Αρχειοθήκη ιστολογίου

Τρίτη 27 Σεπτεμβρίου 2022

A novel animal model of primary blast lung injury and its pathological changes in mice

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imageBACKGROUND Primary blast lung injury (PBLI) is a major cause of death in military conflict and terrorist attacks on civilian populations. However, the mechanisms of PBLI are not well understood, and a standardized animal model is urgently needed. This study aimed to establish an animal model of PBLI for laboratory study. METHODS The animal model of PBLI was established using a self-made mini shock tube simulation device. In brief, mice were randomly divided into two groups: the control group and the model group, the model group were suffered 0.5 bar shock pressures. Mice were sacrificed at 2 hours, 4 hours, 6 hours, 12 hours, and 24 hours after injury. Lung tissue gross observation, hematoxylin and eosin staining and lung pathology scoring were performed to evaluated lung tissue damage. Evans blue dye leakage and bronchoalveolar lavage fluid examination were performed to evaluated pulmonary edema. The relative expression levels of inflammation factors were measured by real-time quantitative polymerase chain reaction and Western blotting analysis. The release of neutrophil extracellular traps was observed by immunofluorescence stain. RESULTS In the model group, the gross observation and hematoxylin and eosin staining assay showed the inflammatory cell infiltration, intra-alveolar hemorrhage, and damaged lung tissue structure. The Evans blue dye and bronchoalveolar lavage fluid examination revealed that the lung tissue permeability and edema was significantly increased after injury. Real-time quantitative polymerase chain reaction and Western blotting assays showed that IL-1β, IL-6, TNF-α were upregulated in the model group. Immunofluorescence assay showed that the level of neutrophil extracellular traps in the lung tissue increased significantly in the model group. CONCLUSION The self-made mini shock tube simulation device can be used to establish the animal model of PBLI successfully. Pathological changes of PBLI mice were characterized by mechanical damage and inflammatory response in lung tissue.
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The anchor point algorithm: A morphometric analysis of anatomic landmarks to guide placement of temporary aortic Rescue stent grafts for noncompressible torso hemorrhage

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imageBACKGROUND Noncompressible hemorrhage remains a high-mortality injury, which requires rapid damage control within minutes to avoid exsanguination. Retrievable stent grafts offer perfusion preserving hemorrhage damage control, and yet algorithms for device selection and positioning are lacking for an anatomically diverse human population. We hypothesized that easily acquired external measurements could be used to rapidly triage patients to receive one of several presized stents and that these metrics may further predict a single target on the aorta by which to optimize both mesenteric perfusion and aortic hemorrhage control. METHODS Metrics were acquired from computed tomography imaging of 203 male and female patients aged 18 to 50 years. Algorithms for metric based triage and stent sizing were examined against the cohort for effectiveness. Linear regression was used to predict a single target on the aorta for alignment of a multitiered stent. Next, the relationship of the anchor point to the palpable xiphoid was determined. RESULTS Clavicle to pubis measurements correlated with aortic length and was used to triage patients to one of three stent grafts. Stents for each triage group were sized to achieve >75% coverage of aortic Zones 1 and 3 in most patients while preserving carotid and visceral perfusion. A metric/sex-based equation that predicts the location of the superior mesenteric artery relative to the palpable xiphoid was derived. By alignment of a single point on the stent with this target, known as the anchor point, the remainder of the stent can be rapidly deployed while minimizing coverage of critical branches. When applied back to the cohort, only 10.4% had potential serious branch coverage events predicted. CONCLUSION Simple anatomic metrics offer rapid triage in this study population to one of three presized stent grafts and predict the location of key vascular branches. Confirmatory human trials will be essential to demonstrate safety and effectiveness of this approach. LEVEL OF EVIDENCE Prognostic/Epidemiological; Level IV.
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Pregnancy in trauma—A Western Trauma Association algorithm

