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BACKGROUND: Traumatic brain injury (TBI) is one of the major health and socioeconomic problems in the world. Immune-enhancing enteral formula has been proven to significantly reduce infection rate in TBI patients. One of the ingredients that can be used in immunonutrition formulas to reduce inflammation and oxidative stress is pycnogenol. OBJECTIVE: The objective of this work is to survey the effect of pycnogenol on the clinical, nutritional, and inflammatory status of TBI patients. METHODS: This is a double-blind, randomized controlled trial. Block randomization will be used. An intervention group will receive pycnogenol supplementation of 150 mg for 10 days and a control group will receive a placebo for the same duration. Inflammatory status (IL-6, IL- 1β, C-reactive protein) and oxidative stress status (malondialdehyde, total antioxidant capacity), at the baseline, at the 5th day, and at the end of the study (10th day) will be measured. Clinical and nutritional status will be assessed three times during the intervention. The Sequential Organ Failure Assessment (SOFA) questionnaire for assessment of organ failure will be filled out every other day. The mortality rate will be calculated within 28 days of the start of the intervention. Weight, body mass index, and body composition will be measured. All analyses will be conducted by an initially assigned study arm in an intention-to-treat analysis. DISCUSSION: We expect that supplementation of 150 mg pycnogenol for 10 days will improve clinical and nutritional status and reduce the inflammation and oxidative stress of the TBI patients. TRIAL REGISTRATION: This trial is registered at clinicaltrials.gov (ref: NCT03777683) at 12/13/2018. |
Infections by multidrug-resistant (MDR) Gram-negative organisms (GN) are associated with a high mortality rate and present an increasing challenge to the healthcare system worldwide. In recent years, increasing evidence supports the association between the healthcare environment and transmission of MDRGN to patients and healthcare workers. To better understand the role of the environment in transmission and acquisition of MDRGN, we conducted a utilitarian review based on literature published from 2014 until 2019. |
BACKGROUND: Prolonged and difficult weaning is associated with higher rates of complications and mortality. Therefore, it is important to identify the associated factors. CASE PRESENTATION: We describe our experience with a 37-year-old man diagnosed with severe viral pneumonia (influenza A). He presented with acute respiratory failure type I on admission. During intubation, his blood pressure and heart rate decreased, and epinephrine and norepinephrine were administered. Although his clinical condition improved 8 days after intensive care unit (ICU) admission, he experienced difficulty weaning. He remained conscious but had a poor spontaneous cough with sputum production and weak limb muscle strength. His cough reflex was absent during bronchoscopic sputum suction, and he used abdominal breathing during the T-tube test. Magnetic resonance imaging revealed an Arnold–Chiari malformation type I, posterior dislocation of the odontoid process, and syringomyelia, with compression and deformation of the medulla and high cervical cord. The patient was successfully weaned from the ventilator at 20 days after ICU admission. CONCLUSIONS: Arnold–Chiari malformation type I and posterior dislocation of the odontoid process, which aggravate medullary compression and increase the risk of cervical nerve injury, might be a rare factor affecting prolonged weaning in critical illness. |
Ebola virus (EBOV) causes severe outbreaks of viral hemorrhagic fever in humans. While virus-host interactions are promising targets for antivirals, there is only limited knowledge regarding the interactions of EBOV with cellular host factors. Recently, we performed a genome-wide siRNA screen that identified the nuclear RNA export factor 1 (NXF1) as an important host factor for the EBOV life cycle. NXF1 is a major component of the nuclear mRNA export pathway that is usurped by many viruses whose life cycles include nuclear stages. However, the role of NXF1 in the life cycle of EBOV, a virus replicating in cytoplasmic inclusion bodies, remains unknown. In order to better understand the role of NXF1 in the EBOV life cycle, we performed a combination of co-immunoprecipitation and double immunofluorescence assays to characterize the interactions of NXF1 with viral proteins and RNAs. Additionally, using siRNA-mediated knockdown of NXF1 together with functional assays, we analyzed the role of NXF1 in individual aspects of the virus life cycle. With this approach we identified the EBOV nucleoprotein (NP) as a viral interaction partner of NXF1. Further studies revealed that NP interacts with the RNA-binding domain of NXF1 and competes with RNA for this interaction. Co-localization studies showed that RNA binding-deficient, but not wildtype NXF1, accumulates in NP-derived inclusion bodies, and knockdown experiments demonstrated that NXF1 is necessary for viral protein expression, but not for viral RNA synthesis. Finally, our results showed that NXF1 interacts with viral mRNAs, but not with viral genomic RNAs. Based on these results we suggest a model whereby NXF1 is recruited into inclusion bodies to promote the export of viral mRNA:NXF1 complexes from these sites. This would represent a novel function for NXF1 in the life cycle of cytoplasmically replicating viruses, and may provide a basis for new therapeutic approaches against EBOV, and possibly other emerging viruses. |
BACKGROUND: Severe blunt chest injury sometimes induces acute respiratory failure (ARF), requiring ventilator use. We aimed to evaluate the effect of performing rib fixation with the addition of video-assisted thoracoscopic surgery (VATS) on patients with ARF caused by blunt thoracic injury with ventilator dependence. METHODS: This observational study prospectively enrolled patients with multiple bicortical rib fractures with hemothorax caused by severe blunt chest trauma. All patients received positive pressure mechanical ventilation within 24 h after trauma because of ARF. Some patients who received rib fixation with VATS were enrolled as group 1, and the others who received only VATS were designated as group 2. The length of ventilator use was the primary clinical outcome. Rates of pneumonia and length of hospital stay constituted secondary outcomes. RESULTS: A total of 61 patients were included in this study. The basic demographic characteristics between the two groups exhibited no statistical differences. All patients received operations within 6 days after trauma. The length of ventilator use was shorter in group 1 (3.19 ± 3.37 days vs. 8.05 ± 8.23, P = 0.002). The rate of pneumonia was higher in group 2 (38.1% vs. 75.0%, P = 0.005). The length of hospital stay was much shorter in group 1 (17.76 ± 8.38 days vs. 24.13 ± 9.80, P = 0.011). CONCLUSION: Rib fixation combined with VATS could shorten the length of ventilator use and reduce the pneumonia rate in patients with severe chest blunt injury with ARF. Therefore, this operation could shorten the overall length of hospital stay. |
BACKGROUND/AIM: The aim of this study was to determine the accuracy of severity scores for predicting the 28-day mortality among adults with severe acute respiratory infection (SARI) admitted to the emergency department. MATERIALS AND METHODS: This study included 159 consecutive adult patients with SARI admitted to the emergency department of a tertiary hospital. A standard form was filled out in order to record demographic information, clinical parameters, laboratory tests, and radiographic findings of the patients. CURB-65, PSI, SIRS, qSOFA, SOFA and APACHE II scores were compared between the survivor and nonsurvivor groups. RESULTS: Of 159 patients included in the study, 38.4% were positive for respiratory viruses and 28.3% were positive for influenza viruses. 35.8% of the patients were admitted to an intensive care unit (ICU) and the mortality rate was 36.5%. The area under the receiver operating characteristic curve of CURB-65, PSI, SIRS criteria, qSOFA, SOFA and APACHE II scores were 0.717, 0.712, 0.607, 0.683, 0.755, and 0.748, respectively in predicting mortality and 0.759, 0.744, 0.583, 0.728, 0.741, and 0.731, respectively in predicting ICU admission. CONCLUSION: SOFA and APACHE II were more accurate than SIRS in predicting the 28-day mortality among adults with SARI. There was no significant difference among these scores in terms of other multivariate comparisons. |
Zika virus (ZIKV) has caused significant disease, with widespread cases of neurological pathology and congenital neurologic defects. Rapid vaccine development has led to a number of candidates capable of eliciting potent ZIKV-neutralizing antibodies (reviewed in refs. (1–3)). Despite advances in vaccine development, it remains unclear how ZIKV vaccination affects immune responses in humans with prior flavivirus immunity. Here we show that a single-dose immunization of ZIKV purified inactivated vaccine (ZPIV)(4–7) in a dengue virus (DENV)-experienced human elicited potent cross-neutralizing antibodies to both ZIKV and DENV. Using a unique ZIKV virion-based sorting strategy, we isolated and characterized multiple antibodies, including one termed MZ4, which targets a novel site of vulnerability centered on the Envelope (E) domain I/III linker region and protects mice from viremia and viral dissemination following ZIKV or DENV-2 challenge. These data demonstrate that Zika vaccination in a DENV-experienced individual can boost pre-existing flavivirus immunity and elicit protective responses against both ZIKV and DENV. ZPIV vaccination in Puerto Rican individuals with prior flavivirus experience yielded similar cross-neutralizing potency after a single vaccination, highlighting the potential benefit of ZIKV vaccination in flavivirus-endemic areas. |
Combination antiretroviral therapy (ART) is highly effective in controlling human immunodeficiency virus (HIV)-1 but requires lifelong medication due to the existence of a latent viral reservoir(1,2). Potent broadly neutralizing antibodies (bNAbs) represent a potential alternative or adjuvant to ART. In addition to suppressing viremia, bNAbs may have T cell immunomodulatory effects as seen for other forms of immunotherapy(3). However, this has not been established in individuals who are infected with HIV-1. Here, we document increased HIV-1 Gag-specific CD8(+) T cell responses in the peripheral blood of all nine study participants who were infected with HIV-1 with suppressed blood viremia, while receiving bNAb therapy during ART interruption(4). Increased CD4(+) T cell responses were detected in eight individuals. The increased T cell responses were due both to newly detectable reactivity to HIV-1 Gag epitopes and the expansion of pre-existing measurable responses. These data demonstrate that bNAb therapy during ART interruption is associated with enhanced HIV-1-specific T cell responses. Whether these augmented T cell responses can contribute to bNAb-mediated viral control remains to be determined. |
BACKGROUND: Right ventricular (RV) function evaluation by echocardiography is key in the management of ICU patients with acute respiratory distress syndrome (ARDS), however, it remains challenging. Quantification of RV deformation by speckle-tracking echocardiography (STE) is a recently available and reproducible technique that provides an integrated analysis of the RV. However, data are scarce regarding its use in critically ill patients. The aim of this study was to assess its feasibility and clinical usefulness in moderate–severe ARDS patients. RESULTS: Forty-eight ARDS patients under invasive mechanical ventilation (MV) were consecutively enrolled in a prospective observational study. A full transthoracic echocardiography was performed within 36 h of MV initiation. STE-derived and conventional parameters were recorded. Strain imaging of the RV lateral, inferior and septal walls was highly feasible (47/48 (98%) patients). Interobserver reproducibility of RV strain values displayed good reliability (intraclass correlation coefficients (ICC) > 0.75 for all STE-derived parameters) in ARDS patients. ROC curve analysis showed that lateral, inferior, global (average of the 3 RV walls) longitudinal systolic strain (LSS) and global strain rate demonstrated significant diagnostic values when compared to several conventional indices (TAPSE, S′, RV FAC). A RV global LSS value > − 13.7% differentiated patients with a TAPSE < vs > 12 mm with a sensitivity of 88% and a specificity of 83%. Regarding clinical outcomes, mortality and cumulative incidence of weaning from MV at day 28 were not different in patients with normal versus abnormal STE-derived parameters. CONCLUSIONS: Global STE assessment of the RV was highly achievable and reproducible in moderate–severe ARDS patients under MV and additionally correlated with several conventional parameters of RV function. In our cohort, STE-derived parameters did not provide any incremental value in terms of survival or weaning from MV prediction. Further investigations are needed to evaluate their theranostic usefulness. Trial registration NCT02638844: NCT |
Lassa fever (LF) is increasingly recognised as an important rodent-borne viral haemorrhagic fever presenting a severe public health threat to sub-Saharan West Africa. In 2017–18, LF caused an unprecedented epidemic in Nigeria and the situation was worsening in 2018–19. This work aims to study the epidemiological features of epidemics in different Nigerian regions and quantify the association between reproduction number (R) and state rainfall. We quantify the infectivity of LF by the reproduction numbers estimated from four different growth models: the Richards, three-parameter logistic, Gompertz and Weibull growth models. LF surveillance data are used to fit the growth models and estimate the Rs and epidemic turning points (τ) in different regions at different time periods. Cochran's Q test is further applied to test the spatial heterogeneity of the LF epidemics. A linear random-effect regression model is adopted to quantify the association between R and state rainfall with various lag terms. Our estimated Rs for 2017–18 (1.33 with 95% CI 1.29–1.37) was significantly higher than those for 2016–17 (1.23 with 95% CI: (1.22, 1.24)) and 2018–19 (ranged from 1.08 to 1.36). We report spatial heterogeneity in the Rs for epidemics in different Nigerian regions. We find that a one-unit (mm) increase in average monthly rainfall over the past 7 months could cause a 0.62% (95% CI 0.20%–1.05%)) rise in R. There is significant spatial heterogeneity in the LF epidemics in different Nigerian regions. We report clear evidence of rainfall impacts on LF epidemics in Nigeria and quantify the impact. |
Lassa virus (LASV) and Mopeia virus (MOPV) are two closely related, rodent-born mammarenaviruses. LASV is the causative agent of Lassa fever, a deadly hemorrhagic fever endemic in West Africa, whereas MOPV is non-pathogenic in humans. The Z matrix protein of arenaviruses is essential to virus assembly and budding by recruiting host factors, a mechanism that remains partially defined. To better characterize the interactions involved, a yeast two-hybrid screen was conducted using the Z proteins from LASV and MOPV as a bait. The cellular proteins ITCH and WWP1, two members of the Nedd4 family of HECT E3 ubiquitin ligases, were found to bind the Z proteins of LASV, MOPV and other arenaviruses. The PPxY late-domain motif of the Z proteins is required for the interaction with ITCH, although the E3 ubiquitin-ligase activity of ITCH is not involved in Z ubiquitination. The silencing of ITCH was shown to affect the replication of the old-world mammarenaviruses LASV, MOPV, Lymphocytic choriomeningitis virus (LCMV) and to a lesser extent Lujo virus (LUJV). More precisely, ITCH was involved in the egress of virus-like particles and the release of infectious progeny viruses. Thus, ITCH constitutes a novel interactor of LASV and MOPV Z proteins that is involved in virus assembly and release. |
Nipah virus (NiV) is an emerging zoonotic virus that is transmitted by bats to humans and to pigs, causing severe respiratory disease and often fatal encephalitis. Antibodies directed against the NiV-glycoprotein (G) protein are known to play a major role in clearing NiV infection and in providing vaccine-induced protective immunity. More recently, T cells have been also shown to be involved in recovery from NiV infection. So far, relatively little is known about the role of T cell responses and the antigenic targets of NiV-G that are recognized by CD8 T cells. In this study, NiV-G protein served as the target immunogen to activate NiV-specific cellular immune responses. Modified Vaccinia virus Ankara (MVA), a safety-tested strain of vaccinia virus for preclinical and clinical vaccine research, was used for the generation of MVA–NiV-G candidate vaccines expressing different versions of recombinant NiV-G. Overlapping peptides covering the entire NiV-G protein were used to identify major histocompatibility complex class I/II-restricted T cell responses in type I interferon receptor-deficient (IFNAR−/−) mice after vaccination with the MVA–NiV-G candidate vaccines. We have identified an H2-b-restricted nonamer peptide epitope with CD8 T cell antigenicity and a H2-b 15mer with CD4 T cell antigenicity in the NiV-G protein. The identification of this epitope and the availability of the MVA–NiV-G candidate vaccines will help to evaluate NiV-G-specific immune responses and the potential immune correlates of vaccine-mediated protection in the appropriate murine models of NiV-G infection. Of note, a soluble version of NiV-G was advantageous in activating NiV-G-specific cellular immune responses using these peptides. |
Dendritic cells (DCs) are among the first cells that recognize incoming viruses at the mucosal portals of entry. Initial interaction between DCs and viruses facilitates cell activation and migration to secondary lymphoid tissues, where these antigen presenting cells (APCs) prime specific adaptive immune responses. Some viruses, however, have evolved strategies to subvert the migratory capacity of DCs as a way to disseminate infection systemically. Here we focus on the role of Siglec-1, a sialic acid-binding type I lectin receptor potently upregulated by type I interferons on DCs, that acts as a double edge sword, containing viral replication through the induction of antiviral immunity, but also favoring viral spread within tissues. Such is the case for distant enveloped viruses like human immunodeficiency virus (HIV)-1 or Ebola virus (EBOV), which incorporate sialic acid-containing gangliosides on their viral membrane and are effectively recognized by Siglec-1. Here we review how Siglec-1 is highly induced on the surface of human DCs upon viral infection, the way this impacts different antigen presentation pathways, and how enveloped viruses have evolved to exploit these APC functions as a potent dissemination strategy in different anatomical compartments. |
