirus discovered in reptiles. Phylogenetic analyses placed Letea virus as a highly divergent species in the Culicoides-/sand fly-borne orbivirus clade. Gene reassortment and intragenic recombination were detected in the majority of the nine Letea virus strains obtained, implying that these mechanisms play important roles in the evolution and diversification of the virus. However, the screening of arthropods, including Culicoides biting midges collected within the same surveillance program, tested negative for Letea virus infection and could not confirm the arthropod vector of the virus. The study provided complete genome sequences for nine Letea virus strains and new information about orbivirus diversity, host range, ecology and evolution. The phylogenetic associations warrant further screening of arthropods, as well as sustained surveillance efforts for elucidation of Letea virus natural cycle and possible implications for animal and human health. |
4,478 | Oxidative Stress in Canine Histiocytic Sarcoma Cells Induced by an Infection with Canine Distemper Virus Led to a Dysregulation of HIF-1α Downstream Pathway Resulting in a Reduced Expression of VEGF-B In Vitro | Histiocytic sarcomas represent malignant tumors which require new treatment strategies. Canine distemper virus (CDV) is a promising candidate due to its oncolytic features reported in a canine histiocytic sarcoma cell line (DH82 cells). Interestingly, the underlying mechanism might include a dysregulation of angiogenesis. Based on these findings, the aim of the present study was to investigate the impact of a persistent CDV-infection on oxidative stress mediated changes in the expression of hypoxia-inducible factor (HIF)-1α and its angiogenic downstream pathway in DH82 cells in vitro. Microarray data analysis, immunofluorescence for 8-hydroxyguanosine, superoxide dismutase 2 and catalase, and flow cytometry for oxidative burst displayed an increased oxidative stress in persistently CDV-infected DH82 cells (DH82Ond pi) compared to controls. The HIF-1α expression in DH82Ond pi increased, as demonstrated by Western blot, and showed an unexpected, often sub-membranous distribution, as shown by immunofluorescence and immunoelectron microscopy. Furthermore, microarray data analysis and immunofluorescence confirmed a reduced expression of VEGF-B in DH82Ond pi compared to controls. In summary, these results suggest a reduced activation of the HIF-1α angiogenic downstream pathway in DH82Ond pi cells in vitro, most likely due to an excessive, unusually localized, and non-functional expression of HIF-1α triggered by a CDV-induced increased oxidative stress. |
4,479 | Lyophilized Matrix Containing Ready-to-Use Primers and Probe Solution for Standardization of Real-Time PCR and RT-qPCR Diagnostics in Virology | Real-time molecular techniques have become the reference methods for direct diagnosis of pathogens. The reduction of steps is a key factor in order to decrease the risk of human errors resulting in invalid series and delayed results. We describe here a process of preparation of oligonucleotide primers and hydrolysis probe in a single tube at predefined optimized concentrations that are stabilized via lyophilization (Lyoph-P&P). Lyoph-P&P was compared versus the classic protocol using extemporaneously prepared liquid reagents using (i) sensitivity study, (ii) long-term stability at 4 °C, and (iii) long-term stability at 37 °C mimicking transportation without cold chain. Two previously published molecular assays were selected for this study. They target two emerging viruses that are listed on the blueprint of the WHO as to be considered for preparedness and response actions: chikungunya virus (CHIKV) and Rift Valley fever phlebovirus (RVFV). Results of our study demonstrate that (i) Lyoph-P&P is stable for at least 4 days at 37 °C supporting shipping without the need of cold chain, (ii) Lyoph-P&P rehydrated solution is stable at +4 °C for at least two weeks, (iii) sensitivity observed with Lyoph-P&P is at least equal to, often better than, that observed with liquid formulation, (iv) validation of results observed with low-copy specimens is rendered easier by higher fluorescence level. In conclusion, Lyoph-P&P holds several advantages over extemporaneously preparer liquid formulation that merit to be considered when a novel real-time molecular assay is implemented in a laboratory in charge of routine diagnostic activity. |