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imageBACKGROUND The Western Trauma Association has undertaken publication of best practice clinical practice guidelines on multiple trauma topics. These guidelines are based on scientific evidence, case reports, and best practices per expert opinion. Some of the topics covered by this consensus group do not have the ability to have randomized controlled studies completed because of complexity, ethical issues, financial considerations or scarcity of experience. Care of the pregnant trauma patient is one of these clinically complex situations that is based on physiologic data, standard trauma care, trauma care experience, and outcomes. METHODS Review of multiple evidence- based guidelines, case reports, and expert opinion were compiled and reviewed. RESULTS The algorithm is attached with detailed explanation of each step, supported by data if available. CONCLUSION Resuscitative and trauma care of the mother is the utmost priority Study Type Algorithm, expert opinion, consensus LEVEL OF EVIDENCE Diagnostic Tests/Criteria; Level III.
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Cellular microRNAs correlate with clinical parameters in multiple injury patients

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imageINTRODUCTION The pathophysiology of the inflammatory response after major trauma is complex, and the magnitude correlates with severity of tissue injury and outcomes. Study of infection-mediated immune pathways has demonstrated that cellular microRNAs may modulate the inflammatory response. The authors hypothesize that the expression of microRNAs would correlate to complicated recoveries in polytrauma patients (PtPs). METHODS Polytrauma patients enrolled in the prospective observational Tissue and Data Acquisition Protocol with Injury Severity Score of >15 were selected for this study. Polytrauma patients were divided into complicated recoveries and uncomplicated recovery groups. Polytrauma patients' blood samples were obtained at the time of admission (T0). Established biomarkers of systemic inflammation, including cytokines and chemokines, were measured using multiplexed Luminex-based methods, and novel microRNAs were measured in plasma samples using multiplex RNA hybridization. RESULTS Polytrauma patients (n = 180) had high Injury Severity Score (26 [20–34]) and complicated recovery rate of 33%. MicroRNAs were lower in PtPs at T0 compared with healthy controls, and bivariate analysis demonstrated that variations of microRNAs correlated with age, race, comorbidities, venous thromboembolism, pulmonary complications, complicated recovery, and mortality. Positive correlations were noted between microRNAs and interleukin 10, vascular endothelial growth factor, Acute Physiology and Chronic Health Evaluation, and Sequential Organ Failure Assessment scores. Multivariable Lasso regression analysis of predictors of complicated recovery based on microRNAs, cytokines, and chemokines revealed that miR-21-3p and monocyte chemoattractant protein-1 were predictive of complicated recovery with an area under the curve of 0.78. CONCLUSION Systemic microRNAs were associated with poor outcomes in PtPs, and results are consistent with previously described trends in critically ill patients. These early biomarkers of inflammation might provide predictive utility in early complicated recovery diagnosis and prognosis. Because of their potential to regulate immune responses, microRNAs may provide therapeutic targets for immunomodulation. LEVEL OF EVIDENCE Diagnostic Tests/Criteria; Level II.
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Paromomycin and Miltefosine Combination as an Alternative to Treat Patients With Visceral Leishmaniasis in Eastern Africa: A Randomized, Controlled, Multicountry Trial

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Abstract
BackgroundThis study aimed to determine whether paromomycin plus miltefosine (PM/MF) is noninferior to sodium stibogluconate plus paromomycin (SSG/PM) for treatment of primary visceral leishmaniasis in eastern Africa.
Methods
An open-label, phase 3, randomized, controlled trial was conducted in adult and pediatric patients at 7 sites in eastern Africa. Patients were randomly assigned to either 20 mg/kg paromomycin plus allometric dose of miltefosine (14 days), or 20 mg/kg sodium stibogluconate plus 15 mg/kg paromomycin (17 days). The primary endpoint was definitive cure after 6 months.
Results
Of 439 randomized patients, 424 completed the trial. Definitive cure at 6 months was 91.2% (155 of 170) and 91.8% (156 of 170) in the PM/MF and SSG/PM arms in primary efficacy modified intention-to-treat analysis (difference, 0.6%; 97.5% confidence interval [CI], −6.2 to 7.4), narrowly missing the noninferiority margin of 7%. In the per-protocol analysis, efficacy was 92% (149 of 162) and 91.7% (155 of 169) in the PM/MF and SSG/PM arms (difference, −0.3%; 97.5% CI, –7.0 to 6.5), demonstrating noninferiority. Treatments were well tolerated. Four of 18 serious adverse events were study drug–related, and 1 death was SSG-related. Allometric dosing ensured similar MF exposure in children (<12 years) and adults.
Conclusions
PM/MF and SSG/PM efficacies were similar, and adverse drug reactions were as expected given the drugs safety profiles. With 1 less injection each day, reduced treatment duration, and no risk of SSG-associated life-threatening cardiotoxicity, PM/MF is a more patient-friendly alternative for children and adults with primary visceral leishmaniasis in eastern Africa.Clinical Trials Registration. NCT03129646.
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Hydrogen sulfide inhibits human T‐cell leukemia virus type‐1 (HTLV‐1) protein expression via regulation of ATG4B

