Management and Discussion of COVID-19 Related Tracheal Stenosis: A Single Center Retrospective Review

Alexander J Sweidan, Haron Y Anaim, Niral M Patel, Javier A Longoria Division of Pulmonary and Critical Care Medicine, Interventional Pulmonary, University of California, Irvine, CA, USACorrespondence: Alexander J Sweidan, Division of Pulmonary and Critical Care Medicine, Interventional Pulmonary, University of California, 101 The City Dr S, Orange, CA, 92868, USA, Tel +1 714-456-5413, Email [email protected]: SARS-CoV-2 virus has led to an unprecedented amount of tracheal stenosis. Rigid bronchoscopy can serve as a curative measure or bridge therapy to tracheal resection. We also briefly discuss the pathophysiology of tracheal stenosis from prolonged intubation and SARS-CoV-2 virus. This should be differentiated from other forms of airway obstruction such as tracheobronchomalacia which would be considered a pseudo-tracheal stenotic disease. The aim of this study is to evaluate stenosis that is unable to be improved with positive airway pressure or “PAP” therapies and required stenting and/or subsequent tracheal resection. By performing Rigid Bronchoscopy and subsequent stenting of airways, we demonstrated outcomes for long term airway patency regarding patients who were intubated secondary to the SARS-CoV-2 virus. We demonstrate superb outcomes in a consecutive case series of 6 patients managed with rigid bronchoscopy, airway stent and tracheal resection. The patients were all managed from a pulmonary perspective by the physicians mentioned in this study.Keywords: tracheal stenosis, COVID-19 intubation, rigid bronchoscop

Pharmacodynamic Modeling of Anti-Cancer Activity of Tetraiodothyroacetic Acid in a Perfused Cell Culture System

Unmodified or as a poly[lactide-co-glycolide] nanoparticle, tetraiodothyroacetic acid (tetrac) acts at the integrin αvβ3 receptor on human cancer cells to inhibit tumor cell proliferation and xenograft growth. To study in vitro the pharmacodynamics of tetrac formulations in the absence of and in conjunction with other chemotherapeutic agents, we developed a perfusion bellows cell culture system. Cells were grown on polymer flakes and exposed to various concentrations of tetrac, nano-tetrac, resveratrol, cetuximab, or a combination for up to 18 days. Cells were harvested and counted every one or two days. Both NONMEM VI and the exact Monte Carlo parametric expectation maximization algorithm in S-ADAPT were utilized for mathematical modeling. Unmodified tetrac inhibited the proliferation of cancer cells and did so with differing potency in different cell lines. The developed mechanism-based model included two effects of tetrac on different parts of the cell cycle which could be distinguished. For human breast cancer cells, modeling suggested a higher sensitivity (lower IC50) to the effect on success rate of replication than the effect on rate of growth, whereas the capacity (Imax) was larger for the effect on growth rate. Nanoparticulate tetrac (nano-tetrac), which does not enter into cells, had a higher potency and a larger anti-proliferative effect than unmodified tetrac. Fluorescence-activated cell sorting analysis of harvested cells revealed tetrac and nano-tetrac induced concentration-dependent apoptosis that was correlated with expression of pro-apoptotic proteins, such as p53, p21, PIG3 and BAD for nano-tetrac, while unmodified tetrac showed a different profile. Approximately additive anti-proliferative effects were found for the combinations of tetrac and resveratrol, tetrac and cetuximab (Erbitux), and nano-tetrac and cetuximab. Our in vitro perfusion cancer cell system together with mathematical modeling successfully described the anti-proliferative effects over time of tetrac and nano-tetrac and may be useful for dose-finding and studying the pharmacodynamics of other chemotherapeutic agents or their combinations

Atomic structures of TDP-43 LCD segments and insights into reversible or pathogenic aggregation.

The normally soluble TAR DNA-binding protein 43 (TDP-43) is found aggregated both in reversible stress granules and in irreversible pathogenic amyloid. In TDP-43, the low-complexity domain (LCD) is believed to be involved in both types of aggregation. To uncover the structural origins of these two modes of β-sheet-rich aggregation, we have determined ten structures of segments of the LCD of human TDP-43. Six of these segments form steric zippers characteristic of the spines of pathogenic amyloid fibrils; four others form LARKS, the labile amyloid-like interactions characteristic of protein hydrogels and proteins found in membraneless organelles, including stress granules. Supporting a hypothetical pathway from reversible to irreversible amyloid aggregation, we found that familial ALS variants of TDP-43 convert LARKS to irreversible aggregates. Our structures suggest how TDP-43 adopts both reversible and irreversible β-sheet aggregates and the role of mutation in the possible transition of reversible to irreversible pathogenic aggregation

Hypersensitivity pneumonitis: an overlooked cause of cough and dyspnea.