The recent outbreak of Zika virus (ZIKV) in the Americas and its devastating developmental and neurological manifestations has prompted the development of field-based diagnostics that are rapid, reliable, handheld, specific, sensitive, and inexpensive. The gold standard molecular method for lab-based diagnosis of ZIKV, from either patient samples or insect vectors, is reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The method, however, is costly and requires lab-based equipment and expertise, which severely limits its use as a point-of-care (POC) tool in resource-poor settings. Moreover, given the lack of antivirals or approved vaccines for ZIKV infection, a POC diagnostic test is urgently needed for the early detection of new outbreaks and to adequately manage patients. Loop-mediated isothermal amplification (LAMP) is a compelling alternative to RT-qPCR for ZIKV and other arboviruses. This low-cost molecular system can be freeze-dried for distribution and exhibits high specificity, sensitivity, and efficiency. A growing body of evidence suggests that LAMP assays can provide greater accessibility to much-needed diagnostics for ZIKV infections, especially in developing countries where the ZIKV is now endemic. This review summarizes the different LAMP methods that have been developed for the virus and summarizes their features, advantages, and limitations. |
Ebola virus infections lead to severe hemorrhagic fevers in humans and nonhuman primates; and human fatality rates are as high as 67%–90%. Since the Ebola virus was discovered in 1976, the only available treatments have been medical support or the emergency administration of experimental drugs. The absence of licensed vaccines and drugs against the Ebola virus impedes the prevention of viral infection. In this study, we generated recombinant baculoviruses (rBV) expressing the Sudan virus (SUDV) matrix structural protein (VP40) (rBV-VP40-VP40) or the SUDV glycoprotein (GP) (rBV-GP-GP), and SUDV virus-like particles (VLPs) were produced by co-infection of Sf9 cells with rBV-SUDV-VP40 and rBV-SUDV-GP. The expression of SUDV VP40 and GP in SUDV VLPs was demonstrated by IFA and Western blot analysis. Electron microscopy results demonstrated that SUDV VLPs had a filamentous morphology. The immunogenicity of SUDV VLPs produced in insect cells was evaluated by the immunization of mice. The analysis of antibody responses showed that mice vaccinated with SUDV VLPs and the adjuvant Montanide ISA 201 produced SUDV GP-specific IgG antibodies. Sera from SUDV VLP-immunized mice were able to block infection by SUDV GP pseudotyped HIV, indicating that a neutralizing antibody against the SUDV GP protein was produced. Furthermore, the activation of B cells in the group immunized with VLPs mixed with Montanide ISA 201 was significant one week after the primary immunization. Vaccination with the SUDV VLPs markedly increased the frequency of antigen-specific cells secreting type 1 and type 2 cytokines. To study the therapeutic effects of SUDV antibodies, horses were immunized with SUDV VLPs emulsified in Freund’s complete adjuvant or Freund’s incomplete adjuvant. The results showed that horses could produce SUDV GP-specific antibodies and neutralizing antibodies. These results showed that SUDV VLPs demonstrate excellent immunogenicity and represent a promising approach for vaccine development against SUDV infection. Further, these horse anti-SUDV purified immunoglobulins lay a foundation for SUDV therapeutic drug research. |
In response to viral infection, host cells activate various antiviral responses to inhibit virus replication. While feline herpesvirus 1 (FHV-1) manipulates the host early innate immune response in many different ways, the host could activate the antiviral response to counteract it through some unknown mechanisms. MicroRNAs (miRNAs) which serve as a class of regulatory factors in the host, participate in the regulation of the host innate immune response against virus infection. In this study, we found that the expression levels of miR-26a were significantly upregulated upon FHV-1 infection. Furthermore, FHV-1 infection induced the expression of miR-26a via a cGAS-dependent pathway, and knockdown of cellular cGAS significantly blocked the expression of miR-26a induced by poly (dA:dT) or FHV-1 infection. Next, we investigated the biological function of miR-26a during viral infection. miR-26a was able to increase the phosphorylation of STAT1 and promote type I IFN signaling, thus inhibiting viral replication. The mechanism study showed that miR-26a directly targeted host SOCS5. Knockdown of SOCS5 increased the phosphorylation of STAT1 and enhanced the type I IFN-mediated antiviral response, and overexpression of suppressor of the cytokine signalling 5 (SOCS5) decreased the phosphorylation of STAT1 and inhibited the type I IFN-mediated antiviral response. Meanwhile, with the knockdown of SOCS5, the upregulated expression of phosphorylated STAT1 and the anti-virus effect induced by miR-26a were significantly inhibited. Taken together, our data demonstrated a new strategy of host miRNAs against FHV-1 infection by enhancing IFN antiviral signaling. |
BACKGROUND: Septoplasty (surgery to straighten a deviation in the nasal septum) is a frequently performed operation worldwide, with approximately 250,000 performed annually in the US and 22,000 in the UK. Most septoplasties aim to improve diurnal and nocturnal nasal obstruction. The evidence base for septoplasty clinical effectiveness is hitherto very limited. AIMS: To establish, and inform guidance for, the best management strategy for individuals with nasal obstruction associated with a deviated septum. METHODS/DESIGN: A multicentre, mixed-methods, open label, randomised controlled trial of septoplasty versus medical management for adults with a deviated septum and a reduced nasal airway. Eligible patients will have septal deflection visible at nasendoscopy and a nasal symptom score ≥ 30 on the NOSE questionnaire. Surgical treatment comprises septoplasty with or without reduction of the inferior nasal turbinate on the anatomically wider side of the nose. Medical management comprises a nasal saline spray followed by a fluorinated steroid spray daily for six months. The recruitment target is 378 patients, recruited from up to 17 sites across Scotland, England and Wales. Randomisation will be on a 1:1 basis, stratified by gender and severity (NOSE score). Participants will be followed up for 12 months post randomisation. The primary outcome measure is the total SNOT-22 score at 6 months. Clinical and economic outcomes will be modelled against baseline severity (NOSE scale) to inform clinical decision-making. The study includes a recruitment enhancement process, and an economic evaluation. DISCUSSION: The NAIROS trial will evaluate the clinical effectiveness and cost-effectiveness of septoplasty versus medical management for adults with a deviated septum and symptoms of nasal blockage. Identifying those individuals most likely to benefit from surgery should enable more efficient and effective clinical decision-making, and avoid unnecessary operations where there is low likelihood of patient benefit. TRIAL REGISTRATION: EudraCT: 2017–000893-12, ISRCTN: 16168569. Registered on 24 March 2017. |
BACKGROUND: We sought to develop and test an objective scorecard-based system for assessing and categorizing available research sites in Lassa fever-affected countries based on their preparedness and capability to host Lassa fever vaccine clinical trials. METHODS: We mapped available clinical research sites through interrogation of online clinical trial registries and relevant disease-based consortia. A structured online questionnaire was used to assess the capability of clinical trial sites to conduct Lassa fever vaccine clinical trials. We developed a new scoring template by allocating scores to questionnaire parameters based on perceived importance to the conduct of clinical trials as described in the WHO/TDR Global Competency Framework for Clinical Research. Cutoff points of 75% and 50% were used to categorize sites into categories A, B, or C. RESULTS: This study identified 44 clinical trial sites in 8 Lassa fever-affected countries. Out of these, 35 sites were characterized based on their capacity to hold Lassa fever vaccine clinical trials. A total of 14 sites in 4 countries were identified as ready to host Lassa fever vaccine trials immediately or with little support. CONCLUSION: It is feasible to hold Lassa fever vaccine trials in affected countries based on the outcome of the survey. However, the findings are to be validated through sites’ visits. This experience with a standardized and objective method of the site assessment is encouraging, and the site selection method used can serve as an orientation to sponsors and researchers planning clinical trials in the region. |
Mycobacterium avium subsp. paratuberculosis (M. paratuberculosis) causes Johne’s disease in ruminants and is characterized by chronic gastroenteritis leading to heavy economic losses to the dairy industry worldwide. The currently available vaccine (inactivated bacterin in oil base) is not effective in preventing pathogen shedding and is rarely used to control Johne’s disease in dairy herds. To develop a better vaccine that can prevent the spread of Johne’s disease, we utilized polyanhydride nanoparticles (PAN) to encapsulate mycobacterial antigens composed of whole cell lysate (PAN-Lysate) and culture filtrate (PAN-Cf) of M. paratuberculosis. These nanoparticle-based vaccines (i.e., nanovaccines) were well tolerated in mice causing no inflammatory lesions at the site of injection. Immunological assays demonstrated a substantial increase in the levels of antigen-specific T cell responses post-vaccination in the PAN-Cf vaccinated group as indicated by high percentages of triple cytokine (IFN-γ, IL-2, TNF-α) producing CD8(+) T cells. Following challenge, animals vaccinated with PAN-Cf continued to produce significant levels of double (IFN-γ, TNF-α) and single cytokine (IFN-γ) secreting CD8(+) T cells compared with animals vaccinated with an inactivated vaccine. A significant reduction in bacterial load was observed in multiple organs of animals vaccinated with PAN-Cf, which is a clear indication of protection. Overall, the use of polyanhydride nanovaccines resulted in development of protective and sustained immunity against Johne’s disease, an approach that could be applied to counter other intracellular pathogens. |
This retrospective study aimed to clarify the short- and mid-term outcomes of elderly patients who underwent surgery to treat left-sided native valve infective endocarditis (LSNIE). Between July 2005 and September 2015, 179 patients underwent surgical treatment for active LSNIE at a single institution. Patients were classified into two groups: ≥65 years (elderly group) and <65 years (non-elderly group). Clinical features, surgical information, postoperative complications, and three-year survival rates were compared. The average ages were 74.2 ± 6.4 and 45.2 ± 12.6 years in the elderly and non-elderly groups, respectively. The elderly group had a higher predicted mortality rate and a lower incidence of preoperative septic emboli-related complications. Echocardiographic assessments of infected valves were generally homogenous between the groups. The elderly patients had a higher in-hospital mortality rate than the non-elderly patients (26.3% vs. 5.7%, P = 0.001). For patients who survived to discharge, the three-year cumulative survival rates were 75.0% ± 8.2% and 81.2% ± 3.4% in the elderly and non-elderly groups, respectively (P = 0.484). In conclusion, elderly patients are at a higher risk of in-hospital mortality after surgery for LSNIE. However, once elderly patients are stabilized by surgical treatment and survive to discharge, the mid-term outcomes are promising. |
Numerous epidemic models have been developed to capture aspects of human contact patterns, making model selection challenging when they fit (often-scarce) early epidemic data equally well but differ in predictions. Here we consider the invasion of a novel directly transmissible infection and perform an extensive, systematic and transparent comparison of models with explicit age and/or household structure, to determine the accuracy loss in predictions in the absence of interventions when ignoring either or both social components. We conclude that, with heterogeneous and assortative contact patterns relevant to respiratory infections, the model’s age stratification is crucial for accurate predictions. Conversely, the household structure is only needed if transmission is highly concentrated in households, as suggested by an empirical but robust rule of thumb based on household secondary attack rate. This work serves as a template to guide the simplicity/accuracy trade-off in designing models aimed at initial, rapid assessment of potential epidemic severity. |
The situation of drug resistance has become more complicated due to the scarcity of plant resistance genes, and overcoming this challenge is imperative. Isatis indigotica has been used for the treatment of wounds, viral infections, and inflammation for centuries. Antimicrobial peptides (AMPs) are found in all classes of life ranging from prokaryotes to eukaryotes. To identify AMPs, I. indigotica was explored using a novel, sensitive, and high-throughput Bacillus subtilis screening system. We found that IiR515 and IiR915 exhibited significant antimicrobial activities against a variety of bacterial (Xanthomonas oryzae, Ralstonia solanacearum, Clavibacter michiganensis, and C. fangii) and fungal (Phytophthora capsici and Botrytis cinerea) pathogens. Scanning electron microscope and cytometric analysis revealed the possible mechanism of these peptides, which was to target and disrupt the bacterial cell membrane. This model was also supported by membrane fluidity and electrical potential analyses. Hemolytic activity assays revealed that these peptides may act as a potential source for clinical medicine development. In conclusion, the plant-derived novel AMPs IiR515 and IiR915 are effective biocontrol agents and can be used as raw materials in the drug discovery field. |
HTLV-1 was the first described human retrovirus and was soon found to be associated with severe clinical diseases, including a devastating lymphoma/leukemia and other inflammatory diseases. Although HTLV-2 is not usually pathogenic, it is widely distributed among native Indian populations in Brazil, particularly in the Amazon region of the country. Presently, HTLV spreads mainly by the sexual route and from mother to child, and virus persistence is an active biological factor aiding its transmission. Recently, the use of illicit drugs has been shown to be an additional risk factor, showing the influence of new habits on the epidemiology of HTLV in the region. Despite the detection of the virus in several different populations in the Amazon region of Brazil for almost 30 years, the exact prevalence of HTLV-1/2 is not well defined. The original biases in sampling and the selection of epidemiologically unsuitable populations were commonly repeated in most prevalence studies, generating unreliable and conflicting figures that do not represent the actual prevalence of HTLV. The improvements in clinical and laboratory facilities have resulted in the description of several clinical manifestations that were previously unknown in the region. The extent of the spread of the virus must be defined in this region, which is the largest geographical area of the country. As prophylaxis advances toward the use of vaccines against HTLV-1, it is important to determine who is at risk of being infected and developing a disease to successfully implement preventive measures, particularly as proposals are made to eradicate the virus among humans. |
BACKGROUND: The number of children requiring long-term home ventilation has consistently increased over the last 25 years. Given the growing population of children with complex care needs (CCNs), this was an important area of focus within the Models of Child Health Appraised (MOCHA) project, funded by the European Union (EU) under the Horizon 2020 programme. We examined the structures and processes of care in place for children with CCNs and identified key constituents for effective integration of care for these children at the community and acute care interface across 30 EU/ European Economic Area (EEA) countries. METHODS: This was a non-experimental descriptive study with an embedded qualitative element. Data were collected by a Country Agent in each of the 30 countries, a local expert in child health services. Data were analysed using descriptive statistics and a thematic analysis was undertaken of the free text data provided. RESULTS: A total of 27 surveys were returned from a possible 30 countries (90.0%) countries. One respondent indicated that their country does not have children on long-term ventilation (LTV) in the home, therefore, responses of 26 countries (86.7%) were analysed. None of the responding countries reported that they had all of the core components in place in their country. Three themes emerged from the free text provided: ‘family preparedness for transitioning to home’, ‘coordinated pathway to specialist care’ and ‘legal and governance structures’. CONCLUSIONS: While the clinical care of children on LTV in the acute sector has received considerable attention, the results identify the need for an enhanced focus on the care required following discharge to the community setting. The results highlight the need for a commitment to supporting care delivery that acknowledges the complexity of contemporary child health issues and the context of the families that become their primary care givers. |
BACKGROUND: Optimal timing for the start of vasopressors (VP) in septic shock has not been widely studied since it is assumed that fluids must be administered in advance. We sought to evaluate whether a very early start of VP, even without completing the initial fluid loading, might impact clinical outcomes in septic shock. METHODS: A total of 337 patients with sepsis requiring VP support for at least 6 h were initially selected from a prospectively collected database in a 90-bed mixed-ICU during a 24-month period. They were classified into very-early (VE-VPs) or delayed vasopressor start (D-VPs) categories according to whether norepinephrine was initiated or not within/before the next hour of the first resuscitative fluid load. Then, VE-VPs (n = 93) patients were 1:1 propensity matched to D-VPs (n = 93) based on age; source of admission (emergency room, general wards, intensive care unit); chronic and acute comorbidities; and lactate, heart rate, systolic, and diastolic pressure at vasopressor start. A risk-adjusted Cox proportional hazard model was fitted to assess the association between VE-VPs and day 28 mortality. Finally, a sensitivity analysis was performed also including those patients requiring VP support for less than 6 h. RESULTS: Patients subjected to VE-VPs received significantly less resuscitation fluids at vasopressor starting (0[0–510] vs. 1500[650–2300] mL, p < 0.001) and during the first 8 h of resuscitation (1100[500–1900] vs. 2600[1600–3800] mL, p < 0.001), with no significant increase in acute renal failure and/or renal replacement therapy requirements. VE-VPs was related with significant lower net fluid balances 8 and 24 h after VPs. VE-VPs was also associated with a significant reduction in the risk of death compared to D-VPs (HR 0.31, CI95% 0.17–0.57, p < 0.001) at day 28. Such association was maintained after including patients receiving vasopressors for < 6 h. CONCLUSION: A very early start of vasopressor support seems to be safe, might limit the amount of fluids to resuscitate septic shock, and could lead to better clinical outcomes. |