4,480 | The Serological Prevalence of Rabies Virus-Neutralizing Antibodies in the Bat Population on the Caribbean Island of Trinidad | Rabies virus (RABV) is the only lyssavirus known to be present within the Caribbean. The island of Trinidad, is richly diverse in chiropteran fauna and endemic for bat-transmitted rabies with low RABV isolation rates observed in this population. We aimed to determine the seroprevalence of rabies virus neutralizing antibodies (RVNA) in light of spatio-temporal and bat demographic factors to infer the extent of natural exposure to RABV in the Trinidadian bat population. RVNA titers were determined by the RABV micro-neutralization test on 383 bat samples representing 21 species, comprising 30.9% of local bat diversity, from 31 locations across the island over 5 years. RVNA was positively detected in 33 samples (8.6%) representing 6 bat species (mainly frugivorous) with titers ranging from 0.1 to 19 IU/mL (mean 1.66 IU/mL). The analyses based on a multivariable binomial generalised linear mixed-effects model showed that bat age and year of capture were significant predictors of seropositivity. Thus, juvenile bats were more likely to be seropositive when compared to adults (estimate 1.13; p = 0.04) which may suggest early exposure to the RABV with possible implications for viral amplification in this population. Temporal variation in rabies seropositivity, 2012–2014 versus 2015–2017 (estimate 1.07; p = 0.03) may have been related to the prevailing rabies epizootic situation. Regarding other factors investigated, RVNA was found in bats from both rural and non-rural areas, as well as in both hematophagous and non-hematophagous bat species. The most common seropositive species, Artibeus jamaicensis planirostris is ubiquitous throughout the island which may potentially facilitate human exposure. The findings of this study should be factored into public health assessments on the potential for rabies transmission by non-hematophagous bats in Trinidad. |
4,481 | Inter-rater reliability of the modified Sarnat examination in preterm infants at 32–36 weeks’ gestation | OBJECTIVE: To test the inter-rater reliability of the modified Sarnat neurologic examination in preterm neonates and to correlate abnormalities with the presence of perinatal acidosis. METHODS: Prospective study of 32–36 weeks’ gestational age infants admitted to the neonatal intensive care unit. Each infant had two Sarnat examinations performed at <6 h, one by a gold standard (GS) study investigator, and the second either by (a) another GS examiner or (b) an attending physician (28 examiners), all blinded to clinical variables. Agreement was calculated using kappa (k) statistics. RESULTS: One hundred and two (9, fetal acidosis) infants underwent a modified Sarnat examination. Among GS examiners, agreement was excellent (k > 0.8) except for Moro, while among all examiners agreement was very good (k > 0.7) except for both Moro and tone. Subgroup analysis at 32–34 weeks’ showed fair/poor Moro compared to excellent agreement at ≥35 weeks. Increasing abnormalities correlated with acidosis (r = −0.6, P < 0.01). CONCLUSIONS: Strong inter-rater reliability for the modified Sarnat was observed except for tone and Moro in preterm infants. Experience of the examiners resulted in improved reliability in tone, while for the Moro agreement improved only beyond 35 weeks. Findings suggest the need of adjustment of the examination form specific for preterm infants. |
4,482 | The 24-Form Tai Chi Improves Anxiety and Depression and Upregulates miR-17-92 in Coronary Heart Disease Patients After Percutaneous Coronary Intervention | BACKGROUND: Anxiety and depression are common symptoms in patients with coronary heart disease (CHD) after percutaneous coronary intervention (PCI). The 24-form Tai Chi may exert a protective function for CHD patients after PCI by improving anxiety and depression. METHODS: Patients who received PCI after 1–4 days were randomly assigned to the 24-form Tai Chi group (TG) and the control group (CG). The differences in anxiety and depression, using the Medical Outcomes Study 36−item Short−Form Health Survey (SF-36), before and after an average of 10 months of Tai Chi intervention were compared in both groups to analyze the effects of Tai Chi on the emotion and the life quality of CHD patients. Meanwhile, the relative levels of miR-17-92 were measured by using real-time qPCR. The association between the relative levels of miR-17-92 and the anxiety and the depression of CHD patients after PCI was analyzed. Adjusted Cox models were used to explore the effect of Tai Chi exercise in CHD patients. RESULTS: After 10 months of intervention, the changes in the anxiety subscale (P = 0.002), in the depression subscale (P = 0.008), and in the stress (P = 0.015) scores were higher in the TG group when compared to those of the CG group. The proportion of anxious (P = 0.045) and depressed subjects (P = 0.042) in the TG group was lower than that in the CG group. On the other hand, the increase in the SF-36 scores and in the relative levels of miR-17-92 was significantly higher in the TG group when compared with that of the CG group (P < 0.05). The serum level of miR-17-92 had a negative correlation with the anxiety, the depression, and the stress scores (P < 0.01). CONCLUSION: The 24-form Tai Chi improved the anxiety and the depression symptoms and upregulated the miR-17-92 levels in CHD patients after PCI. |