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Abstract

Hydrogen sulfide（H2S）is a redox gasotransmitter. It has been shown that H2S has a key role in host antiviral defense by inhibiting interleukin (IL)-6 production and S-sulfhydrating Keap1 lead to Nrf2/ARE pathway activation. However, it is yet unclear whether H2S can play an antiviral role by regulating autophagy. In this research, we found that exogenous H2S decreased the expression of HTLV-1 protein and HTLV-1 induced autophagosomes accumulation. Transmission electron microscope assays indicated that autophagosomes accumulation decreased after H2S administration. HTLV-1-transformed T-cell lines had a high level of CSE (H2S endogenous enzyme) which could be induced in Hela by HTLV-1 infection. Immunoblot demonstrated that overexpression of CSE inhibited HTLV-1 protein expression and autophagy. And we got the opposite after CSE knockdown. Meanwhile, H2S could not restrain the aut ophagy when ATG4B had a mutant at its site of 89. In a word, these results suggested that H2S modulated HTLV-1 protein expression via ATG4B. Therefore, our findings suggested a new mechanism by which H2S defended against virus infection.

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Description of Opioid Involved Hospital Deaths that Do Not Have a Subsequent Autopsy

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Background: Surveillance systems rely on death records to monitor the most severe outcome of the opioid epidemic. However, few studies have linked data from hospital systems with death records to determine potential undercount of opioid involved deaths occurring in hospitals. This study describes characteristics of decedents less likely to have an autopsy following an opioid-involved death in hospitals and estimates the resulting undercount. Methods: A probabilistic data linkage of hospital and medical examiner data involving 4,936 opioid involved deaths among residents of Cook County, Illinois, US from 2016 to 2019. We included only hospital deaths that met a national case definition and presented with clinical signs of opioid overdose. Results: Decedents had higher odds of not having an autopsy if they were 50+ years, admitted to the hospital (aOR=3.7: 2.1, 6.5), hospitalized for 4+ days (aOR=2.2: 1.5, 3.1), and had a comorbid diagnosis of malignant cancer (aOR=4.3: 1.8, 10.1). However, decedents exposed to heroin and synthetic opioids (aOR=0.39: 0.28, 0.55), and concurrent exposure to stimulants (aOR=0.44: 0.31, 0.64) were more likely to have an autopsy). Compared to estimates from the US Centers for Disease Control and Prevention (CDC), we observed undercounts of opioid overdose deaths ranging from 6%-15%. Conclusions: Surveillance systems may undercount decedents that do not meet the typical profile of those more likely to have an autopsy, particularly older patients with chronic health conditions. Our undercount estimate likely exists in addition to the estimated 20-40% undercount reported elsewhere. Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.
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Environmental exposures and anti-Müllerian hormone: a mixture analysis in the Nurses’ Health Study II