Vaccination is the most effective measure at preventing influenza virus infections. However, current seasonal influenza vaccines are only protective against closely matched circulating strains. Even with extensive monitoring and annual reformulation our efforts remain one step behind the rapidly evolving virus, often resulting in mismatches and low vaccine effectiveness. Fortunately, many next-generation influenza vaccines are currently in development, utilizing an array of innovative techniques to shorten production time and increase the breadth of protection. This review summarizes the production methods of current vaccines, recent advances that have been made in influenza vaccine research, and highlights potential challenges that are yet to be overcome. Special emphasis is put on the potential role of glycoengineering in influenza vaccine development, and the advantages of removing the glycan shield on influenza surface antigens to increase vaccine immunogenicity. The potential for future development of these novel influenza vaccine candidates is discussed from an industry perspective. |
BACKGROUND: MicroRNAs (miRNAs) play an essential role in gene regulators in many biological and molecular phenomena. Unraveling the involvement of miRNA as a key cellular factor during in vitro canine parvovirus (CPV) infection may facilitate the discovery of potential intervention candidates. However, the examination of miRNA expression profiles in CPV in tissue culture systems has not been fully elucidated. METHOD: In the present study, we utilized high-throughput small RNA-seq (sRNA-seq) technology to investigate the altered miRNA profiling in miRNA libraries from uninfected (Control) and CPV-2c infected Crandell Reese Feline Kidney cells. RESULTS: We identified five of known miRNAs (miR-222-5p, miR-365-2-5p, miR-1247-3p, miR-322-5p and miR-361-3p) and three novel miRNAs (Novel 137, Novel 141 and Novel 102) by sRNA-seq with differentially expressed genes in the miRNA repertoire of CPV-infected cells over control. We further predicted the potential target genes of the aforementioned miRNAs using sequence homology algorithms. Notably, the targets of miR-1247-3p exhibited a potential function associated with cellular defense and humoral response to CPV. To extend the probing scheme for gene targets of miR-1247-3p, we explored and performed Gene Ontology (GO) enrichment analysis of its target genes. We discovered 229 putative targets from a total of 38 enriched GO terms. The top over-represented GO enrichment in biological process were lymphocyte activation and differentiation, marginal zone B cell differentiation, negative regulation of cytokine production, negative regulation of programed cell death, and negative regulation of signaling. We next constructed a GO biological process network composed of 28 target genes of miR-1247-3p, of which, some genes, namely BCL6, DLL1, GATA3, IL6, LEF1, LFNG and WNT1 were among the genes with obviously intersected in multiple GO terms. CONCLUSION: The miRNA-1247-3p and its cognate target genes suggested their great potential as novel therapeutic targets or diagnostic biomarkers of CPV or other related viruses. |
Lactic acid bacteria (LAB) are major microorganisms used for probiotic purposes and prime parts of the human and mammalian gut microbiota, which exert important health-promoting effects on the host. The present study aimed to evaluate and compare the probiotic potential and safety of LAB strains isolated from the gastrointestinal tract of a wild boar from the Greater Khingan Mountains, China. Amongst all of the isolated LAB strains, five isolates identified as Lactobacillus mucosae, Lactobacillus salivarius, Enterococcus hirae, Enterococcus durans, and Enterococcus faecium, were remarkably resistant to acid and bile salt. The probiotic characteristics (including adhesion capability, antimicrobial activities, autoaggregation, and coaggregation abilities), and safety properties (including hemolytic activity, antibiotic resistance, absence/presence of virulence factors, and in vivo safety) were evaluated. The results showed that all five isolates exhibited high adhesive potential, remarkable aggregation capacity, and antibacterial activities. Upon assessment of the safety, these strains were negative for hemolytic activity and all tested virulence genes. In vivo safety assessment showed no adverse effects of isolated strains supplementation on the body weight gain and organ indices of the treated mice. This study revealed that these LAB isolates, especially L. salivarius M2-71, possess desirable probiotic properties and have great potentials for the development of feed additives for animals to promote health. |
BACKGROUND: Usage of chloroquine was discontinued from the treatment of Plasmodium falciparum infection in almost all endemic regions because of global spread of resistant parasites. Since the first report in Malawi, numerous epidemiological studies have demonstrated that the discontinuance led to re-emergence of chloroquine-susceptible P. falciparum, suggesting a possible role in future malaria control. However, most studies were cross-sectional, with few studies looking at the persistence of chloroquine recovery in long term. This study fills the gap by providing, for a period of at least 6 years, proof of persistent re-emergence/stable recovery of susceptible parasite populations using both molecular and phenotypic methods. METHODS: Ex vivo drug-susceptibility assays to chloroquine (n = 319) and lumefantrine (n = 335) were performed from 2013 to 2018 in Gulu, Northern Uganda, where chloroquine had been removed from the official malaria treatment regimen since 2006. Genotyping of pfcrt and pfmdr1 was also performed. RESULTS: Chloroquine resistance (≥ 100 nM) was observed in only 3 (1.3%) samples. Average IC(50) values for chloroquine were persistently low throughout the study period (17.4–24.9 nM). Parasites harbouring pfcrt K76 alleles showed significantly lower IC(50)s to chloroquine than the parasites harbouring K76T alleles (21.4 nM vs. 43.1 nM, p-value = 3.9 × 10(−8)). Prevalence of K76 alleles gradually increased from 71% in 2013 to 100% in 2018. CONCLUSION: This study found evidence of stable persistence of chloroquine susceptibility with the fixation of pfcrt K76 in Northern Uganda after discontinuation of chloroquine in the region. Accumulation of similar evidence in other endemic areas in Uganda could open channels for possible future re-use of chloroquine as an option for malaria treatment or prevention. |
BACKGROUND: Optimal antimicrobial drug exposure in the lung is required for successful treatment outcomes for nosocomial pneumonia. Little is known about the intrapulmonary pharmacokinetics (PK) of meropenem when administered by continuous infusion (CI). The aim of this study was to evaluate the PK of two dosages of meropenem (3 g vs 6 g/day by CI) in the plasma and epithelial lining fluid (ELF) in critically ill patients with nosocomial pneumonia. METHODS: Thirty-one patients (81% male, median (IQR) age 72 (22) years) were enrolled in a prospective, randomized, clinical trial. Sixteen patients received 1 g/8 h and 15 2 g/8 h by CI (8 h infusion). Plasma and ELF meropenem concentrations were modeled using a population methodology, and Monte Carlo simulations were performed to estimate the probability of attaining (PTA) a free ELF concentration of 50% of time above MIC (50% fT>MIC), which results in logarithmic killing and the suppression of resistance in experimental models of pneumonia. RESULTS: The median (IQR) of meropenem AUC(0–24 h) in the plasma and ELF was 287.6 (190.2) and 84.1 (78.8) mg h/L in the 1 g/8 h group vs 448.1 (231.8) and 163.0 (201.8) mg h/L in the 2 g/8 h group, respectively. The penetration ratio was approximately 30% and was comparable between the dosage groups. In the Monte Carlo simulations, only the highest approved dose of meropenem of 2 g/8 h by CI allowed to achieve an optimal PTA for all isolates with a MIC < 4 mg/L. CONCLUSIONS: An increase in the dose of meropenem administered by CI achieved a higher exposure in the plasma and ELF. The use of the highest licensed dose of 6 g/day may be necessary to achieve an optimal coverage in ELF for all susceptible isolates (MIC ≤ 2 mg/L) in patients with conserved renal function. An alternative therapy should be considered when the presence of microorganisms with a MIC greater than 2 mg/L is suspected. TRIAL REGISTRATION: The trial was registered in the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT-no. 2016-002796-10). Registered on 27 December 2016. |
BACKGROUND: We aimed to synthesize up-to-date trials to validate the effects of neuromuscular blocking agent (NMBA) use in patients with moderate-to-severe acute respiratory distress syndrome (ARDS). METHODS: Several databases including PubMed, EMBASE, Web of Science, and Cochrane Central Register were searched up to November 14, 2019. All randomized trials investigating the use of NMBAs in patients with moderate-to-severe ARDS and reporting mortality data were included in the meta-analysis. The primary outcome was mortality, and the secondary outcomes were clinical outcomes, including respiratory physiological parameters, incidence of barotrauma, ICU-free days, and ventilation-free days. RESULTS: A total of 7 trials enrolling 1598 patients were finally included in this meta-analysis. The results revealed that the use of NMBAs in moderate-to-severe ARDS could significantly decrease the mortality truncated to day 28 (RR 0.74, 95% CI 0.56 to 0.98, P = 0.03) and day 90 (RR 0.77, 95% CI 0.60 to 0.99, P = 0.04). NMBA use could significantly decrease the incidence of barotrauma (RR 0.56, 95% CI 0.36 to 0.87, P = 0.009). No significant difference was observed in ICU-free days or ventilation-free days between the NMBA and control groups. CONCLUSION: The use of NMBAs could significantly decrease mortality in moderate-to-severe ARDS patients and decrease the incidence of barotrauma during mechanical ventilation. However, more large-scale randomized trials are needed to further validate the effect of NMBA use in ARDS. |
BACKGROUND: Whether Borna disease virus (BDV-1) is a human pathogen remained controversial until recent encephalitis cases showed BDV-1 infection could even be deadly. This called to mind previous evidence for an infectious contribution of BDV-1 to mental disorders. Pilot open trials suggested that BDV-1 infected depressed patients benefitted from antiviral therapy with a licensed drug (amantadine) which also tested sensitive in vitro. Here, we designed a double-blind placebo-controlled randomized clinical trial (RCT) which cross-linked depression and BDV-1 infection, addressing both the antidepressant and antiviral efficacy of amantadine. METHODS: The interventional phase II RCT (two 7-weeks-treatment periods and a 12-months follow-up) at the Hannover Medical School (MHH), Germany, assigned currently depressed BDV-1 infected patients with either major depression (MD; N = 23) or bipolar disorder (BD; N = 13) to amantadine sulphate (PK-Merz®; twice 100 mg orally daily) or placebo treatment, and contrariwise, respectively. Clinical changes were assessed every 2–3 weeks by the 21-item Hamilton rating scale for depression (HAMD) (total, single, and combined scores). BDV-1 activity was determined accordingly in blood plasma by enzyme immune assays for antigens (PAG), antibodies (AB) and circulating immune complexes (CIC). RESULTS: Primary outcomes (≥25% HAMD reduction, week 7) were 81.3% amantadine vs. 35.3% placebo responder (p = 0.003), a large clinical effect size (ES; Cohen’s d) of 1.046, and excellent drug tolerance. Amantadine was safe reducing suicidal behaviour in the first 2 weeks. Pre-treatment maximum infection levels were predictive of clinical improvement (AB, p = 0.001; PAG, p = 0.026; HAMD week 7). Respective PAG and CIC levels correlated with AB reduction (p = 0,001 and p = 0.034, respectively). Follow-up benefits (12 months) correlated with dropped cumulative infection measures over time (p < 0.001). In vitro, amantadine concentrations as low as 2.4–10 ng/mL (50% infection-inhibitory dose) prevented infection with human BDV Hu-H1, while closely related memantine failed up to 100,000-fold higher concentration (200 μg/mL). CONCLUSIONS: Our findings indicate profound antidepressant efficacy of safe oral amantadine treatment, paralleling antiviral effects at various infection levels. This not only supports the paradigm of a link of BDV-1 infection and depression. It provides a novel possibly practice-changing low cost mental health care perspective for depressed BDV-1-infected patients addressing global needs. TRIAL REGISTRATION: The trial was retrospectively registered in the German Clinical Trials Registry on 04th of March 2015. The trial ID is DRKS00007649; https://www.drks.de/drks_web/setLocale_EN.do |
In the present study, a new hepatic tissue‐origin cell line from European eel Anguilla anguilla has been developed and characterized. This cell line designated EL has been maintained in Leibovitz L‐15 supplemented with 10% fetal bovine serum over 72 months, and subcultured more than 90 times. The EL cell line consisted predominantly of fibroblast‐like cells, which could survive over 100 days in vitro, and could grow at 15–32°C. The optimum temperature for growth was 27°C. The chromosome analysis revealed a modal diploid karyotype of 2n = 38. The origin of this cell line was confirmed by the 18S recombinant (r)RNA sequencing. The susceptibility test indicated significant cytopathic effects in the EL cells with regard to the Rana grylio virus and the Herpesvirus anguillae. The viral replication was confirmed by transmission electron microscopy and polymerase chain reaction analysis. Following poly (I:C) exposure, the expression levels of the immune‐related molecules interferon regulatory factor‐7 (irf7) and transforming growth factor‐β (TGF‐β) were downregulated in EL cells, whereas the expression levels of the rf3 and the cytochrome P450 (CYP450) were upregulated. All four genes were significantly upregulated following inflammation by lipopolysaccharide (LPS). These data suggested the application of EL cell line for viral identification, as well as for immunodiagnosis and pharmacological targeting. |
Human metapneumovirus (hMPV) is an important pathogen that causes upper and lower respiratory tract infections in children worldwide. hMPV has two major genotypes, hMPV-A and hMPV-B. Epidemiological studies have shown that the two hMPV genotypes alternate in predominance worldwide in recent years. Co-circulation of the two genotypes of hMPV was usually observed and there is no study about the interaction between them, such as competitive replication, which maybe the possible mechanisms for alternating prevalence of subtypes. Our present study have used two different genotypes of hMPV (genotype A: NL/1/00; B: NL/1/99) in different proportions in animal model (BALB/c mice) and cell model (Vero-E6) separately. The result showed that the competitive growth does exist in BALB/c mice, genotype B had a strong competitive advantage. However, genotype B did not cause more severe disease than non-predominant (genotype A) or mixed strains in the study, which were evaluated by the body weight, airway hyperresponsiveness and lung pathology of mouse. In cell model, competitive growth and the two genotypes alternately prevalence were observed. In summary, we confirmed that there was a competitive replication between hMPV genotype A and B, and no difference in disease severity caused by the two subtypes. This study shows a new insight to understand the alternation of hMPV genotype prevalence through genotype competition and provide experimental evidence for disease control and vaccine design. |
BACKGROUND: Miller Fisher syndrome is a variant of acute inflammatory demyelinating polyneuropathy classically characterized by ataxia, ophthalmoplegia, and areflexia. Miller Fisher syndrome can present with uncommon symptoms such as bulbar, facial, and somatic muscle palsies and micturition disturbance. CASE PRESENTATION: We describe the case of a 76-year-old white man with new-onset ataxia, stridor, areflexia, and upper and lower extremity weakness who required intubation at presentation. An initial work-up including imaging studies and serum tests was inconclusive. Eventually, neurophysiological testing and cerebrospinal fluid analysis suggested a diagnosis of Miller Fisher syndrome. Our patient responded to treatment with intravenous immunoglobulin and supportive therapy. CONCLUSION: The occurrence of acute or subacute descending paralysis with involvement of bulbar muscles and respiratory failure can often divert clinicians to a diagnosis of neuromuscular junction disorders (such as botulism or myasthenia gravis), vascular causes like stroke, or electrolyte and metabolic abnormalities. Early identification of Miller Fisher syndrome with appropriate testing is essential to prompt treatment and prevention of further, potentially fatal, deterioration. |
BACKGROUND: Novel methods are necessary to reduce morbidity and mortality of patients suffering from infections with Pseudomonas aeruginosa. Being the most common infectious species of the Pseudomonas genus, P. aeruginosa is the primary Gram-negative etiology responsible for nosocomial infections. Due to the ubiquity and high adaptability of this species, an effective universal treatment method for P. aeruginosa infection still eludes investigators, despite the extensive research in this area. RESULTS: We report bacterial inhibition by iron-oxide (nominally magnetite) nanoparticles (NPs) alone, having a mean hydrodynamic diameter of ~ 16 nm, as well as alginate-capped iron-oxide NPs. Alginate capping increased the average hydrodynamic diameter to ~ 230 nm. We also investigated alginate-capped iron-oxide NP-drug conjugates, with a practically unchanged hydrodynamic diameter of ~ 232 nm. Susceptibility and minimum inhibitory concentration (MIC) of the NPs, NP-tobramycin conjugates, and tobramycin alone were determined in the PAO1 bacterial colonies. Investigations into susceptibility using the disk diffusion method were done after 3 days of biofilm growth and after 60 days of growth. MIC of all compounds of interest was determined after 60-days of growth, to ensure thorough establishment of biofilm colonies. CONCLUSIONS: Positive inhibition is reported for uncapped and alginate-capped iron-oxide NPs, and the corresponding MICs are presented. We report zero susceptibility to iron-oxide NPs capped with polyethylene glycol, suggesting that the capping agent plays a major role in enabling bactericidal ability in of the nanocomposite. Our findings suggest that the alginate-coated nanocomposites investigated in this study have the potential to overcome the bacterial biofilm barrier. Magnetic field application increases the action, likely via enhanced diffusion of the iron-oxide NPs and NP-drug conjugates through mucin and alginate barriers, which are characteristic of cystic-fibrosis respiratory infections. We demonstrate that iron-oxide NPs coated with alginate, as well as alginate-coated magnetite–tobramycin conjugates inhibit P. aeruginosa growth and biofilm formation in established colonies. We have also determined that susceptibility to tobramycin decreases for longer culture times. However, susceptibility to the iron-oxide NP compounds did not demonstrate any comparable decrease with increasing culture time. These findings imply that iron-oxide NPs are promising lower-cost alternatives to silver NPs in antibacterial coatings, solutions, and drugs, as well as other applications in which microbial abolition or infestation prevention is sought. |