4,483 | Protocol for TRAUMADORNASE: a prospective, randomized, multicentre, double-blinded, placebo-controlled clinical trial of aerosolized dornase alfa to reduce the incidence of moderate-to-severe hypoxaemia in ventilated trauma patients | BACKGROUND: Acute respiratory distress syndrome continues to drive significant morbidity and mortality after severe trauma. The incidence of trauma-induced, moderate-to-severe hypoxaemia, according to the Berlin definition, could be as high as 45%. Its pathophysiology includes the release of damage-associated molecular patterns (DAMPs), which propagate tissue injuries by triggering neutrophil extracellular traps (NETs). NETs include a DNA backbone coated with cytoplasmic proteins, which drive pulmonary cytotoxic effects. The structure of NETs and many DAMPs includes double-stranded DNA, which prevents their neutralization by plasma. Dornase alfa is a US Food and Drug Administration-approved recombinant DNase, which cleaves extracellular DNA and may therefore break up the backbone of NETs and DAMPs. Aerosolized dornase alfa was shown to reduce trauma-induced lung injury in experimental models and to improve arterial oxygenation in ventilated patients. METHODS: TRAUMADORNASE will be an institution-led, multicentre, double-blinded, placebo-controlled randomized trial in ventilated trauma patients. The primary trial objective is to demonstrate a reduction in the incidence of moderate-to-severe hypoxaemia in severe trauma patients during the first 7 days from 45% to 30% by providing aerosolized dornase alfa as compared to placebo. The secondary objectives are to demonstrate an improvement in lung function and a reduction in morbidity and mortality. Randomization of 250 patients per treatment arm will be carried out through a secure, web-based system. Statistical analyses will include a descriptive step and an inferential step using fully Bayesian techniques. The study was approved by both the Agence Nationale de la Sécurité du Médicament et des Produits de Santé (ANSM, on 5 October 2018) and a National Institutional Review Board (CPP, on 6 November 2018). Participant recruitment began in March 2019. Results will be published in international peer-reviewed medical journals. DISCUSSION: If early administration of inhaled dornase alfa actually reduces the incidence of moderate-to-severe hypoxaemia in patients with severe trauma, this new therapeutic strategy may be easily implemented in many clinical trauma care settings. This treatment may facilitate ventilator weaning, reduce the burden of trauma-induced lung inflammation and facilitate recovery and rehabilitation in severe trauma patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03368092. Registered on 11 December 2017. |
4,484 | Trends, risk factors and outcomes of healthcare-associated infections in a neonatal intensive care unit in Italy during 2013–2017 | BACKGROUND: Healthcare-associated infections (HAIs) occur frequently in intensive care units (NICUs). The aim of this study was to analyze the results of surveillance of HAIs in a III level NICU in Naples, Italy during 2013–2017 and to compare with those obtained during 2006–2010. METHODS: The surveillance included 1265 neonates of all birth weight (BW) classes with > 2 days NICU stay. Infections were defined using standard Centers for Disease Control and Prevention definitions adapted to neonatal pathology. RESULTS: A total of 125 HAIs were registered during 2013–2017 with a frequency of 9.9% and an incidence density of 3.2 per 1000 patient days. HAIs occurred in all BW classes with a decreasing trend from the lowest to the highest BW classes (p = < 0.001). Central line-associated blood stream infection (CLABSI) was the most frequent infection (69.6%), followed by ventilator associated pneumonia (VAP) (20%), urinary tract infection (UTI) (8.8%) and necrotizing enterocolitis (NEC) (1.6%). Also, CLABSI and VAP incidence density decreased from lower to highest BW classes showing a significant trend (p = 0.007). Most frequent pathogens responsible for CLABSI were: Coagulase-negative staphylococci (CONS) (25.3%), Candida parapsilosis (21.8%), Pseudomonas aeruginosa (5.7), Escherichia coli and Klebsiella pneumoniae (6.8%). No microbiological diagnosis was achieved for 20.7% of CLABSI. Pseudomonas aeruginosa (28%), Stenotrophomonas maltophilia (20%), and CONS (20%) were the most frequent pathogens responsible for VAP. CLABSI incidence density showed no