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Background: Previous studies have linked environmental exposures with anti-Müllerian hormone (AMH), a marker of ovarian reserve. However, associations with multiple environment factors has to our knowledge not been addressed. Methods We included a total of 2,447 premenopausal women in the Nurses' Health Study II (NHSII) who provided blood samples during 1996-1999. We selected environmental exposures linked previously with reproductive outcomes that had measurement data available in NHSII, including greenness, particulate matter, noise, outdoor light at night, ultraviolet radiation, and six hazardous air pollutants (1,3-butadiene, benzene, diesel particulate matter, formaldehyde, methylene chloride, and tetrachloroethylene). For these we calculated cumulative averages from enrollment (1989) to blood draw and estimated associations with AMH in adjusted single exposure models, principal component analysis (PCA), and hierarchical Bayesian kernel machine regression (BKMR). Results Single exposure models showed negative associations of AMH with benzene (percentage reduction in AMH per interquartile range (IQR) increase = 5.5%, 95%CI=1.0, 9.8) and formaldehyde (6.1%, 95%CI=1.6, 10). PCA identified four major exposure patterns but only one with high exposure to air pollutants and light at night was associated with lower AMH. Hierarchical BKMR pointed to benzene, formaldehyde, and greenness, and suggested an inverse joint association with AMH (percentage reduction comparing all exposures at the 75th percentile to median= 8.2%, 95%CI=0.7, 15.1. Observed associations were mainly among women above age 40. Conclusions We found exposure to benzene and formaldehyde to be consistently associated with lower AMH levels. The associations among older women are consistent with the hypothesis that environmental exposures accelerate reproductive aging. Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
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Using Latent Profile Analysis to Identify Associations Between Gestational Chemical Mixtures and Child Neurodevelopment

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Background: Unsupervised machine learning techniques have become increasingly popular for studying associations between gestational exposure mixtures and human health. Latent profile analysis is one method that has not been fully explored. Methods: We estimated associations between gestational chemical mixtures and child neurodevelopment using latent profile analysis. Using data from the Maternal-Infant Research on Environmental Chemicals (MIREC) research platform, a longitudinal cohort of pregnant Canadian women and their children, we generated latent profiles from 27 gestational exposure biomarkers. We then examined the associations between these profiles and child Verbal IQ, Performance IQ, and Full-Scale IQ, measured with the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III). We validated our findings using k-means clustering. Results: Latent profile analysis detected five latent profiles of exposure: a reference profile containing 61% of the study participants, a high Mono-ethyl Phthalate (MEP) profile with moderately low persistent organic pollutants (POPs) containing 26%, a high POP profile containing 6%, a low POP profile containing 4%, and a smoking chemicals profile containing 3%. We observed negative associations between both the smoking chemicals and high MEP profiles and all IQ scores, and between the high POP profile and Full-Scale and Verbal IQ scores. We also found a positive association between the low POP profile and Full-Scale and Performance IQ scores. All associations had wide 95% confidence intervals. Conclusion: Latent profile analysis is a promising technique for identifying patterns of chemical exposure, and is worthy of further study for its use in examining complicated exposure mixtures. Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
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Accounting for misclassification and selection bias in estimating effectiveness of self-managed medication abortion

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Background: Studies on the effectiveness of self-managed medication abortion may suffer from misclassification and selection bias due to self-reported outcomes and loss to follow-up. Monte Carlo sensitivity analysis can estimate self-managed abortion effectiveness accounting for these potential biases. Methods: We conducted a Monte Carlo sensitivity analysis based on data from the Studying Accompaniment model Feasibility and Effectiveness Study (the SAFE Study), to generate bias-adjusted estimates of effectiveness of self-managed abortion with accompaniment group support. Between July 2019 and April 2020, we enrolled a total of 1051 callers who contacted accompaniment groups in Argentina and Nigeria for self-managed abortion information; 961 took abortion medications and completed at least one follow-up. Using these data, we calculated measures of effectiveness adjusted for ineligibility, misclassification, and selection bias across 50,000 simulations with bias parameters drawn from pre-specified Beta distributions in R. Results: After accounting for potential influence of various sources of bias, bias-adjusted estimates of effectiveness were similar to observed estimates, conditional on chosen bias parameters: 92.68% (95% simulation interval: 87.80%, 95.74%) for mifepristone in combination with misoprostol (versus 93.7% in the observed data) and 98.47% (95% simulation interval: 96.79%, 99.39%) for misoprostol alone (versus 99.3% in the observed data). Conclusions: After adjustment for multiple potential sources of bias, estimates of self-managed medication abortion effectiveness remain high. Monte Carlo sensitivity analysis may be useful in studies measuring an epidemiologic proportion (i.e., effectiveness, prevalence, cumulative incidence), while accounting for possible selection or misclassification bias. Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
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