BACKGROUND: According to the World Health Organization reports, billions of people around the world are at risk for malaria disease and it is important to consider the preventive strategies for protecting the people that are living in high risk areas. One of the main reasons of disease survival is diversity of vectors and parasites in different malaria regions that have their specific features, behaviour and biology. Therefore, specific regional strategies are necessary for successful control of malaria. One of the tools that needs to be developed for elimination and prevention of reintroduction of malaria is a vaccine that interrupt malaria transmission (VIMTs). VIMT is a broad concept that should be adjusted to the biological characteristics of the disease in each region. One type of VIMT is a vector-based vaccine that affects the sexual stage of Plasmodium life cycle. According to recent studies, the aminopeptidase N-1 of Anopheles gambiae (AgAPN-1) is as a potent vector-based VIMT with considerable inhibition activity against the sexual stage of Plasmodium parasite. METHODS: Systems for rapid amplification of cDNA ends (3ʹ-RACE) and genome walking methods were used for sequence determination of apn-1 gene from Anopheles stephensi and distinct bioinformatics software were used for structural analysis. AsAPN-1 was expressed in Spodoptera frugiperda (Sf9) insect cell line using the baculovirus expression system. Recombinant AsAPN-1 was purified under the hybrid condition and its biological activity was assayed. RESULTS: Asapn-1 gene and its coded protein from An. stephensi were characterized for the first time in this study. Subsequently, the structural features and immunological properties of its coded protein were evaluated by in silico approaches. Enzymatic activity of the recombinant AsAPN-1, which was expressed in Sf9 insect cell line, was equal to 6 unit/μl. CONCLUSIONS: Results of this study revealed that AsAPN-1 is very similar to its counterpart in An. gambiae. In silico evaluation and fundamental data which are necessary for its evaluation as a VIMT-based vaccine in the next steps were acquired in this study and those could be useful for research groups that study on malaria vaccine for countries that An. stephensi is the main malaria vector there. |
BACKGROUND: Intraoperative driving pressure (ΔP) is associated with development of postoperative pulmonary complications (PPC). When tidal volume (V(T)) is kept constant, ΔP may change according to positive end-expiratory pressure (PEEP)-induced changes in lung aeration. ΔP may decrease if PEEP leads to a recruitment of collapsed lung tissue but will increase if PEEP mainly causes pulmonary overdistension. This study tests the hypothesis that individualized high PEEP, when compared to fixed low PEEP, protects against PPC in patients undergoing open abdominal surgery. METHODS: The “Driving prESsure durIng GeNeral AnesThesIa for Open abdomiNal surgery trial” (DESIGNATION) is an international, multicenter, two-group, double-blind randomized clinical superiority trial. A total of 1468 patients will be randomly assigned to one of the two intraoperative ventilation strategies. Investigators screen patients aged ≥ 18 years and with a body mass index ≤ 40 kg/m(2), scheduled for open abdominal surgery and at risk for PPC. Patients either receive an intraoperative ventilation strategy with individualized high PEEP with recruitment maneuvers (RM) (“individualized high PEEP”) or one in which PEEP of 5 cm H(2)O without RM is used (“low PEEP”). In the “individualized high PEEP” group, PEEP is set at the level at which ΔP is lowest. In both groups of the trial, V(T) is kept at 8 mL/kg predicted body weight. The primary endpoint is the occurrence of PPC, recorded as a collapsed composite of adverse pulmonary events. DISCUSSION: DESIGNATION will be the first randomized clinical trial that is adequately powered to compare the effects of individualized high PEEP with RM versus fixed low PEEP without RM on the occurrence of PPC after open abdominal surgery. The results of DESIGNATION will support anesthesiologists in their decisions regarding PEEP settings during open abdominal surgery. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03884543. Registered on 21 March 2019. |
Despite evidence supporting the effectiveness of best practices in infection prevention and management, many healthcare workers fail to implement them and evidence-based practices tend to be underused in routine practice. Prevention and management of infections across the surgical pathway should always focus on collaboration among all healthcare workers sharing knowledge of best practices. To clarify key issues in the prevention and management of infections across the surgical pathway, a multidisciplinary task force of experts convened in Ancona, Italy, on May 31, 2019, for a national meeting. This document represents the executive summary of the final statements approved by the expert panel. |
BACKGROUND: The influenza virus spreads rapidly around the world in seasonal epidemics, resulting in significant morbidity and mortality. Influenza-related incidence data are limited in many countries in Africa despite established sentinel surveillance. This study aimed to address the information gap by estimating the burden and seasonality of medically attended influenza like illness in Ethiopia. METHOD: Influenza sentinel surveillance data collected from 3 influenza like illness (ILI) and 5 Severe Acute Respiratory Illness (SARI) sites from 2012 to 2017 was used for analysis. Descriptive statistics were applied for simple analysis. The proportion of medically attended influenza positive cases and incidence rate of ILI was determined using total admitted patients and catchment area population. Seasonality was estimated based on weekly trend of ILI and predicted threshold was done by applying the “Moving Epidemic Method (MEM)”. RESULT: A total of 5715 medically attended influenza suspected patients who fulfills ILI and SARI case definition (77% ILI and 23% SARI) was enrolled. Laboratory confirmed influenza virus (influenza positive case) among ILI and SARI suspected case was 25% (1130/4426) and 3% (36/1289). Of which, 65% were influenza type A. The predominantly circulating influenza subtype were seasonal influenza A(H3N2) (n = 455, 60%) and Influenza A(H1N1)pdm09 (n = 293, 38.81%). The estimated mean annual influenza positive case proportion and ILI incidence rate was 160.04 and 52.48 per 100,000 population. The Incidence rate of ILI was higher in the age group of 15–44 years of age [‘Incidence rate (R) = 254.6 per 100,000 population’, 95% CI; 173.65, 335.55] and 5–14 years of age [R = 49.5, CI 95%; 31.47, 130.43]. The seasonality of influenza has two peak seasons; in a period from October–December and from April–June. CONCLUSION: Significant morbidity of influenza like illness was observed with two peak seasons of the year and seasonal influenza A (H3N2) remains the predominantly circulating influenza subtype. Further study need to be considered to identify potential risks and improving the surveillance system to continue early detection and monitoring of circulating influenza virus in the country has paramount importance. |
A novel coronavirus (2019-nCoV) originating in Wuhan, China presents a potential respiratory viral pandemic to the world population. Current efforts are focused on containment and quarantine of infected individuals. Ultimately, the outbreak could be controlled with a protective vaccine to prevent 2019-nCoV infection. While vaccine research should be pursued intensely, there exists today no therapy to treat 2019-nCoV upon infection, despite an urgent need to find options to help these patients and preclude potential death. Herein, I review the potential options to treat 2019-nCoV in patients, with an emphasis on the necessity for speed and timeliness in developing new and effective therapies in this outbreak. I consider the options of drug repurposing, developing neutralizing monoclonal antibody therapy, and an oligonucleotide strategy targeting the viral RNA genome, emphasizing the promise and pitfalls of these approaches. Finally, I advocate for the fastest strategy to develop a treatment now, which could be resistant to any mutations the virus may have in the future. The proposal is a biologic that blocks 2019-nCoV entry using a soluble version of the viral receptor, angiotensin-converting enzyme 2 (ACE2), fused to an immunoglobulin Fc domain (ACE2-Fc), providing a neutralizing antibody with maximal breath to avoid any viral escape, while also helping to recruit the immune system to build lasting immunity. The ACE2-Fc therapy would also supplement decreased ACE2 levels in the lungs during infection, thereby directly treating acute respiratory distress pathophysiology as a third mechanism of action. The sequence of the ACE2-Fc protein is provided to investigators, allowing its possible use in recombinant protein expression systems to start producing drug today to treat patients under compassionate use, while formal clinical trials are later undertaken. Such a treatment could help infected patients before a protective vaccine is developed and widely available in the coming months to year(s). |
A simple susceptible–infectious–removed epidemic model for smallpox, with birth and death rates based on historical data, produces oscillatory dynamics with remarkably accurate periodicity. Stochastic population data cause oscillations to be sustained rather than damped, and data analysis regarding the oscillations provides insights into the same set of population data. Notably, oscillations arise naturally from the model, instead of from a periodic forcing term or other exogenous mechanism that guarantees oscillation: the model has no such mechanism. These emergent natural oscillations display appropriate periodicity for smallpox, even when the model is applied to different locations and populations. The model and datasets, in turn, offer new observations about disease dynamics and solution trajectories. These results call for renewed attention to relatively simple models, in combination with datasets from real outbreaks. |
In ecological systems, heterogeneous interactions between pathogens take place simultaneously. This occurs, for instance, when two pathogens cooperate, while at the same time, multiple strains of these pathogens co-circulate and compete. Notable examples include the cooperation of human immunodeficiency virus with antibiotic-resistant and susceptible strains of tuberculosis or some respiratory infections with Streptococcus pneumoniae strains. Models focusing on competition or cooperation separately fail to describe how these concurrent interactions shape the epidemiology of such diseases. We studied this problem considering two cooperating pathogens, where one pathogen is further structured in two strains. The spreading follows a susceptible-infected-susceptible process and the strains differ in transmissibility and extent of cooperation with the other pathogen. We combined a mean-field stability analysis with stochastic simulations on networks considering both well-mixed and structured populations. We observed the emergence of a complex phase diagram, where the conditions for the less transmissible, but more cooperative strain to dominate are non-trivial, e.g. non-monotonic boundaries and bistability. Coupled with community structure, the presence of the cooperative pathogen enables the coexistence between strains by breaking the spatial symmetry and dynamically creating different ecological niches. These results shed light on ecological mechanisms that may impact the epidemiology of diseases of public health concern. |
Eliciting protective titers of HIV-1 broadly neutralizing antibodies (bnAbs) is a goal of HIV-1 vaccine development, but current vaccine strategies have yet to induce bnAbs in humans. Many bnAbs isolated from HIV-1-infected individuals are encoded by immunoglobulin gene rearrangments with infrequent naive B cell precursors and with unusual genetic features that may be subject to host regulatory control. Here, we administer antibodies targeting immune cell regulatory receptors CTLA-4, PD-1 or OX40 along with HIV envelope (Env) vaccines to rhesus macaques and bnAb immunoglobulin knock-in (KI) mice expressing diverse precursors of CD4 binding site HIV-1 bnAbs. CTLA-4 blockade augments HIV-1 Env antibody responses in macaques, and in a bnAb-precursor mouse model, CTLA-4 blocking or OX40 agonist antibodies increase germinal center B and T follicular helper cells and plasma neutralizing antibodies. Thus, modulation of CTLA-4 or OX40 immune checkpoints during vaccination can promote germinal center activity and enhance HIV-1 Env antibody responses. |
Oral rabies vaccination (ORV) is highly effective in foxes and raccoon dogs, whereas for unknown reasons the efficacy of ORV in other reservoir species is less pronounced. To investigate possible variations in species-specific cell tropism and local replication of vaccine virus, different reservoir species including foxes, raccoon dogs, raccoons, mongooses, dogs and skunks were orally immunised with a highly attenuated, high-titred GFP-expressing rabies virus (RABV). Immunofluorescence and RT-qPCR screenings revealed clear differences among species suggesting host specific limitations to ORV. While for responsive species the palatine tonsils (tonsilla palatina) were identified as a main site of virus replication, less virus dissemination was observed in the tonsils of rather refractory species. While our comparison of vaccine virus tropism emphasizes the important role that the tonsilla palatina plays in eliciting an immune response to ORV, our data also indicate that other lymphoid tissues may have a more important role than originally anticipated. Overall, these data support a model in which the susceptibility to oral live RABV vaccine infection of lymphatic tissue is a major determinant in vaccination efficacy. The present results may help to direct future research for improving vaccine uptake and efficacy of oral rabies vaccines under field conditions. |
The clinical implications of bacteremia among septic patients remain unclear, although a vast amount of data have been accumulated on sepsis. We aimed to compare the clinical characteristics and outcomes of severe sepsis patients with and without bacteremia. This secondary analysis of a multicenter, prospective cohort study included 59 intensive care units (ICUs) in Japan between January 2016 and March 2017. The study cohort comprised 1,184 adults (aged ≥ 16 years) who were admitted to an ICU with severe sepsis and diagnosed according to the Sepsis-2 criteria. Of 1,167 patients included in the analysis, 636 (54.5%) had bacteremia. Those with bacteremia had significantly higher rates of septic shock (66.4% vs. 58.9%, p = 0.01) and higher sepsis severity scores, including the Acute Physiology and Chronic Health Evaluation (APACHE) II and the Sequential Organ Failure Assessment (SOFA). No significant difference in in-hospital mortality was seen between patients with and without bacteremia (25.6% vs. 21.0%, p = 0.08). In conclusion, half of severe sepsis patients in ICUs have bacteremia. Although patients with bacteremia had more severe state, between-group differences in patient-centered outcomes, such as in-hospital mortality, have not been fully elucidated. |
Adiponectin is a prime determinant of the status of insulin resistance. Association studies between adiponectin (ADIPOQ) gene single nucleotide polymorphisms (SNPs) and metabolic diseases have been reported earlier. However, results are ambiguous due to apparent contradictions. Hence, we investigated (1) the association between ADIPOQ SNPs: −11377C/G, +10211T/G, +45T/G and +276G/T for the risk towards type 2 diabetes (T2D) and, (2) genotype-phenotype association of these SNPs with various biochemical parameters in two cohorts. Genomic DNA of diabetic patients and controls from Gujarat and, Jammu and Kashmir (J&K) were genotyped using PCR-RFLP, TaqMan assay and MassArray. Transcript levels of ADIPOQ were assessed in visceral adipose tissue samples, and plasma adiponectin levels were estimated by qPCR and ELISA respectively. Results suggest: (i) reduced HMW adiponectin/total adiponectin ratio in Gujarat patients and its association with +10211T/G and +276G/T, and reduced ADIPOQ transcript levels in T2D, (ii) association of the above SNPs with increased FBG, BMI, TG, TC in Gujarat patients and (iii) increased GGTG haplotype in obese patients of Gujarat population and, (iv) association of −11377C/G with T2D in J&K population. Reduced HMW adiponectin, in the backdrop of obesity and ADIPOQ genetic variants might alter metabolic profile posing risk towards T2D. |
Cooperation is a fundamental behaviour observed in all forms of life. The evolution of cooperation has been widely studied, but almost all theories focused on the cooperating individual and its genes. We suggest a different approach, taking into account the microbes carried by the interacting individuals. Accumulating evidence reveals that microbes can affect their host's well-being and behaviour, yet hosts can evolve mechanisms to resist the manipulations of their microbes. We thus propose that coevolution of microbes with their hosts may favour microbes that induce their host to cooperate. Using computational modelling, we show that microbe-induced cooperation can evolve and be maintained in a wide range of conditions, including when facing hosts' resistance to the microbial effect. We find that host–microbe coevolution leads the population to a rock–paper–scissors dynamics that enables maintenance of cooperation in a polymorphic state. Our results suggest a mechanism for the evolution and maintenance of cooperation that may be relevant to a wide variety of organisms, including cases that are difficult to explain by current theories. This study provides a new perspective on the coevolution of hosts and their microbiome, emphasizing the potential role of microbes in shaping their host's behaviour. |