differences between 2006 and 2010 and 2013–2017, while VAP incidence density for the 751–100 g BW class was higher during 2006–2010 than during 2013–2017 (p = 0.006). A higher incidence of the CLABSI caused by Gram positive bacteria (p = 0.002) or by undetermined etiology (p = 0.01) was observed during 2013–2017 than during 2006–2010, while a significant lower incidence of VAP caused by Gram-negative bacteria was found during 2013–2017 than during 2006–2010 (p = 0.007). CONCLUSION: HAIs in the NICU developed in all BW classes with a decreasing trend from the lowest to the highest BW classes in both study periods. Differences in the aetiology of CLABSI and VAP were found between the two study periods. This reinforces the importance of HAIs surveillance protocol in the NICU, which monitors microbiological isolates and use of medical devices for all BW classes of neonates. |
4,485 | DNA vaccines: are they still just a powerful tool for the future? | Vaccination is historically one of the most successful strategies for the prevention of infectious diseases. For safety reasons, modern vaccinology tends toward the usage of inactivated or attenuated microorganisms and uses predominantly subunit vaccines. The antigens need to be clearly defined, pure, stable, appropriately composed, and properly presented to the immune system of the host. Differing ratios of various proportions between specific CD4(+) and CD8(+) T cell responses are essential for conferring the required protection in the case of individual vaccines. To stimulate both CD4(+) and CD8(+) T cells, the antigens must be processed and presented to both antigen-presentation pathways, MHC I and MHC II. Protein antigens delivered by vaccination are processed as extracellular antigens. However, extracellularly delivered antigen can be directed towards intracellular presentation pathways in conjugation with molecules involved in antigen cross-presentation, e.g. heat shock proteins, or by genomic-DNA vaccination. In this overview, current knowledge of the host immune response to DNA vaccines is summarized in the introduction. The subsequent sections discuss techniques for enhancing DNA vaccine efficacy, such as DNA delivery to specific tissues, delivery of DNA to the cell cytoplasm or nucleus, and enhancement of the immune response using molecular adjuvants. Finally, the prospects of DNA vaccination and ongoing clinical trials with various DNA vaccines are discussed. |
4,486 | Dipyrithione inhibits IFN-γ-induced JAK/STAT1 signaling pathway activation and IP-10/CXCL10 expression in RAW264.7 cells | OBJECTIVE: This study investigates the effects of dipyrithione (PTS2) on the expression of IP-10/CXCL10, which has been observed in a wide variety of chronic inflammatory disorders and autoimmune conditions. METHODS: RAW264.7 cells (a murine macrophage-like cell line) were cultured in the absence or in the presence of PTS2 (3–10 μM) together with or without IFN-γ (10 ng/ml). IP-10/CXCL10 expression was measured by specific enzyme-amplified immunoassays and reverse transcriptase-PCR (RT-PCR). Phosphorylation of JAK1, JAK2 and STAT1 were detected by Western blot analysis. RESULTS: We found that PTS2 inhibited IFN-γ-induced up-regulation of IP-10/CXCL10 protein level in a dose- and time-dependent manner in RAW264.7 cells. RT-PCR experiments showed that PTS2 suppressed IFN-γ-induced IP-10/CXCL10 expression at mRNA levels. Mechanistically, PTS2 prevented phosphorylation of JAK1, JAK2 and STAT1, but did not interfere with the p38 pathway. Furthermore, the inhibitory effect of PTS2 on IP-10/CXCL10 up-regulation was slightly stronger than JAK2 inhibitor AG490. CONCLUSION: PTS2 inhibits IFN-γ-induced IP-10/CXCL10 expression in RAW264.7 cells by targeting the JAK/STAT1 signaling pathway, suggesting that PTS2 could exert anti-inflammatory effects through attenuating the formation of chemokine IP-10/CXCL10. |
4,487 | Nuclear functions of heterogeneous nuclear ribonucleoproteins A/B | The hnRNP A/B proteins are among the most abundant RNA-binding proteins, forming the core of the ribonucleoprotein complex that associates with nascent transcripts in eukaryotic cells. There are several paralogs in this subfamily, each of which is subject to alternative transcript splicing and post-translational modifications. The structural diversity of these proteins generates a multitude of functions that involve interactions with DNA or, more commonly, RNA. They also recruit regulatory proteins associated with pathways related to DNA and RNA metabolism, and appear to accompany transcripts throughout the life of the mRNA. We have highlighted here recent progress in elucidation of molecular mechanisms underlying the roles of these hnRNPs in a wide range of nuclear processes, including DNA replication and repair, telomere maintenance, transcription, pre-mRNA splicing, and mRNA nucleo-cytoplasmic export. |
