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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Ventilator-associated pneumonia and intubation location in adults with traumatic injuries: Systematic review and meta-analysis

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imageBACKGROUND Ventilator-associated pneumonia (VAP) is an important cause of morbidity and mortality among critically ill patients, particularly those who present with traumatic injuries. This review aims to determine whether patients with traumatic injuries who are intubated in the prehospital setting are at higher risk of developing VAP compared with those intubated in the hospital. METHODS A systematic review of Medline, Scopus, and Cochrane electronic databases was conducted from inception to January 2021. Inclusion criteria were patients with traumatic injuries who were intubated in the prehospital or hospital settings with VAP as an outcome. Using a random-effects model, the risk of VAP across study arms was compared by calculating a summary relative risk with 95% confidence intervals. The results of individual studies were also summarized qualitatively. RESULTS The search identified 754 articles of which 6 studies (N = 2,990) met the inclusion criteria. All studies were good quality based on assessment with the Newcastle Ottawa scale. Prehospital intubation demonstrated an increased risk of VAP development in two of the six studies. Among the six studies, the overall quality weighted risk ratio was 1.09 (95% confidence interval, 0.90–1.31). CONCLUSION Traumatically injured patients who are intubated in the prehospital setting have a similar risk of developing VAP compared with those that are intubated in the hospital setting. LEVEL OF EVIDENCE Systematic review and meta-analysis; Level IV.
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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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Scalable deep learning algorithm to compute percent pulmonary contusion among patients with rib fractures

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imageBACKGROUND Pulmonary contusion exists along a spectrum of severity, yet is commonly binarily classified as present or absent. We aimed to develop a deep learning algorithm to automate percent pulmonary contusion computation and exemplify how transfer learning could facilitate large-scale validation. We hypothesized that our deep learning algorithm could automate percent pulmonary contusion computation and that greater percent contusion would be associated with higher odds of adverse inpatient outcomes among patients with rib fractures. METHODS We evaluated admission-day chest computed tomography scans of adults 18 years or older admitted to our institution with multiple rib fractures and pulmonary contusions (2010–2020). We adapted a pretrained convolutional neural network that segments three-dimensional lung volumes and segmented contused lung parenchyma, pulmonary blood vessels, and computed percent pulmonary contusion. Exploratory analysis evaluated associations between percent pulmonary contusion (quartiles) and odds of mechanical ventilation, mortality, and prolonged hospital length of stay using multivariable logistic regression. Sensitivity analysis included pulmonary blood vessel volumes during percent contusion computation. RESULTS A total of 332 patients met inclusion criteria (median, 5 rib fractures), among whom 28% underwent mechanical ventilation and 6% died. The study population's median (interquartile range) percent pulmonary contusion was 4% (2%–8%). Compared to the lowest quartile of percent pulmonary contusion, each increasing quartile was associated with higher adjusted odds of undergoing mechanical ventilation (odds ratio [OR], 1.5; 95% confidence interval [95% CI], 1.1–2.1) and prolonged hospitalization (OR, 1.6; 95% CI, 1.1–2.2), but not with mortality (OR, 1.1; 95% CI, 0.6–2.0). Findings were similar on sensitivity analysis. CONCLUSION We developed a scalable deep learning algorithm to automate percent pulmonary contusion calculating using chest computed tomography scans of adults admitted with rib fractures. Open code sharing and collaborative research are needed to validate our algorithm and exploratory analysis at a large scale. Transfer learning can help harness the full potential of big data and high-performing algorithms to bring precision medicine to the bedside. LEVEL OF EVIDENCE Prognostic and epidemiological, Level III.
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Tracheostomy decreases continuous analgesia and sedation requirements

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imageBACKGROUND The goals of sedation in the critically ill surgical patient are to minimize pain, anxiety, and agitation without hindering cardiopulmonary function. One potential benefit of tracheostomy during endotracheal intubation is the reduction of sedation and analgesia; however, there are little data to support this supposition. We hypothesized that patients undergoing tracheostomy would have a rapid reduction in sedation and analgesia following tracheostomy. METHODS A retrospective review of tracheostomies performed at a single Level I trauma center from January 2013 to June 2018 was completed. An evaluation of Glasgow Coma Scale, Richmond Agitation-Sedation Scale, and Confusion Assessment Method for the intensive care unit 72 hours pretracheostomy to 72 hours posttracheostomy was performed. The total daily dose of sedation, anxiolytic, and analgesic medications administered were recorded. Mixed-effects models were used to evaluate longitudinal drug does over time (hours). RESULTS Four hundred sixty-eight patients included for analysis with a mean age of 58.8 ± 18.3 years. There was a significant decrease in propofol and fentanyl utilization from 24 hours pretracheostomy to 24 hours posttracheostomy in both dose and number of patients receiving these continuous intravenous medications. Similarly, total morphine milligram equivalents (MME) use and continuous midazolam significantly decreased from 24 hours pretracheostomy to 24 hours posttracheostomy. By contrast, intermittent enteral quetiapine and methadone administration increased after tracheostomy. Importantly, Richmond Agitation-Sedation Scale, Glasgow Coma Scale, and Confusion Assessment Method scoring were also significantly improved as early as 24 hours posttracheostomy. Total MME use was significantly elevated in patients younger than 65 years and in male patients pretracheostomy compared with female patients. Patients admitted to the medical intensive care unit had significantly higher MME use compar ed with those in the surgical intensive care unit pretracheostomy. CONCLUSION Tracheostomy allows for a rapid and significant reduction in intravenous sedation and analgesia medication utilization. Posttracheostomy sedation can transition to intermittent enteral medications, potentially contributing to the observed improvements in postoperative mental status and agitation. LEVEL OF EVIDENCE Therapeutic/Care Management; Level III.
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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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A novel variant in the transmembrane 4 domain of ANO3 identified in a two-year-old girl with developmental delay and tremor

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Journal of Human Genetics, Published online: 27 September 2022; doi:10.1038/s10038-022-01082-5

A novel variant in the transmembrane 4 domain of ANO3 identified in a two-year-old girl with developmental delay and tremor
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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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