BACKGROUND: A key focus of health systems strengthening in low- and middle-income countries is increasing reach and access through task-shifting. As such models become more common, it is critical to understand the experiences of lay providers because they are on the forefront for delivering care services. A greater understanding would improve lay provider support and help them provide high-quality care. This is especially the case for those providing mental health services, as providing psychological care may pose unique stressors. We sought to understand experiences of lay counselors, focusing on identity, motivation, self-efficacy, stress, and burnout. The goal was to understand how taking on a new provider role influences their lives beyond simply assuming a new task, which would in turn help identify actionable steps to improve interventions with task-shifting components. METHODS: Semi-structured interviews (n = 20) and focus group discussions (n = 3) were conducted with three lay counselor groups with varying levels of experience delivering a community-based family therapy intervention in Eldoret, Kenya. Thematic analysis was conducted, including intercoder reliability checks. A Stress Map was created to visualize stress profiles using free-listing and pile-sorting data collected during interviews and focus group discussions. RESULTS: Counselors described high intrinsic motivation to become counselors and high self-efficacy after training. They reported positive experiences in the counselor role, with new skills improving their counseling and personal lives. As challenges arose, including client engagement difficulties and balancing many responsibilities, stress and burnout increased, dampening motivation and self-efficacy. In response, counselors described coping strategies, including seeking peer and supervisor support, that restored their motivation to persevere. At case completion, they again experienced high self-efficacy and a desire to continue. CONCLUSIONS: Findings informed suggestions for ways to incorporate support for lay providers into task-shifting interventions at initiation, during training, and throughout implementation. These include acknowledging and preparing counselors for challenges during training, increasing explicit attention to counselor stress in supervision, fostering peer support among lay providers, and ensuring a fair balance between workload and compensation. Improving and building an evidence base around practices for supporting lay providers will improve the effectiveness and sustainability of lay provider-delivered interventions. |
BACKGROUND: The mechanisms and pathways to impacts from public health research in the UK have not been widely studied. Through the lens of one funder (NIHR), our aims are to map the diversity of public health research, in terms of funding mechanisms, disciplinary contributions, and public health impacts, identify examples of impacts, and pathways to impact that existing reporting mechanisms may not otherwise have captured, and provide illustrations of how public health researchers perceive the generation of non-academic impact from their work. METHODS: A total of 1386 projects were identified as ‘public health research’ by the NIHR and listed in the NIHR Public Health Overview database (2000–2016). From these, a subset of 857 projects were matched as potentially having begun reporting impacts via an external data-gathering platform (Researchfish). Data on the 857 projects were analyzed quantitatively, and nine projects were selected to investigate further through semi-structured interviews with principal investigators. Two workshops took place to validate emerging and final findings and facilitate analysis. RESULTS: In addition to the NIHR School for Public Health Research and the NIHR Public Health Research Programme, 89% of projects contained in the NIHR Public Health Overview portfolio as ‘public health research’ are funded via other NIHR research programmes, suggesting significant diversity in disciplines contributing to public health research and outcomes. The pathways to impact observed in our in-depth case studies include contributing to debates on what constitutes appropriate evidence for national policy change, acknowledging local ‘unintended’ impacts, building trusted relationships with stakeholders across health and non-health sectors and actors, collaborating with local authorities, and using non-academic dissemination channels. CONCLUSIONS: Public health as a discipline contributes substantially to impact beyond academia. To support the diversity of these impacts, we need to recognise localized smaller-scale impacts, and the difference in types of evidence required for community and local authority-based impacts. This will also require building capacity and resources to enable impact to take place from public health research. Finally, support is required for engagement with local authorities and working with non-health sectors that contribute to health outcomes. |
BACKGROUND: The emergence of human infection with avian influenza A(H7N9) virus was reported in Wenshan City, southwestern China in 2017. The study describes the epidemiological and virological features of the outbreak and discusses the origin of the infection. METHODS: Poultry exposure and timelines of key events for each patient were collected. Samples derived from the patients, their close contacts, and environments were tested for influenza A(H7N9) virus by real-time reverse transcription polymerase chain reaction. Genetic sequencing and phylogenetic analysis were also conducted. RESULTS: Five patients were reported in the outbreak. An epidemiological investigation showed that all patients had been exposed at live poultry markets. The A(H7N9) isolates from these patients had low pathogenicity in avian species. Both epidemiological investigations of chicken sources and phylogenetic analysis of viral gene sequences indicated that the source of infection was from Guangxi Province, which lies 100 km to the east of Wenshan City. CONCLUSIONS: In the study, a sudden emergence of human cases of H7N9 was documented in urban area of Wenshan City. Chickens were an important carrier in the H7N9 virus spreading from Guangxi to Wenshan. Hygienic management of live poultry markets and virological screening of chickens transported across regions should be reinforced to limit the spread of H7N9 virus. |
This paper presents the performance of two eukaryotic genomic ribosomal regions, ITS1 and ITS2, in describing fungal diversity in aerosol samples using amplicon-based High-Throughput Sequencing (HTS). Composting sites, biomethanization facilities, and dairy farms, all affected by the presence of fungi, were visited to collect air samples. The amplicon-based HTS approach is a target enrichment method that relies on the amplification of a specific target using particular primers before sequencing. Thus, the results are highly dependent on the quality of amplification. For this reason, the authors of this paper used a shotgun metagenomic approach to compare its outcome with the amplicon-based method. Indeed, shotgun metagenomic does not rely on any amplification prior to sequencing, because all genes are sequenced without a specific target. In addition, culture methods were added to the analyses in biomethanization and dairy farms samples to validate their contribution to fungal diversity of aerosols. The results obtained are unequivocal towards ITS1 outperformance to ITS2 in terms of richness, and taxonomic coverage. The differential abundance analysis did demonstrate that some taxa were exclusively detected only by ITS2, and vice-versa for ITS1. However, the shotgun metagenomic approach showed a taxonomic profile more resembling to ITS1 than ITS2. Based on these results, neither of the barcodes evaluated is perfect in terms of distinguishing all species. Using both barcodes offers a broader view of the fungal aerosol population. However, with the actual knowledge, the authors strongly recommend using ITS1 as a universal fungal barcode for quick general analyses of diversity and when limited financial resources are available, primarily due its ability to capture taxonomic profiles similar to those obtained using the shotgun metagenomic. The culture comparison with amplicon-based sequencing showed the complementarity of both approaches in describing the most abundant taxa. |
Acute aortic syndromes (AASs) are difficult to diagnose emergencies. Plasma soluble ST2 (sST2), a prognostic biomarker for heart failure, has been proposed as a diagnostic biomarker of AASs outperforming D-dimer, the current diagnostic standard. We performed a prospective diagnostic accuracy study of sST2 for AASs in the Emergency Department (ED). In 2017–2018, patients were enrolled if they had ≥1 red-flag symptoms (chest/abdominal/back pain, syncope, perfusion deficit) and a clinical suspicion of AAS. sST2 was detected with the Presage® assay. Adjudication was based on computed tomography angiography (CTA) or on diagnostic outcome inclusive of 30-day follow-up. 297 patients were enrolled, including 88 with AASs. The median age was 67 years. In 162 patients with CTA, the median sST2 level was 41.7 ng/mL (IQR 29.4–103.2) in AASs and 34.6 ng/mL (IQR 21.4–51.5) in alternative diagnoses (P = 0.005). In ROC analysis, the AUC of sST2 was 0.63, as compared to 0.82 of D-dimer (P < 0.001). Sensitivity and specificity values of sST2 associated with different cutoffs were: 95.5% and 10.8% (≥12 ng/mL), 84.1% and 29.7% (≥23.7 ng/mL), 35.2% and 85.1% (≥66.5 ng/mL). Results were similar in the full cohort. In conclusion, in patients from a European ED, plasma sST2 provided modest accuracy for diagnosis of AASs. |
UV light is a widely-employed, and environmentally-sensitive bactericide but its mechanism of action is not fully defined. Proteins are major chromophores and targets for damage due to their abundance, but the role of proteins in inducing damage to bound DNA, and the effects on DNA-protein interactions is less well characterized. In E. coli (and other Gram-negative bacteria) the cyclic AMP receptor protein (CRP/CAP) regulates more than 500 genes. In this study we show that exposure of isolated dimeric CRP-cAMP to UV modifies specific Met, Trp, Tyr, and Pro side-chains, induces inter-protein Tyr63-Tyr41 cross-links, and decreases DNA binding via oxidation of Met114/Pro110 residues in close proximity at the CRP dimer interface. UV exposure also modifies DNA-bound cAMP-CRP, with this resulting in DNA cleavage at specific G/C residues within the sequence bound to CRP, but not at other G/C sites. Oxidation also increases CRP dissociation from DNA. The modifications at the CRP dimer interface, and the site-specific DNA strand cleavage are proposed to occur via oxidation of two species Met residues (Met114 and Met189, respectively) to reactive persulfoxides that damage neighbouring amino acids and DNA bases. These data suggest that modification to CRP, and bound DNA, contributes to UV sensitivity. |
The recommended antiviral drugs available for the treatment and prevention of influenza are neuraminidase inhibitors (NAIs). The aim of this study was to evaluate age-related clinical manifestations of adverse events (AEs) related to NAIs. FAERS and WebMD data were downloaded. The available NAIs selected for the analysis were oseltamivir, peramivir, zanamivir, and laninamivir. Disproportionality was analyzed using the proportional reporting ratio (PRR), the reporting odds ratio (ROR), and the information component (IC) methods. In total, 16729 AEs from 4598 patients and 575 AEs from 440 patients in the FAERS and WebMD, respectively, were included in the analysis. In the FAERS, AEs were more common among those who were younger (<19 years) for zanamivir, while for those who were older (>65 years) for peramivir. A disproportionality analysis showed that signals for vomiting and hallucinations were detected in younger patients given oseltamivir, while an abnormal hepatic function, cardiac failure, shock, and cardio-respiratory arrest were detected in older patients given peramivir. Psychiatric disorders were most common in younger and older patients, while gastrointestinal disorders were most common in adult given oseltamivir in the WebMD. Adverse symptoms related to NAIs varied and depended on the drugs used and the age of the patient. |
Emergence and spread of antibiotic resistance calls for development of non-chemical treatment options for bacterial infections. Plasma medicine applies low-temperature plasma (LTP) physics to address biomedical problems such as wound healing and tumor suppression. LTP has also been used for surface disinfection. However, there is still much to be learned regarding the effectiveness of LTP on bacteria in suspension in liquids, and especially on porous surfaces. We investigated the efficacy of LTP treatments against bacteria using an atmospheric-pressure plasma jet and show that LTP treatments have the ability to inhibit both gram-positive (S. aureus) and gram-negative (E. coli) bacteria on solid and porous surfaces. Additionally, both direct LTP treatment and plasma-activated media were effective against the bacteria suspended in liquid culture. Our data indicate that reactive oxygen species are the key mediators of the bactericidal effects of LTP and hydrogen peroxide is necessary but not sufficient for antibacterial effects. In addition, our data suggests that bacteria exposed to LTP do not develop resistance to further treatment with LTP. These findings suggest that this novel atmospheric-pressure plasma jet could be used as a potential alternative to antibiotic treatments in vivo. |
Hookworms are intestinal parasites that cause major public health problems, especially in developing countries. To differentiate eggs from different hookworm species, it is necessary to use molecular methodologies, since the eggs are morphologically similar. Here, we performed the molecular identification of single hookworm eggs from six Brazilian states. Of the 634 eggs individually analyzed, 98.1% (622/634) represented Necator americanus, and surprisingly, 1.9% (12/634 eggs from the same patient) represented Ancylostoma caninum. DNA analysis of the A. caninum-positive stool sample revealed no contamination with animal feces. This is the first report of the presence of A. caninum eggs in human feces, which may have a direct implication for the epidemiology of hookworm infection caused by this species. This suggests the need for special attention regarding prophylaxis, as different reservoirs, previously not described, may have great relevance for the spread of A. caninum. |
The vaccine elicitation of broadly neutralizing antibodies against HIV-1 is a long-sought goal. We previously reported the amino-terminal eight residues of the HIV-1-fusion peptide (FP8) – when conjugated to the carrier protein, keyhole limpet hemocyanin (KLH) – to be capable of inducing broadly neutralizing responses against HIV-1 in animal models. However, KLH is a multi-subunit particle derived from a natural source, and its manufacture as a clinical product remains a challenge. Here we report the preclinical development of recombinant tetanus toxoid heavy chain fragment (rTTHC) linked to FP8 (FP8-rTTHC) as a suitable FP-conjugate vaccine immunogen. We assessed 16 conjugates, made by coupling the 4 most prevalent FP8 sequences with 4 carrier proteins: the aforementioned KLH and rTTHC; the H. influenzae protein D (HiD); and the cross-reactive material from diphtheria toxin (CRM197). While each of the 16 FP8-carrier conjugates could elicit HIV-1-neutralizing responses, rTTHC conjugates induced higher FP-directed responses overall. A Sulfo-SIAB linker yielded superior results over an SM(PEG)2 linker but combinations of carriers, conjugation ratio of peptide to carrier, or choice of adjuvant (Adjuplex or Alum) did not significantly impact elicited FP-directed neutralizing responses in mice. Overall, SIAB-linked FP8-rTTHC appears to be a promising vaccine candidate for advancing to clinical assessment. |
The repeating unit of the C. difficile Toxin A (rARU, also known as CROPS [combined repetitive oligopeptides]) C-terminal region, was shown to elicit protective immunity against C. difficile and is under consideration as a possible vaccine against this pathogen. However, expression of recombinant rARU in E. coli using the standard vaccine production process was very low. Transcriptome and proteome analyses showed that at restricted dissolved oxygen (DO) the numbers of differentially expressed genes (DEGs) was 2.5-times lower than those expressed at unrestricted oxygen. Additionally, a 7.4-times smaller number of ribosome formation genes (needed for translation) were down-regulated as compared with unrestricted DO. Higher rARU expression at restricted DO was associated with up-regulation of 24 heat shock chaperones involved in protein folding and with the up-regulation of the global regulator RNA chaperone hfq. Cellular stress response leading to down-regulation of transcription, translation, and energy generating pathways at unrestricted DO were associated with lower rARU expression. Investigation of the C. difficile DNA sequence revealed the presence of cell wall binding profiles, which based on structural similarity prediction by BLASTp, can possibly interact with cellular proteins of E. coli such as the transcriptional repressor ulaR, and the ankyrins repeat proteins. At restricted DO, rARU mRNA was 5-fold higher and the protein expression 27-fold higher compared with unrestricted DO. The report shows a strategy for improved production of C. difficile vaccine candidate in E. coli by using restricted DO growth. This strategy could improve the expression of recombinant proteins from anaerobic origin or those with cell wall binding profiles. |
Porphyromonas gulae is a major periodontal pathogen in dogs, which can be transmitted to their owners. A major virulence factor of P. gulae consists of a 41-kDa filamentous appendage (FimA) on the cell surface, which is classified into three genotypes: A, B, and C. Thus far, inhibition of periodontal disease in dogs remains difficult. The present study assessed the inhibitory effects of a combination of clindamycin and interferon alpha (IFN-α) formulation against P. gulae and periodontal disease. Growth of P. gulae was significantly inhibited by clindamycin; this inhibition had a greater effect on type C P. gulae than on type A and B isolates. In contrast, the IFN-α formulation inhibited the expression of IL-1β and COX-2 elicited by type A and B isolates, but not that elicited by type C isolates. Furthermore, periodontal recovery was promoted by the administration of both clindamycin and IFN-α formulation to dogs undergoing periodontal treatment; moreover, this combined treatment reduced the number of FimA genotypes in oral specimens from treated dogs. These results suggest that a combination of clindamycin and IFN-α formulation inhibit P. gulae virulence and thus may be effective for the prevention of periodontal disease induced by P. gulae. |
Influenza-related severe pneumonia and acute respiratory distress syndrome (ARDS) are severe threats to human health. The objective of this study was to assess the effects of systematic corticosteroid therapy in patients with pneumonia or ARDS. The PubMed, EMBASE, Web of Science and SCOPUS databases were searched up to July, 2019. Nineteen studies including 6637 individuals were identified, and fifteen studies (6427 patients) were included in the meta-analysis of mortality. Eighteen were observational studies and one was a randomized controlled trial (RCT). The meta-analysis results showed that corticosteroid therapy was associated with significantly higher mortality (OR 1.53, 95% CI [1.16, 2.01]) and incidence of nosocomial infection (OR 3.15, 95% CI [1.54, 6.45]). Subgroup analysis showed that among patients with unadjusted estimates, the odds of mortality were higher in patients receiving corticosteroid treatment (OR 1.98, 95% CI [1.23, 3.17]), however, among patients with adjusted estimates, the result showed no statistically significant difference between corticosteroid group and control group (OR 1.31, 95% CI [0.95, 1.80]). Current data do not support the routine use of corticosteroids in patients with influenza severe pneumonia or ARDS. RCTs are needed to provide more robust evidence. |