4,488 | Membrane traffic in the secretory pathway: Take the ’A’ train: on fast tracks to the cell surface | Cholesterol, certain lipids, membrane-bound and soluble proteins, as well as viruses that are synthesized in the endoplasmic reticulum (ER), reach the plasma membrane (PM) via non-classical pathway(s) that remain poorly understood. Typical for this transport is (i) its insensitivity to brefeldin A (BFA), which dissociates selected coat complexes from membranes, resulting in the disassembly of the Golgi apparatus; (ii) its rapid kinetics as compared to the classical secretory pathway; and (iii) its role in the trafficking of lipid raft components. Based on results showing that the intermediate compartment (IC) at the ER-Golgi boundary constitutes a stable tubular network that maintains its dynamics in the presence of BFA, we propose that two bidirectional Golgi-bypass pathways to the PM exist, a direct route from early IC elements, and another, reminescent of the yeast secretory pathway, from late IC elements via the endosomal system. These pathways have implications for the organization of the secretory processes in different cell types. (Part of a Multi-author Review) |
4,489 | Biological weapons: Development of a matrix to evaluate the threat of biological agents used for bioterrorism | Adequate public health preparedness for bioterrorism includes the elaboration of an agreed list of biological and chemical agents that might be used in an attack or as threats of deliberate release. In the absence of counterterrorism intelligence information, public health authorities can also base their preparedness on the agents for which the national health structures would be most vulnerable. This article aims to describe a logical method and the characteristics of the variables to be brought in a weighing process to reach a priority list for preparedness. The European Union, in the aftermath of the anthrax events of October 2001 in the United States, set up a task force of experts from multiple member states to elaborate and implement a health security programme. One of the first tasks of this task force was to come up with a list of priority threats. The model, presented here, allows Web-based updates for newly identified agents and for the changes occurring in preventive measures for agents already listed. The same model also allows the identification of priority protection action areas. |
4,490 | Molecular mechanisms underlying Th1-like Treg generation and function | Since their ‘re-discovery’ more than two decades ago, FOXP3(+) regulatory T cells (Tregs) have been an important subject of investigation in the biomedical field and our understanding of the mechanisms that drive their phenotype and function in health and disease has advanced tremendously. During the past few years it has become clear that Tregs are not a terminally differentiated population but show some degree of plasticity, and can, under specific environmental conditions, acquire the phenotype of effector T cells. In particular, recent works have highlighted the acquisition of a Th1-like phenotype by Tregs in several pathological environments. In this review we give an update on the concept of Treg plasticity and the advances in defining the molecular mechanisms that underlie the generation of Th1-like Tregs during an immune response and in different disease settings. |
4,491 | Sumoylation regulates diverse biological processes | Ten years after its discovery, the small ubiquitin-like protein modifier (SUMO) has emerged as a key regulator of proteins. While early studies indicated that sumoylation takes place mainly in the nucleus, an increasing number of non-nuclear substrates have recently been identified, suggesting a wider stage for sumoylation in the cell. Unlike ubiquitylation, which primarily targets a substrate for degradation, sumoylation regulates a substrate’s functions mainly by altering the intracellular localization, protein-protein interactions or other types of post-translational modifications. These changes in turn affect gene expression, genomic and chromosomal stability and integrity, and signal transduction. Sumoylation is counter-balanced by desumoylation, and well-balanced sumoylation is essential for normal cellular behaviors. Loss of the balance has been associated with a number of diseases. This paper reviews recent progress in the study of SUMO pathways, substrates, and cellular functions and highlights important findings that have accelerated advances in this study field and link sumoylation to human diseases. |
4,492 | Polarization of immunity induced by direct injection of naked sequence-stabilized mRNA vaccines | In the context of developing a safe genetic vaccination strategy we tested and studied globin-stabilized mRNA-based vaccination in mice. This vaccination strategy has the advantages of genetic vaccination (easy production, adaptability to any disease and inexpensive storage when lyophilized), but not the drawbacks of DNA vaccination (long-term uncontrolled expression of a transgene, possibility of integration into the host genome and possible induction of anti-DNA antibodies). We report here that injection of naked β-globin untranslated region (UTR)-stabilized mRNA coding for β-galactosidase is followed by detectable translation in vivo. In addition, we show that such a vaccination strategy primes a T helper 2 (Th2) type of response which can be enhanced and shifted to a Th1-type immune response by application of recombinant granulocyte/macrophage colony-stimulating factor 1 day after mRNA injection. Our data demonstrate that the administration of globin UTR-stabilized mRNA is a versatile vaccination strategy that can be manipulated to fit the requirement of antiviral, antibacterial or antitumor immunity. |
4,493 | Capsid-deficient alphaviruses generate propagative infectious microvesicles at the plasma membrane | Alphavirus budding is driven by interactions between nucleocapsids assembled in the cytoplasm and envelope proteins present at the plasma membrane. So far, the expression of capsid and envelope proteins in infected cells has been considered an absolute requirement for alphavirus budding and propagation. In the present study, we show that Semliki Forest virus and Sindbis virus lacking the capsid gene can propagate in mammalian and insect cells. This propagation is mediated by the release of infectious microvesicles (iMVs), which are pleomorphic and have a larger size and density than wild-type virus. iMVs, which contain viral RNA inside and viral envelope proteins on their surface, are released at the plasma membrane and infect cells using the endocytic pathway in a similar way to wild-type virus. iMVs are not pathogenic in immunocompetent mice when injected intravenously, but can infect different organs like lungs and heart. Finally, we also show that alphavirus genomes without capsid can mediate the propagation of heterologous genes, making these vectors potentially interesting for gene therapy or vaccination studies. The minimalist infectious system described in this study shows that a self-replicating RNA able to express membrane proteins with binding and fusion properties is able to propagate, providing some insights into virus evolution. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00018-016-2230-1) contains supplementary material, which is available to authorized users. |
4,494 | Caliciviren Virale Auslöser akuter Gastroenteritiden: Virale Auslöser akuter Gastroenteritiden | Human caliciviruses are highly infectious and co-circulate worldwide. They are responsible for many individual cases and extensive outbreaks of acute gastroenteritis. The ability of the viruses to survive in the environment facilitates the fecal-oral spread through water, food, aerosols, and person-to-person contact. Therefore, they are an important global public health problem. Despite the lack of a cell culture or animal model system to grow caliciviruses, great advances in our understanding of these pathogens, especially of the NLVs, have been made by using molecular methods. More and more information about the viral genome is being accumulated in data bases. This information will be used to develop sensitive molecular methods for the better understanding of the viral biology and epidemiology and will assist in developing strategies to prevent and control infections. |
4,495 | Ethische Aspekte eines Influenzapandemiemanagements und Schlussfolgerungen für die Gesundheitspolitik: Ein Überblick | Infectious diseases are among the major global health threats. Although associated with these diseases there are vast ethical challenges, ethics has more focused on other health related issues – e.g. associated with rare diseases, embryo research, genetic diagnosis. Nowadays we are facing a possible influenza pandemic caused by a new human influenza virus subtype. This article presents issues and ethical challenges of the pandemic threat. The authors argue that it is necessary to consider ethical implications of pandemic influenza preparedness early on and to include ethical reasoning when deciding on the measures for the pandemic management. |