BACKGROUND: In malaria-endemic areas, human populations are frequently exposed to immunomodulatory salivary components injected during mosquito blood feeding. The consequences on pathogen-specific immune responses are not well known. This study evaluated and compared the humoral responses specific to merozoite stage vaccine candidates of Plasmodium falciparum, in children differentially exposed to Anopheles bites in a natural setting. METHODS: The cross-sectional study was carried out in Bouaké (Côte d’Ivoire) where entomological data and blood samples from children (0–14 years) were collected in two sites with similar malaria prevalence. Antibody (IgG, IgG1, IgG3) responses to PfAMA1 and PfMSP1 were evaluated by ELISA. Univariate and multivariate analysis were performed to assess the relationship between the immune responses to P. falciparum antigens and exposure to Anopheles bites in the total cohort and in each site, separately. The individual level of exposure to Anopheles bites was evaluated by quantifying specific IgG response to the Anopheles gSG6-P1 salivary peptide, which represents a proxy of Anopheles exposure. RESULTS: The anti-Plasmodium humoral responses were different according to the level of exposure of children, with those highly exposed to Anopheles presenting significantly lower antibody responses to PfMSP1 in total population (IgG and IgG3) and in Petessou village (IgG, IgG1, IgG3). No significant difference was seen for PfAMA1 antigen between children differently exposed to Anopheles. In Dar-es-Salam, a neighbourhood where a high Culex density was reported, children presented very low antibody levels specific to both antigens, and no difference according to the exposure to Anopheles bites was found. CONCLUSION: These findings may suggest that immunomodulatory components of Anopheles saliva, in addition to other factors, may participate to the modulation of the humoral response specific to Plasmodium merozoite stage antigens. This epidemiological observation may form a starting point for additional work to decipher the role of mosquito saliva on the modulation of the anti-Plasmodium acquired immunity and clinical protection in combining both field and ex vivo immunological studies. |
OBJECTIVES: The requirement of prolonged mechanical ventilation (PMV) is associated with increased medical care demand and expenses, high early and long-term mortality, and worse life quality. However, no study has assessed the prognostic factors associated with 1-year mortality among PMV patients, not less than 21 days after surgery. This study analyzed the predictors of 1-year mortality in patients requiring PMV in intensive care units (ICUs) after surgery. METHODS: In this multicenter, respective cohort study, 124 patients who required PMV after surgery in the ICUs of five tertiary hospitals in Beijing between January 2007 and June 2016 were enrolled. The primary outcome was the duration of survival within 1 year. Predictors of 1-year mortality were identified with a multivariable Cox proportional hazard model. The predictive effect of the ProVent score was also validated. RESULTS: Of the 124 patients enrolled, the cumulative 1-year mortality was 74.2% (92/124). From the multivariable Cox proportional hazard analysis, cancer diagnosis (hazard ratio [HR] 2.14, 95% confidence interval [CI] 1.37–3.35; P < 0.01), no tracheostomy (HR 2.01, 95% CI 1.22–3.30; P < 0.01), enteral nutrition intolerance (HR 1.88, 95% CI 1.19–2.97; P = 0.01), blood platelet count ≤150 × 10(9)/L (HR 1.77, 95% CI 1.14–2.75; P = 0.01), requirement of vasopressors (HR 1.78, 95% CI 1.13–2.80; P = 0.02), and renal replacement therapy (HR 1.71, 95% CI 1.01–2.91; P = 0.047) on the 21st day of mechanical ventilation (MV) were associated with shortened 1-year survival. CONCLUSIONS: For patients who required PMV after surgery, cancer diagnosis, no tracheostomy, enteral nutrition intolerance, blood platelet count ≤150 × 10(9)/L, vasopressor requirement, and renal replacement therapy on the 21st day of MV were associated with shortened 1-year survival. The prognosis in PMV patients in ICUs can facilitate the decision-making process of physicians and patients’ family members on treatment schedule. |
Hand, foot and mouth disease (HFMD) is a major public health concern in China. The most predominant enteroviruses that cause HFMD have traditionally been attributed to enterovirus A71 (EVA71) and coxsackievirus A16 (CVA16). Since its first large outbreak in 2008, the dominant HFMD pathogens are constantly changing. In 2013 and 2015, CVA6 exceeded both EVA71 and CVA16 to become the leading cause of HFMD in some provinces. However, there still lacks a comprehensive overview on the molecular epidemiology and evolution of HFMD-related enteroviruses at the national level. In this study, we performed systematic epidemiological analyses of HFMD-related enteroviruses using the data of 64 published papers that met the inclusion criteria, and conducted phylogenetic analyses based on 12,080 partial VP1 sequences identified in China before 31st June 2018. We found that EVA71 prevalence has decreased sharply but other enteroviruses have increased rapidly from 2008 to 2016 and that one subtype of each enterovirus is represented during the epidemic. In addition, four genotypes EVA71_C4, CVA16_B1, CVA6_D and CVA10_C are the most predominant enterovirus strains and collectively they cause over 90% of all HFMD cases in China according to the phylogenetic trees using representative partial VP1 sequences. These four major enterovirus genotypes have different geographical distributions, and they may co-circulate with other genotypes and serotypes. These results suggest that more molecular epidemiological studies should be performed on several enteroviruses simultaneously, and such information should have implications for virological surveillance, disease management, vaccine development and policy-making on the prevention and control of HFMD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12250-019-00169-2) contains supplementary material, which is available to authorized users. |
BACKGROUND: Real-time bedside information on regional ventilation and perfusion during mechanical ventilation (MV) may help to elucidate the physiological and pathophysiological effects of MV settings in healthy and injured lungs. We aimed to study the effects of positive end-expiratory pressure (PEEP) and tidal volume (V(T)) on the distributions of regional ventilation and perfusion by electrical impedance tomography (EIT) in healthy and injured lungs. METHODS: One-hit acute lung injury model was established in 6 piglets by repeated lung lavages (injured group). Four ventilated piglets served as the control group. A randomized sequence of any possible combination of three V(T) (7, 10, and 15 ml/kg) and four levels of PEEP (5, 8, 10, and 12 cmH(2)O) was performed in all animals. Ventilation and perfusion distributions were computed by EIT within three regions-of-interest (ROIs): nondependent, middle, dependent. A mixed design with one between-subjects factor (group: intervention or control), and two within-subjects factors (PEEP and V(T)) was used, with a three-way mixed analysis of variance (ANOVA). RESULTS: Two-way interactions between PEEP and group, and V(T) and group, were observed for the dependent ROI (p = 0.035 and 0.012, respectively), indicating that the increase in the dependent ROI ventilation was greater at higher PEEP and V(T) in the injured group than in the control group. A two-way interaction between PEEP and V(T) was observed for perfusion distribution in each ROI: nondependent (p = 0.030), middle (p = 0.006), and dependent (p = 0.001); no interaction was observed between injured and control groups. CONCLUSIONS: Large PEEP and V(T) levels were associated with greater pulmonary ventilation of the dependent lung region in experimental lung injury, whereas they affected pulmonary perfusion of all lung regions both in the control and in the experimental lung injury groups. |
Rotavirus (RV) is a major foodborne pathogen. For RV prevention and control, it is a key to uncover the interaction mechanism between virus and its receptors. However, it is hard to specially purify the viral receptors, including histo-blood group antigens (HBGAs). Previously, the protruding domain protein (P protein) of human norovirus (genotype II.4) was displayed on the surface of Escherichia coli, and it specifically recognized and captured the viral ligands. In order to further verify the feasibility of the system, P protein was replaced by VP8* of RV (G9P[8]) in this study. In the system, VP8* could be correctly released by thrombin treatment with antigenicity retaining, which was confirmed by Western blot and Enzyme-Linked Immunosorbent Assays. Type A HBGAs from porcine gastric mucin (PGM) were recognized and captured by this system. From saliva mixture, the captured viral receptor bound with displayed VP8* was confirmed positive with monoclonal antibody against type A HBGAs. It indicated that the target ligands could be easily separated from the complex matrix. These results demonstrate that the bacterial surface display system will be an effective platform to explore viral receptors/ligands from cell lines or food matrix. |
BACKGROUND: Several studies have assessed predictors of weaning and extubation outcome in short-term mechanically ventilated patients, but there are only few studies on predictors of weaning from prolonged mechanical ventilation. METHODS: Retrospective, single-center, observational study at a specialized national weaning center in Germany. Patients’ medical records were reviewed to obtain data on demographics, comorbidities, respiratory indices, and the result of a prospectively documented, standardized spontaneous breathing trial (SBT) upon admission to the weaning center. Respiratory indices assessed were the ventilatory ratio (VR) and parameters derived from calculated mechanical power (MP). Predictors associated with failure of prolonged weaning and failure of the SBT were assessed using a binary logistic regression model. RESULTS: A total of 263 prolonged mechanically ventilated, tracheotomized patients, treated over a 5-year period were analyzed. After 3 weeks of mechanical ventilation, patients with unsuccessful weaning failed a SBT more frequently and showed significantly increased values for inspiratory positive airway pressure, driving pressure, VR, absolute MP, and MP normalized to predicted body weight and dynamic lung-thorax compliance (LTC-MP). In the logistic regression analyses, variables independently correlated with weaning failure were female gender (adjusted odds ratio 0.532 [95% CI 0.291–0.973]; p = 0.040), obesity (body mass index ≥ 30 kg/m(2)) (2.595 [1.210–5.562]; p = 0.014), COPD (3.209 [1.563–6.589]; p = 0.002), LTC-MP (3.470 [1.067–11.284]; p = 0.039), P(a)CO(2) on mechanical ventilation (1.101 [95% CI 1.034–1.173]; p = 0.003), and failure of the SBT (4.702 [2.250–9.825]; p < 0.001). In addition, female gender (0.401 [0.216–0.745]; p = 0.004), LTC-MP (3.017 [1.027–8.862]; p = 0.046), and P(a)CO(2) on mechanical ventilation (1.157 [1.083–1.235]; p < 0.001) were independent risk factors for an unsuccessful SBT. CONCLUSIONS: In the present study, the derived predictors of weaning point to a crucial role of the workload imposed on respiratory muscles during spontaneous breathing. Mechanical power normalized to lung-thorax compliance was independently correlated with weaning outcome and may identify patients at high risk for weaning failure. |
BACKGROUND: We evaluated the epidemiology of fluid balance (FB) over the first postnatal week and its impact on outcomes in a multi-center cohort of premature neonates from the AWAKEN study. METHODS: Retrospective analysis of infants <36 weeks’ gestational age from the AWAKEN study (N = 1007). FB was defined by percentage of change from birth weight. Outcome: Mechanical ventilation (MV) at postnatal day 7. RESULTS: One hundred and forty-nine (14.8%) were on MV at postnatal day 7. The median peak FB was 0% (IQR: −2.9, 2) and occurred on postnatal day 2 (IQR: 1,5). Multivariable models showed that the peak FB (aOR 1.14, 95% CI 1.10–1.19), lowest FB in first postnatal week (aOR 1.12, 95% CI 1.07–1.16), and FB on postnatal day 7 (aOR 1.10, 95% CI 1.06–1.13) were independently associated with MV on postnatal day 7. In a similar analysis, a negative FB at postnatal day 7 protected against the need for MV at postnatal day 7 (aOR 0.21, 95% CI 0.12–0.35). CONCLUSIONS: Positive peak FB during the first postnatal week and more positive FB on postnatal day 7 were independently associated with MV at postnatal day 7. Those with a negative FB at postnatal day 7 were less likely to require MV. |
OBJECTIVE: In septic patients, multiple retrospective studies show an association between large volumes of fluids administered in the first 24 h and mortality, suggesting a benefit to fluid restrictive strategies. However, these studies do not directly estimate the causal effects of fluid-restrictive strategies, nor do their analyses properly adjust for time-varying confounding by indication. In this study, we used causal inference techniques to estimate mortality outcomes that would result from imposing a range of arbitrary limits (“caps”) on fluid volume administration during the first 24 h of intensive care unit (ICU) care. DESIGN: Retrospective cohort study SETTING: ICUs at the Beth Israel Deaconess Medical Center, 2008–2012 PATIENTS: One thousand six hundred thirty-nine septic patients (defined by Sepsis-3 criteria) 18 years and older, admitted to the ICU from the emergency department (ED), who received less than 4 L fluids administered prior to ICU admission MEASUREMENTS AND MAIN RESULTS: Data were obtained from the Medical Information Mart for Intensive Care III (MIMIC-III). We employed a dynamic Marginal Structural Model fit by inverse probability of treatment weighting to obtain confounding adjusted estimates of mortality rates that would have been observed had fluid resuscitation volume caps between 4 L–12 L been imposed on the population. The 30-day mortality in our cohort was 17%. We estimated that caps between 6 and 10 L on 24 h fluid volume would have reduced 30-day mortality by − 0.6 to − 1.0%, with the greatest reduction at 8 L (− 1.0% mortality, 95% CI [− 1.6%, − 0.3%]). CONCLUSIONS: We found that 30-day mortality would have likely decreased relative to observed mortality under current practice if these patients had been subject to “caps” on the total volume of fluid administered between 6 and 10 L, with the greatest reduction in mortality rate at 8 L. |
BACKGROUND: Even though enterococci can cause serious infections in multiple sites, they are a rare cause of pneumonia. We reported a uremic patient with vancomycin-resistant E. faecium (VRE-fm) pneumonia, possibly related to epileptic seizures. CASE PRESENTATION: A 57-year old man with uremia on hemodialysis was admitted to the hospital with complaint of recurrent epileptic seizures, followed by a two-week history of recurrent fever and cough with purulent sputum. Chest CT demonstrated multiple exudation of both lungs. He was diagnosed as community acquired pneumonia. Despite antibiotic combination therapy, abnormal chest shadows aggravated. Sputum and blood cultures were initially negative, but later blood culture grew VRE-fm. We suspected aspiration of gastrointestinal content induced by epilepsy as the most likely mechanism. The patient was successfully treated with a four-week course of linezolid according to the antibiotic susceptibility testing. CONCLUSIONS: Physicians should consider multi-drug resistant organisms such as VRE in uremic patients with pneumonia that fails to resolve with broad-spectrum antibiotics, especially in the cases with aspiration induced by epilepsy, immunocompromised conditions, and repeated or prolonged hospitalizations. |
BACKGROUND: Identifying immunogens that induce HIV-1-specific immune responses is a lengthy process that can benefit from computational methods, which predict T-cell epitopes for various HLA types. METHODS: We tested the performance of the NetMHCpan4.0 computational neural network in re-identifying 93 T-cell epitopes that had been previously independently mapped using the whole proteome IFN-γ ELISPOT assays in 6 HLA class I typed Ugandan individuals infected with HIV-1 subtypes A1 and D. To provide a benchmark we compared the predictions for NetMHCpan4.0 to MHCflurry1.2.0 and NetCTL1.2. RESULTS: NetMHCpan4.0 performed best correctly predicting 88 of the 93 experimentally mapped epitopes for a set length of 9-mer and matched HLA class I alleles. Receiver Operator Characteristic (ROC) analysis gave an area under the curve (AUC) of 0.928. Setting NetMHCpan4.0 to predict 11-14mer length did not improve the prediction (37–79 of 93 peptides) with an inverse correlation between the number of predictions and length set. Late time point peptides were significantly stronger binders than early peptides (Wilcoxon signed rank test: p = 0.0000005). MHCflurry1.2.0 similarly predicted all but 2 of the peptides that NetMHCpan4.0 predicted and NetCTL1.2 predicted only 14 of the 93 experimental peptides. CONCLUSION: NetMHCpan4.0 class I epitope predictions covered 95% of the epitope responses identified in six HIV-1 infected individuals, and would have reduced the number of experimental confirmatory tests by > 80%. Algorithmic epitope prediction in conjunction with HLA allele frequency information can cost-effectively assist immunogen design through minimizing the experimental effort. |
BACKGROUND: Available data on antibiotic resistance in sub-Saharan Africa is limited despite its increasing threat to global public health. As there is no previous study on antibiotic resistance in patients with clinical features of healthcare-associated infections (HAIs) in Sierra Leone, research is needed to inform public health policies. Our study aimed to assess antibiotic resistance rates from isolates in the urine and sputum samples of patients with clinical features of HAIs. METHODOLOGY: We conducted a cross-sectional study of adult inpatients aged ≥18 years at Connaught Hospital, an urban tertiary care hospital in Freetown between February and June 2018. RESULTS: Over the course of the study, we enrolled 164 patients. Risk factors for HAIs were previous antibiotic use (93.3%), comorbidities (58.5%) and age (≥65 years) (23.9%). Of the 164 samples, 89.6% were urine. Bacterial growth was recorded in 58.8% of cultured specimens; the type of specimen was an independent predictor of bacterial growth (p < 0.021). The most common isolates were Escherichia coli and Klebsiella pneumoniae; 29.2% and 19.0% in urine samples and 18.8% and 31.3% in sputum samples, respectively. The overall resistance rates were 58% for all extended-spectrum beta-lactamase (ESBL)-producing organisms, 13.4% for carbapenem-resistant non-lactose fermenting gram-negative bacilli, 8.7% for carbapenem-resistant Acinetobacter baumannii (CRAB) and 1.3% for carbapenem-resistant Enterobacteriaceae (CRE). There were no carbapenem-resistant P. aeruginosa (CRPA) isolates but all Staphylococcus aureus isolates were methicillin-resistant S. aureus. CONCLUSION: We demonstrated a high prevalence rate of ESBL-producing organisms which are a significant burden at the main tertiary hospital in Sierra Leone. Urgent action is needed to strengthen microbiological diagnostic infrastructure, initiate surveillance on antibiotic resistance and develop and implement policy framework on antibiotic stewardship. |