4,496 | Viren im Trinkwasser | Viruses in drinking water can cause infectious diseases. In the past, hepatitis A and E were the most frequently observed drinking- water-borne viral infections, but in recent years several small- and large-scale norovirus epidemics have been described, even in Europe. All virus species spread via drinking water are of fecal origin. They are regularly identified in waste water even after conventional multi-stage water treatment. The approved disinfection methods can cope with these viruses if they are not integrated in larger particles. For this reason particle separation is particularly important in water treatment. Virological tests are not reliable enough to ensure that drinking water is sufficiently virus-free. The examination of 100 mL of water for E. coli and coliform bacteria is not adequate proof either. If potentially contaminated raw water is used, consumer safety must be ensured by calculating the performance of water treatment plants on a case-by-case basis. Such a calculation takes into account the virus load of the raw water, the efficiency of the physical and chemical particle elimination steps and the effect of disinfection. Those factors which determine the effectiveness of disinfection, namely concentration and exposure time or UV radiation strength, must be adjusted according to the risk of viral infection, and calculated settings must be adhered to, even if favorable E. coli levels may make them seem excessive. |
4,497 | Helicase-dependent isothermal amplification: a novel tool in the development of molecular-based analytical systems for rapid pathogen detection | Highly sensitive testing of nucleic acids is essential to improve the detection of pathogens, which pose a major threat for public health worldwide. Currently available molecular assays, mainly based on PCR, have a limited utility in point-of-need control or resource-limited settings. Consequently, there is a strong interest in developing cost-effective, robust, and portable platforms for early detection of these harmful microorganisms. Since its description in 2004, isothermal helicase-dependent amplification (HDA) has been successfully applied in the development of novel molecular-based technologies for rapid, sensitive, and selective detection of viruses and bacteria. In this review, we highlight relevant analytical systems using this simple nucleic acid amplification methodology that takes place at a constant temperature and that is readily compatible with microfluidic technologies. Different strategies for monitoring HDA amplification products are described. In addition, we present technological advances for integrating sample preparation, HDA amplification, and detection. Future perspectives and challenges toward point-of-need use not only for clinical diagnosis but also in food safety testing and environmental monitoring are also discussed. [Figure: see text] |
4,498 | Aufgaben und Funktion der Ständigen Arbeitsgemeinschaft der Kompetenz- und Behandlungszentren für hochkontagiöse, lebensbedrohliche Erkrankungen | The introduction of tropical diseases into Germany is becoming a more and more frequent public health problem due to increasing long distance travel and the globalization of economic activities. A network of centers of excellence for imported, highly contagious diseases has proven efficient and shown that the linking of public health service, clinical care, laboratory-based special diagnostics, ambulance service, and hospital hygiene can react quickly and professionally in even unexpected situations in clinical infectiology. These networks joined forces in the “Permanent Working Group of the Medical Competence and Treatment Centers“ (Ständigen Arbeitsgemeinschaft der Kompetenz- und Behandlungszentren, StAKoB). Not only in Germany but also worldwide, the StAKoB is a unique system for the treatment of imported highly contagious diseases. The goals and structure of the StAKoB are presented in this article. |
4,499 | Neues zur Pathophysiologie der Pneumonie | Pneumonia can lead to the critical impairment of gas exchange in the lung. Due to the great variability of pneumonia causing pathogens, a large variety of diverse virulence factors act on the lung. Besides stimulation of unspecific defense mechanisms, activation of receptor-dependent cell-mediated innate immune defense mechanisms are critical for the pulmonary immune defense. Pathogen-associated molecules are detected via transmembraneous and cytosolic receptors of the host. This interaction stimulates the expression of immunomodulatory molecules via signal cascades. Of particular importance, in addition to direct pathogen-caused lung damage, is the overwhelming activation of the inflammatory response which can result in lung barrier failure and impairment of pulmonary gas exchange. In addition to the design of new antibiotics, innovative therapeutic strategies should therefore concentrate on the enhancement of antimicrobial mechanisms by concurrent limitation of inflammation. |
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