BACKGROUND: Respiratory tract infection (RTI) in young children is a leading cause of morbidity and hospitalization worldwide. There are few studies assessing the performance for bronchoalveolar lavage fluid (BALF) versus oropharyngeal swab (OPS) specimens in microbiological findings for children with RTI. The primary purpose of this study was to compare the detection rates of OPS and paired BALF in detecting key respiratory pathogens using suspension microarray. METHODS: We collected paired OPS and BALF specimens from 76 hospitalized children with respiratory illness. The samples were tested simultaneously for 8 respiratory viruses and 5 bacteria by suspension microarray. RESULTS: Of 76 paired specimens, 62 patients (81.6%) had at least one pathogen. BALF and OPS identified respiratory pathogen infections in 57 (75%) and 49 (64.5%) patients, respectively (P > 0.05). The etiology analysis revealed that viruses were responsible for 53.7% of the patients, whereas bacteria accounted for 32.9% and Mycoplasma pneumoniae for 13.4%. The leading 5 pathogens identified were respiratory syncytial virus, Streptococcus pneumoniaee, Haemophilus influenzae, Mycoplasma pneumoniae and adenovirus, and they accounted for 74.2% of etiological fraction. For detection of any pathogen, the overall detection rate of BALF (81%) was marginally higher than that (69%) of OPS (p = 0.046). The differences in the frequency distribution and sensitivity for most pathogens detected by two sampling methods were not statistically significant. CONCLUSIONS: In this study, BALF and OPS had similar microbiological yields. Our results indicated the clinical value of OPS testing in pediatric patients with respiratory illness. |
Type III IFNs, or IFN-λ, are the newest members of the IFN family and were long believed to play roles that were redundant with those of type I IFNs. However, IFN-λ displays unique traits that delineate them as primary protectors of barrier integrity at mucosal sites. This unique role stems both from the restricted expression of IFN-λ receptor, confined to epithelial cells and to a limited pool of immune cells, and from unique immunomodulatory properties of IFN-λ. Here, we discuss recent findings that establish the unique capacity of IFN-λ to act at the barriers of the host to balance tissue tolerance and immune resistance against viral and bacterial challenges. |
BACKGROUND: Low cardiac output syndrome (LCOS) is an important complication of cardiac surgery. It is associated with increased morbidity and mortality. The incidence of LCOS after surgery is high in patients with congenital heart disease (CHD). Therefore, determining the risk factors of LCOS has clinical significance for the management of CHD. This study aimed to analyze the risk factors of LCOS. METHODS: We conducted a retrospective analysis of children with CHD who underwent cardiac surgery at Shanghai Children’s Medical Center between January 1, 2014, and December 31, 2017. Demographic characteristics and baseline data were extracted from the health data resource center of the hospital, which integrates clinical routine data including medical records, diagnoses, orders, surgeries, laboratory tests, imaging, nursing, and other subsystems. Logistic regressions were performed to analyze the risk factors of LCOS. RESULTS: Overall, 8660 infants with CHD were included, and 864 (9.98%) had LCOS after surgery. The multivariate regression analysis identified that age (OR 0.992, 95% CI: 0.988–0.997, p = 0.001), tricuspid regurgitation (1.192, 1.072–1.326, p = 0.001), Risk Adjustment in Congenital Heart Surgery-1 risk grade (1.166, 1.011–1.345, p = 0.035), aortic shunt (left-to-right: 1.37, 1.005–1.867, p = 0.046; bi-directional: 1.716, 1.138–2.587, p = 0.01), atrial shunt (left-to-right: 1.407, 1.097–1.805, p = 0.007; right-to-left: 3.168, 1.944–5.163, p < 0.001; bi-directional: 1.87, 1.389–2.519, p < 0.001), ventricular level shunt (left-to-right: 0.676, 0.486–0.94, p = 0.02; bi-directional: 2.09, 1.611–2.712, p < 0.001), residual shunt (3.489, 1.502–8.105, p = 0.004), left ventricular outflow tract obstruction (3.934, 1.673–9.254, p = 0.002), right ventricular outflow tract obstruction (3.638, 1.225–10.798, p = 0.02), circulating temperature (mild hypothermia: 1.526, 95% CI: 1.205–1.934, p < 0.001; middle and low temperature: 1.738, 1.236–2.443, p = 0.001), duration of cardiopulmonary bypass (1.009, 1.006–1.012, p < 0.001), myocardial preservation using histidine-tryptophan-ketoglutarate (1.677, 1.298–2.167, p < 0.001), and mitral insufficiency (1.714, 1.239–2.37, p < 0.001) were independent risk predictors of LCOS. CONCLUSIONS: The incidence of postoperative LCOS in CHD children remains high. Circulation temperature, myocardial preservation using histidine-tryptophan-ketoglutarate, and usage of residual shunt after surgery were independent risk predictors for LCOS. |
Non-structural protein 1 (NS1) of influenza virus is a multifunctional protein that plays an important role in virus replication and virulence. In this study, an acetylation modification was identified at the K108 residue of the NS1 protein of H1N1 influenza virus. To further explore the function of the K108 acetylation modification of the NS1 protein, a deacetylation-mimic mutation (K108R) and a constant acetylation-mimic mutation (K108Q) were introduced into the NS1 protein in the background of A/WSN/1933 H1N1 (WSN), resulting in two mutant viruses (WSN-NS1-108R and WSN-NS1-108Q). In vitro and mouse studies showed that the deacetylation-mimic mutation K108R in the NS1 protein attenuated the replication and virulence of WSN-NS1-108R, while the constant acetylation-mimic mutant virus WSN-NS1-108Q showed similar replication and pathogenicity as the wild-type WSN virus (WSN-wt). The results indicated that acetylation at K108 of the NS1 protein has an important role in the replication and virulence of influenza virus. To further explore the potential mechanism, the type I interferon (IFN-I) antagonistic activity of the three NS1 proteins (NS1-108Q, NS1-108R, and NS1-wt) was compared in cells, which showed that the K108R mutation significantly attenuated the IFN-β antagonistic activity of the NS1 protein compared with NS1-wt and NS1-108Q. Both NS1-wt and NS1-108Q inhibited the IFN-β response activated by RIG-I CARD domain, MAVS, TBK1, and IRF3 more efficiently than the NS1-108R protein in cells. Taken together, the results indicated that acetylation at NS1 K108 is important for the IFN antagonistic activity of the NS1 protein and virulence of the influenza virus. |
Millions are exposed to the human immunodeficiency virus type 1 (HIV-1) every year, but not all acquire the virus, suggesting a potential role for host genetics in the moderation of HIV-1 acquisition. Here, we analyzed summary statistics from the largest genome-wide association study of HIV-1 acquisition to-date, consisting of 6,334 infected patients and 7,247 population controls, to advance our understanding of the genetic mechanisms implicated in this trait. We found that HIV-1 acquisition is polygenic and heritable, with SNP heritability estimates explaining 28–42% of the variance in this trait at a population level. Genetic correlations alongside UK Biobank data revealed associations with smoking, prospective memory and socioeconomic traits. Gene-level enrichment analysis identified EF-hand calcium binding domain 14 as a novel susceptibility gene for HIV–1 acquisition. We also observed that susceptibility variants for HIV-1 acquisition were significantly enriched for genes expressed in T-cells, but also in striatal and hippocampal neurons. Finally, we tested how polygenic risk scores for HIV-1 acquisition influence blood levels of 35 inflammatory markers in 406 HIV-1-negative individuals. We found that higher genetic risk for HIV-1 acquisition was associated with lower levels of C-C motif chemokine ligand 17. Our findings corroborate a complex model for HIV-1 acquisition, whereby susceptibility is partly heritable and moderated by specific behavioral, cellular and immunological parameters. |
In the absence of a correlate(s) of protection against human tuberculosis and a validated animal model of the disease, tools to facilitate vaccine development must be identified. We present an optimised ex vivo mycobacterial growth inhibition assay (MGIA) to assess the ability of host cells within the lung to inhibit mycobacterial growth, including Bacille Calmette–Guérin (BCG) and Mycobacterium tuberculosis (MTB) Erdman. Growth of BCG was reduced by 0.39, 0.96 and 0.73 log(10) CFU following subcutaneous (s.c.) BCG, intranasal (i.n.) BCG, or BCG s.c. + mucosal boost, respectively, versus naïve mice. Comparatively, a 0.49 (s.c.), 0.60 (i.n.) and 0.81 (s.c. + mucosal boost) log(10) reduction in MTB CFU was found. A BCG growth inhibitor, 2-thiophenecarboxylic acid hydrazide (TCH), was used to prevent quantification of residual BCG from i.n. immunisation and allow accurate MTB quantification. Using TCH, a further 0.58 log(10) reduction in MTB CFU was revealed in the i.n. group. In combination with existing methods, the ex vivo lung MGIA may represent an important tool for analysis of vaccine efficacy and the immune mechanisms associated with vaccination in the organ primarily affected by MTB disease. |
BACKGROUND: Topical 0.12% chlorhexidine has been used widely to prevent ventilator-associated pneumonia in patients undergoing mechanical ventilation. However, it is not approved for mucosal application in Japan. The aims of this study were to investigate if topical povidone iodine (i) inhibits bacterial growth and (ii) disrupts the balance of the oral microbiota. METHODS: This randomized controlled clinical trial included 23 patients who underwent mechanical ventilation in the intensive care unit. The patients were divided randomly into two groups: the intervention group (n = 16) and the control group (n = 7). All patients received oral cleaning with 3% hydrogen peroxide, followed by irrigation with tap water. The patients in the intervention group received 10% povidone iodine applied topically to the oral cavity. The concentration of total bacteria in the oropharyngeal fluid were determined before, immediately after, 1 h, 2 h, and 3 h after oral care using the Rapid Oral Bacteria Quantification System, which is based on dielectrophoresis and impedance measurements. The number of streptococci, methicillin-resistant Staphylococcus aureus, Streptococcus pneumoniae, Pseudomonas aeruginosa, Porphyromonas gingivalis, and Candida albicans before, immediately after, 1 h, and 3 h after oral care were estimated based on real-time polymerase chain reaction data. RESULTS: After irrigation of the oral cavity, the number of bacteria decreased, but increased again at 1 h after oral care in the control group; however, in the intervention group, the concentration of bacteria was significantly lower than that in the control group at 1 hour (p = 0.009), 2 h (p = 0.001), and 3 h (p = 0.001) after oral care. The growth of all bacterial species tested was inhibited in the intervention group at 3 h after oral care, suggesting that povidone iodine did not disturb the balance of the oral microbiota. CONCLUSIONS: Topical application of povidone iodine after cleaning and irrigation of the oral cavity inhibited bacterial growth in the oropharyngeal fluid of patients on mechanical ventilation while not disrupting the balance of the oral microbiota. TRIAL REGISTRATION: University Hospitals Medical Information Network Clinical Trials Registry (UMIN-CTR), UMIN000028307. Registered 1 September 2017. |
BACKGROUND: An extreme and persistent dysbiosis occurs among critically ill patients, regardless of the heterogeneity of disease. Dysbiosis in critically ill patients may make them prone to hospital-acquired infections, sepsis, multi-organ failure (MOF), energy homeostasis disturbance, muscle wasting, and cachexia. Modulation of gut microbiota through synbiotics can be considered as a potential treatment for muscle wasting and macronutrient homeostasis disturbances. METHODS: This is a prospective, single-center, double-blind, parallel randomized controlled trial with the aim to evaluate the effects of synbiotic supplementation on energy and macronutrient homeostasis and muscle wasting in critically ill patients. A total of 40 hemodynamically stable, adult, critically ill patients who receive enteral nutrition via a nasogasteric tube (NGT) in the 24–48 h after admission to critical care will be included in this study. Eligible patients will be randomly assigned to receive Lactocare (ZistTakhmir) capsules 500 mg every 12 h or a placebo capsule, which contains only the sterile maize starch and is similar to synbiotic capsules for 14 days. The synbiotic and placebo capsules will be given through the nasogastric tube, separately from gavage, after feeding. DISCUSSION: Gut microbiota modulation through synbiotics is proposed to improve clinical prognosis and reduce infectious complications, ventilator dependency, and length of ICU stay by improving energy and macronutrient homeostasis and reducing muscle protein catabolism. TRIAL REGISTRATION: Iranian Registry of Clinical Trials, IRCT20190227042857N1. Registered on 17 March 2019. |
Data on spontaneous pathology are substantially scarce for common marmosets, compared to other laboratory animals, but is essential for the interpretation of histological findings in the context of toxicological and experimental studies. Especially if common marmosets are used as experimental animals in respiratory research, detailed knowledge on the spectrum, occurrence, and incidence of spontaneous histopathological pulmonary lesions in this non-human primate species is required. In this study, lung tissue of 638 common marmosets from the marmoset colony of the German Primate Center was examined histologically. The analysis revealed a high incidence of predominantly mild and multifocal interstitial pneumonia (32.99 %) of unknown etiology in most cases. Only few marmosets exhibited lobar pneumonia (1.41 %) and bronchopneumonia (0.94), which were mainly caused by bacterial pathogens such as Bordetella bronchiseptica and Klebsiella pneumoniae. Lung immaturity and atelectasis were common histological findings in newborn marmosets. Typical background lesions included anthracosis (8.15 %), hemosiderosis (1.72 %), extramedullary hematopoiesis (11.6 %), mineralization (10.97 %), and inflammatory cell foci (10.34 %). In addition, three cases of pulmonary arteriopathy (0.47 %) and 1 case of foreign-body granuloma (0.16 %) were detected in the marmoset study cohort. The high prevalence of circulatory disturbances (congestion, edema, hemorrhage) and changes in air content (secondary atelectasis, alveolar emphysema) could partly be explained by euthanasia-related artifacts or agonal changes. The present study provides a comprehensive overview of the range and incidence of spontaneous pulmonary histopathology in common marmosets, serving as valuable reference data for the interpretation of lung lesions in toxicological and experimental marmoset studies. |
Public health policymakers face increasingly complex questions and decisions and need to deal with an increasing quantity of data and information. For policy advisors to make use of scientific evidence and to assess available intervention options effectively and therefore indirectly for those deciding on and implementing public health policies, mathematical modeling has proven to be a useful tool. In some areas, the use of mathematical modeling for public health policy support has become standard practice at various levels of decision-making. To make use of this tool effectively within public health organizations, it is necessary to provide good infrastructure and ensure close collaboration between modelers and policymakers. Based on experience from a national public health institute, we discuss the strategic requirements for good modeling practice for public health. For modeling to be of maximal value for a public health institute, the organization and budgeting of mathematical modeling should be transparent, and a long-term strategy for how to position and develop mathematical modeling should be in place. |
The PLOS Medicine editors discuss prospects for health and development in the coming decade. |
Selective decontamination of the digestive tract (SDD) is an infection prevention measure for intensive care unit (ICU) patients that was proposed more than 30 years ago, and that is currently considered standard of care in the Netherlands, but only used sporadically in ICUs in other countries. In this narrative review, we first describe the rationale of the individual components of SDD and then review the evidence base for patient-centered outcomes, where we distinguish ICUs with low prevalence of antibiotic resistance from ICUs with moderate–high prevalence of resistance. In settings with low prevalence of antibiotic resistance, SDD has been associated with improved patient outcome in three cluster-randomized studies. These benefits were not confirmed in a large international cluster-randomized study in settings with moderate-to-high prevalence of antibiotic resistance. There is no evidence that SDD increases antibiotic resistance. We end with future directions for research. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00134-019-05883-9) contains supplementary material, which is available to authorized users. |
Concerted evolution is often observed in multigene families such as the CEA gene family. As a result, sequence similarity of paralogous genes is significantly higher than expected from their evolutionary distance. Gene conversion, a “copy paste” DNA repair mechanism that transfers sequences from one gene to another and homologous recombination are drivers of concerted evolution. Nevertheless, some gene family members escape concerted evolution and acquire sufficient sequence differences that orthologous genes can be assigned in descendant species. Reasons why some gene family members can escape while others are captured by concerted evolution are poorly understood. By analyzing the entire CEA gene family in cattle (Bos taurus) we identified a member (CEACAM32) that was created by gene duplication and cooption of a unique transmembrane domain exon in the most recent ancestor of ruminants. CEACAM32 shows a unique, testis-specific expression pattern. Phylogenetic analysis indicated that CEACAM32 is not involved in concerted evolution of CEACAM1 paralogs in ruminants. However, analysis of gene conversion events revealed that CEACAM32 is subject to gene conversion but remarkably, these events are found in the leader exon and intron sequences but not in exons coding for the Ig-like domains. These findings suggest that natural selection hinders gene conversion affecting protein sequences of the mature protein and thereby support escape of CEACAM32 from concerted evolution. |
Renin angiotensin system (RAS) is an endocrine system widely known for its physiological roles in electrolyte homeostasis, body fluid volume regulation and cardiovascular control in peripheral circulation. However, brain RAS is an independent form of RAS expressed locally in the brain, which is known to be involved in brain functions and disorders. There is strong evidence for a major involvement of excessive brain angiotensin converting enzyme (ACE)/Angiotensin II (Ang II)/Angiotensin type-1 receptor (AT-1R) axis in increased activation of oxidative stress, apoptosis and neuroinflammation causing neurodegeneration in several brain disorders. Numerous studies have demonstrated strong neuroprotective effects by blocking AT1R in these brain disorders. Additionally, the angiotensin converting enzyme 2 (ACE2)/Angiotensin (1–7)/Mas receptor (MASR), is another axis of brain RAS which counteracts the damaging effects of ACE/Ang II/AT1R axis on neurons in the brain. Thus, angiotensin II receptor blockers (ARBs) and activation of ACE2/Angiotensin (1–7)/MASR axis may serve as an exciting and novel method for neuroprotection in several neurodegenerative diseases. Here in this review article, we discuss the expression of RAS in the brain and highlight how altered RAS level may cause neurodegeneration. Understanding the pathophysiology of RAS and their links to neurodegeneration has enormous potential to identify potentially effective pharmacological tools to treat neurodegenerative diseases in the brain. |
BACKGROUND: Hospice workers are required to regularly use emotional regulation strategies in an attempt to encourage and sustain terminally ill patients and families. Daily emotional regulation in reaction to constantly watching suffering patients may be intensified among those hospice professionals who have high levels of compassion fatigue. The main object of this study was to examine the relationship between daily exposition to seeing patient suffering and daily emotional work, and to assess whether compassion fatigue (secondary traumatic stress and burnout) buffers this relationship. METHODS: We used a diary research design for collecting daily fluctuations in seeing patients suffering and emotional work display. Participants filled in a general survey and daily survey over a period of eight consecutive workdays. A total of 39 hospice professionals from two Italian hospices participated in the study. RESULTS: Multilevel analyses demonstrated that daily fluctuations in seeing patients suffering was positively related to daily emotional work display after controlling for daily death of patients. Moreover, considering previous levels of compassion fatigue, a buffering effect of high burnout on seeing patients suffering - daily emotional work display relationship was found. CONCLUSIONS: A central finding of our study is that fluctuations in daily witness of patients suffering are positively related to daily use of positive emotional regulations. Further, our results show that burnout buffers this relationship such that hospice professionals with high burnout use more emotional display in days where they recurrently witness patients suffering. |
BACKGROUND: Salmonella enterica serovar Typhi (S. Typhi) is a highly invasive bacterium that infects the human intestinal mucosa and causes ~ 11.9–20.6 million infections and ~ 130,000–223,000 deaths annually worldwide. Oral typhoid vaccine Ty21a confers a moderate level of long-lived protection (5–7 years) in the field. New and improved vaccines against enteric pathogens are needed but their development is hindered by a lack of the immunological correlates of protection especially at the site of infection. Tissue resident memory T (T(RM)) cells provide immediate adaptive effector immune responsiveness at the infection site. However, the mechanism(s) by which S. Typhi induces T(RM) in the intestinal mucosa are unknown. Here, we focus on the induction of S. Typhi-specific CD4+T(RM) subsets by Ty21a in the human terminal ileum lamina propria and epithelial compartments. METHODS: Terminal ileum biopsies were obtained from consenting volunteers undergoing routine colonoscopy who were either immunized orally with 4 doses of Ty21a or not. Isolated lamina propria mononuclear cells (LPMC) and intraepithelial lymphocytes (IEL) CD4+T(RM) immune responses were determined using either S. Typhi-infected or non-infected autologous EBV-B cell lines as stimulator cells. T-CMI was assessed by the production of 4 cytokines [interferon (IFN)γ, interleukin (IL)-2, IL-17A and tumor necrosis factor (TNF)α] in 36 volunteers (18 vaccinees and 18 controls volunteers). RESULTS: Although the frequencies of LPMC CD103+ CD4+T(RM) were significant decreased, both CD103+ and CD103− CD4+T(RM) subsets spontaneously produced significantly higher levels of cytokines (IFNγ and IL-17A) following Ty21a-immunization. Importantly, we observed significant increases in S. Typhi-specific LPMC CD103+ CD4+T(RM) (IFNγ and IL-17A) and CD103− CD4+T(RM) (IL-2 and IL-17A) responses following Ty21a-immunization. Further, differences in S. Typhi-specific responses between these two CD4+T(RM) subsets were observed following multifunctional analysis. In addition, we determined the effect of Ty21a-immunization on IEL and observed significant changes in the frequencies of IEL CD103+ (decrease) and CD103− CD4+T(RM) (increase) following immunization. Finally, we observed that IEL CD103− CD4+T(RM), but not CD103+ CD4+T(RM), produced increased cytokines (IFNγ, TNFα and IL-17A) to S. Typhi-specific stimulation following Ty21a-immunization. CONCLUSIONS: Oral Ty21a-immunization elicits distinct compartment specific immune responses in CD4+T(RM) (CD103+ and CD103−) subsets. This study provides novel insights in the generation of local vaccine-specific responses. Trial registration This study was approved by the Institutional Review Board and registered on ClinicalTrials.gov (identifier NCT03970304, Registered 29 May 2019—Retrospectively registered, http://www.ClinicalTrials.gov/NCT03970304) |
Tissue-resident memory T cells (T(RM) cells) are critical for cellular immunity to respiratory pathogens and reside in both the airways and the interstitium. In the present study, we found that the airway environment drove transcriptional and epigenetic changes that specifically regulated the cytolytic functions of airway T(RM) cells and promoted apoptosis due to amino acid starvation and activation of the integrated stress response. Comparison of airway T(RM) cells and splenic effector-memory T cells transferred into the airways indicated that the environment was necessary to activate these pathways, but did not induce T(RM) cell lineage reprogramming. Importantly, activation of the integrated stress response was reversed in airway T(RM) cells placed in a nutrient-rich environment. Our data defined the genetic programs of distinct lung T(RM) cell populations and show that local environmental cues altered airway T(RM) cells to limit cytolytic function and promote cell death, which ultimately leads to fewer T(RM) cells in the lung. |
Angiotensin-converting enzyme 2 (ACE2) is critically involved in cardiovascular physiology and pathology, and is currently clinically evaluated to treat acute lung failure. Here we show that the B38-CAP, a carboxypeptidase derived from Paenibacillus sp. B38, is an ACE2-like enzyme to decrease angiotensin II levels in mice. In protein 3D structure analysis, B38-CAP homolog shares structural similarity to mammalian ACE2 with low sequence identity. In vitro, recombinant B38-CAP protein catalyzed the conversion of angiotensin II to angiotensin 1–7, as well as other known ACE2 target peptides. Treatment with B38-CAP suppressed angiotensin II-induced hypertension, cardiac hypertrophy, and fibrosis in mice. Moreover, B38-CAP inhibited pressure overload-induced pathological hypertrophy, myocardial fibrosis, and cardiac dysfunction in mice. Our data identify the bacterial B38-CAP as an ACE2-like carboxypeptidase, indicating that evolution has shaped a bacterial carboxypeptidase to a human ACE2-like enzyme. Bacterial engineering could be utilized to design improved protein drugs for hypertension and heart failure. |
Peripheral arterial disease (PAD) develops due to the narrowing or blockage of arteries supplying blood to the lower limbs. Surgical and endovascular interventions are the main treatments for advanced PAD but alternative and adjunctive medical therapies are needed. Currently the main preclinical experimental model employed in PAD research is based on induction of acute hind limb ischemia (HLI) by a 1-stage procedure. Since there are concerns regarding the ability to translate findings from this animal model to patients, we aimed to develop a novel clinically relevant animal model of PAD. HLI was induced in male Apolipoprotein E (ApoE(−/−)) deficient mice by a 2-stage procedure of initial gradual femoral artery occlusion by ameroid constrictors for 14 days and subsequent excision of the femoral artery. This 2-stage HLI model was compared to the classical 1-stage HLI model and sham controls. Ischemia severity was assessed using Laser Doppler Perfusion Imaging (LDPI). Ambulatory ability was assessed using an open field test, a treadmill test and using established scoring scales. Molecular markers of angiogenesis and shear stress were assessed within gastrocnemius muscle tissue samples using quantitative polymerase chain reaction. HLI was more severe in mice receiving the 2-stage compared to the 1-stage ischemia induction procedure as assessed by LDPI (p = 0.014), and reflected in a higher ischemic score (p = 0.004) and lower average distance travelled on a treadmill test (p = 0.045). Mice undergoing the 2-stage HLI also had lower expression of angiogenesis markers (vascular endothelial growth factor, p = 0.004; vascular endothelial growth factor- receptor 2, p = 0.008) and shear stress response mechano-transducer transient receptor potential vanilloid 4 (p = 0.041) within gastrocnemius muscle samples, compared to animals having the 1-stage HLI procedure. Mice subjected to the 2-stage HLI receiving an exercise program showed significantly greater improvement in their ambulatory ability on a treadmill test than a sedentary control group. This study describes a novel model of HLI which leads to more severe and sustained ischemia than the conventionally used model. Exercise therapy, which has established efficacy in PAD patients, was also effective in this new model. This new model maybe useful in the evaluation of potential novel PAD therapies. |
Nigeria has the highest number of AIDS-related deaths in the world. In this study, we characterised the HIV-1 molecular epidemiology by analysing 1442 HIV-1 pol sequences collected 1999–2014 from four geopolitical zones in Nigeria using state-of-the-art maximum-likelihood and Bayesian phylogenetic analyses. The main circulating forms were the circulating recombinant form (CRF) 02_AG (44% of the analysed sequences), CRF43_02G (16%), and subtype G (8%). Twenty-three percent of the sequences represented unique recombinant forms (URFs), whereof 37 (11%) could be grouped into seven potentially novel CRFs. Bayesian phylodynamic analysis suggested that five major Nigerian HIV-1 sub-epidemics were introduced in the 1960s and 1970s, close to the Nigerian Civil War. The analysis also indicated that the number of effective infections decreased in Nigeria after the introduction of free antiretroviral treatment in 2006. Finally, Bayesian phylogeographic analysis suggested gravity-like dynamics in which virus lineages first emerge and expand within large urban centers such as Abuja and Lagos, before migrating towards smaller rural areas. This study provides novel insight into the Nigerian HIV-1 epidemic and may have implications for future HIV-1 prevention strategies in Nigeria and other severely affected countries. |
A critical global health need exists for a Zika vaccine capable of mitigating the effects of future Zika epidemics. In this study we evaluated the antibody responses and efficacy of an aluminum hydroxide adjuvanted purified inactivated Zika vaccine (PIZV) against challenge with Zika virus (ZIKV) strain PRVABC59. Indian rhesus macaques received two doses of PIZV at varying concentrations ranging from 0.016 µg − 10 µg and were subsequently challenged with ZIKV six weeks or one year following the second immunization. PIZV induced a dose-dependent immune response that was boosted by a second immunization. Complete protection against ZIKV infection was achieved with the higher PIZV doses of 0.4 µg, 2 µg, and 10 µg at 6 weeks and with 10 ug PIZV at 1 year following vaccination. Partial protection was achieved with the lower PIZV doses of 0.016 µg and 0.08 µg. Based on these data, a neutralizing antibody response above 3.02 log(10) EC50 was determined as a correlate of protection in macaques. PIZV elicited a dose-dependent neutralizing antibody response which is protective for at least 1 year following vaccination. |
Respiratory Distress Syndrome (RDS) is the commonest diagnosis after premature birth. We aimed to audit clinical practices before and after introduction of a national guideline in Wales on RDS management. Anonymised, prospective data on all infants born at <34 weeks of gestation and cared for at one of the participating neonatal units in Wales were collected in two six-month time periods in 2015 and 2018. A national guideline was introduced in 2016 by the Wales Neonatal Network. Data collection included areas of antenatal management, delivery room stabilisation, invasive and non-invasive respiratory support, surfactant treatment and elements of supportive care. Univariate and multivariate methods were used to compare data between the two epochs. Comparing care before and after introduction of the national guideline, areas of significant improvement include use of targeted tidal volume ventilation, use of caffeine therapy, oxygen therapy post-surfactant and increasing early use of parenteral nutrition. Areas of poorer management included levels of positive end expiratory pressures and timing of introduction of enteral feeds. Little variation was seen between level two and three units, although gestational age was a significant independent variable for several practices, including delayed cord clamping, stabilisation with intubation, early enteral feeding and caffeine administration. A national guideline for management of RDS in Wales has significantly improved practice in several areas. However, despite a large volume of high-quality evidence and robust guidance, there remains a significant variation in some elements of best practice for RDS management. Further work should focus on education and training, especially for elements requiring cross-departmental work. |
We conducted a systematic review and meta-analysis to assess the clinical efficacy of high-flow nasal cannula (HFNC) therapy as apneic oxygenation in critically ill patients who require endotracheal intubation in the intensive care unit (ICU). This systematic review and meta-analysis included six randomized controlled trials and a prospective study identified in PubMed, Embase, Cochrane Library, and the Web of Science until August 18, 2019. In this meta-analysis including 956 participants, HFNC was noninferior to standard of care during endotracheal intubation regarding incidence of severe hypoxemia, mean lowest oxygen saturation, and in-hospital mortality. HFNC significantly shortened the ICU stay by a mean of 1.8 days. In linear meta-regression interaction analysis, the risk ratio of severe hypoxemia decreased with increasing baseline partial oxygen pressure (PaO(2)) to fraction of inspired oxygen (FiO(2)) ratio. In subgroup analysis, HFNC significantly reduced the incidence of severe hypoxemia during endotracheal intubation in patients with mild hypoxemia (PaO(2)/FiO(2)> 200 mmHg; risk difference, −0.06; 95% confidence interval, −0.12 to −0.01; number needed to treat = 16.7). In conclusion, HFNC was noninferior to standard of care for oxygen delivery during endotracheal intubation and was associated with a significantly shorter ICU stay. The beneficial effect of HFNC in reducing the incidence of severe hypoxemia was observed in patients with mild hypoxemia. |
BACKGROUND: Mosquito-borne viral infections have in recent years, become a public health threat globally. This review aimed to provide an overview of the ecological and epidemiological profiles of mosquito-borne viral infections in the Democratic Republic of the Congo (DRC). METHODS: A search of literature was conducted using Google Scholar, PubMed and the WHO website using the following keywords: “Democratic Republic of the Congo”, “Zaire”, “Belgian Congo” and either of the following: “mosquito-borne virus”, “arbovirus”, “yellow fever”, “dengue”, “chikungunya”, “West Nile”, “Rift Valley fever”, “O’nyong’nyong”, “Zika”, “epidemiology”, “ecology”, “morbidity”, “mortality”. Published articles in English or French covering a period between 1912 and October 2018 were reviewed. RESULTS: A total of 37 articles were included in the review. The findings indicate that the burden of mosquito-borne viral infections in DRC is increasing over time and space. The north-western, north-eastern, western and central regions have the highest burden of mosquito-borne viral infections compared to south and eastern highland regions. Yellow fever, chikungunya, dengue, Zika, Rift Valley fever, West Nile and O’nyong’nyong have been reported in the country. These mosquito-borne viruses were found circulating in human, wildlife and domestic animals. Yellow fever and chikungunya outbreaks have been frequently reported. Aedes aegypti and Ae. simpsoni were documented as the main vectors of most of the mosquito-borne viral infections. Heavy rains, human movements, forest encroachment and deforestation were identified as drivers of mosquito-borne viruses occurrence in DRC. CONCLUSIONS: Mosquito-borne viral infections are becoming common and a serious public health problem in DRC. In the current context of climate change, there is urgent need to improve understanding on ecological and epidemiology of the diseases and strengthen surveillance systems for prompt response to epidemics in DRC. |
BACKGROUND: The effect of alternative spontaneous breathing trial (SBT) techniques on extubation success and other clinically important outcomes is uncertain. A systematic review and meta-analysis was performed to clarify the preferable SBT (T-piece or pressure support ventilation [PSV]). METHODS: We searched the PubMed, Cochrane, and Embase databases for randomized controlled trials (RCTs) from inception to the 31st of July 2019. We included RCTs involving adult patients (> 18 years) who underwent at least two different SBT methods. All authors reported our primary outcome of successful extubation rate and clearly compared PS versus T-piece with clinically relevant secondary outcomes (rate of reintubation, ICU and hospital length of stay, and ICU and hospital mortality). Results were expressed as odds ratio (OR) and mean difference (MD) with accompanying 95% confidence interval (CI). RESULTS: Ten RCTs including 3165 patients were included. The results of this meta-analysis showed that there was no significant difference in the successful extubation rate between the T-piece group and PS group (odds ratio [OR] = 0.91; 95% CI, 0.78–1.07; P = 0.27; I(2) = 79%). In addition, compared with the PS group, the T-piece group showed no significant difference in the rate of reintubation (odds ratio [OR] = 0.99; 95% CI, 0.78–1.26; P = 0.95; I(2) = 5%), ICU mortality (odds ratio [OR] = 1.22; 95% CI, 0.83–1.80; P = 0.30; I(2) = 0%), hospital mortality (odds ratio [OR] = 1.36; 95% CI, 0.99–1.87; P = 0.06; I(2) = 19%), ICU length of stay (mean difference = − 0.10; 95% CI, − 0.59 to 0.39; P = 0.69; I(2) = 13%), and hospital length of stay (mean difference = − 0.82;95% CI, − 2.2 to 0.55; P = 0.24; I(2) = 0%). CONCLUSIONS: T-piece and PSV as SBTs are considered to have comparable predictive power of successful extubation in critically ill patients. The analysis of secondary outcomes also shows no significant difference in the rate of reintubation, ICU and hospital length of stay, and ICU and hospital mortality between the two groups. Further randomized controlled studies of SBTs are still required. |
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