Hypersensitivity pneumonitis (HP) is an immune-mediated pulmonary disorder involving inflammation of the lung interstitium, terminal bronchioles, and alveoli caused by the immune response to the inhalation of an offending environmental airborne agent. It can manifest as exertional dyspnea, fatigue, weight loss, and progressive respiratory failure if left untreated. Because of its protean features, it can be misdiagnosed as other common obstructive lung conditions such as asthma. If triggers are not avoided, it can progress to irreversible pulmonary fibrosis. In this article, we present the case of a 51-year-old male who presented to our hospital with recurrent bouts of dyspnea and cough, initially diagnosed as an asthma exacerbation. He received a final diagnosis of HP after investigation of his workplace revealed airborne spores and surface molds from multiple fungal species, serology revealed eosinophilia, and computed tomography showed bronchiectasis. Avoidance of occupational exposure resulted in significant improvement of his respiratory symptoms after two months

Antimicrobial Stewardship from Policy to Practice: Experiences from UK Antimicrobial Pharmacists

Antimicrobial stewardship in the UK has evolved dramatically in the last 15 years. Factors driving this include initial central funding for specialist pharmacists and mandatory reductions in healthcare-associated infections (particularly Clostridium difficile infection). More recently, the introduction of national stewardship guidelines, and an increased focus on stewardship as part of the UK five-year antimicrobial resistance strategy, have accelerated and embedded developments. Antimicrobial pharmacists have been instrumental in effecting changes at an organizational and national level. This article describes the evolution of the antimicrobial pharmacist role, its impact, the progress toward the actions listed in the five-year resistance strategy, and novel emerging areas in stewardship in the UK

Enhanced expressions of microvascular smooth muscle receptors after focal cerebral ischemia occur via the MAPK MEK/ERK pathway

<p>Abstract</p> <p>Background</p> <p>MEK1/2 is a serine/threonine protein that phosphorylates extracellular signal-regulated kinase (ERK1/2). Cerebral ischemia results in enhanced expression of cerebrovascular contractile receptors in the middle cerebral artery (MCA) leading to the ischemic region. Here we explored the role of the MEK/ERK pathway in receptor expression following ischemic brain injury using the specific MEK1 inhibitor U0126.</p> <p>Methods and result</p> <p>Rats were subjected to a 2-h middle cerebral artery occlusion (MCAO) followed by reperfusion for 48-h and the ischemic area was calculated. The expression of phosphorylated ERK1/2 and Elk-1, and of endothelin ET_Aand ET_B, angiotensin AT₁, and 5-hydroxytryptamine 5-HT_1Breceptors were analyzed with immunohistochemistry using confocal microscopy in cerebral arteries, microvessels and in brain tissue. The expression of endothelin ET_Breceptor was analyzed by quantitative Western blot. We demonstrate that there is an increase in the number of contractile smooth muscle receptors in the MCA and in micro- vessels within the ischemic region. The enhanced expression occurs in the smooth muscle cells as verified by co-localization studies. This receptor upregulation is furthermore associated with enhanced expression of pERK1/2 and of transcription factor pElk-1 in the vascular smooth muscle cells. Blockade of transcription with the MEK1 inhibitor U0126, given at the onset of reperfusion or as late as 6 hours after the insult, reduced transcription (pERK1/2 and pElk-1), the enhanced vascular receptor expression, and attenuated the cerebral infarct and improved neurology score.</p> <p>Conclusion</p> <p>Our results show that MCAO results in upregulation of cerebrovascular ET_B, AT₁and 5-HT_1Breceptors. Blockade of this event with a MEK1 inhibitor as late as 6 h after the insult reduced the enhanced vascular receptor expression and the associated cerebral infarction.</p

Thyroid disease is a favorable prognostic factor in achieving sustained virologic response in chronic hepatitis C undergoing combination therapy: A nested case control study

<p>Abstract</p> <p>Background</p> <p>Interferon-α in combination with ribavirin is the current gold standard for treatment of chronic hepatitis C. It is unknown if the development of autoimmune thyroid disease (TD) during treatment confers an improved chance of achieving sustained virologic response. The aim of this study is to assess the chance of achieving sustained virologic response (SVR) in patients who developed TD during treatment when compared with those who did not.</p> <p>Methods</p> <p>We performed a tertiary hospital-based retrospective nested case-control analysis of 19 patients treated for hepatitis C who developed thyroid disease, and 76 controls (matched for age, weight, gender, cirrhosis and aminotransferase levels) who did not develop TD during treatment. Multivariate logistic-regression models were used to compare cases and controls.</p> <p>Results</p> <p>The development of TD was associated with a high likelihood of achieving SVR (odds ratio, 6.0; 95% confidence interval, 1.5 to 24.6) for the pooled group containing all genotypes. The likelihood of achieving SVR was increased in individuals with genotype 1 HCV infection who developed TD (odds ratio, 5.2; 95% confidence interval, 1.2 to 22.3), and all genotype 3 patients who developed TD achieved SVR.</p> <p>Conclusions</p> <p>Development of TD during treatment for hepatitis C infection is associated with a significantly increased chance of achieving SVR. The pathophysiogical mechanisms for this observation remain to be determined.</p> <p>Trial Registration</p> <p><it>The Australian New Zealand Clinical Trials Registry (ANZCTR)</it>: <a href="http://www.anzctr.org.au/ACTRB12610000830099.aspx">ACTRB12610000830099</a></p

Gene expression signatures of morphologically normal breast tissue identify basal-like tumors

INTRODUCTION: The role of the cellular microenvironment in breast tumorigenesis has become an important research area. However, little is known about gene expression in histologically normal tissue adjacent to breast tumor, if this is influenced by the tumor, and how this compares with non-tumor-bearing breast tissue. METHODS: To address this, we have generated gene expression profiles of morphologically normal epithelial and stromal tissue, isolated using laser capture microdissection, from patients with breast cancer or undergoing breast reduction mammoplasty (n = 44). RESULTS: Based on this data, we determined that morphologically normal epithelium and stroma exhibited distinct expression profiles, but molecular signatures that distinguished breast reduction tissue from tumor-adjacent normal tissue were absent. Stroma isolated from morphologically normal ducts adjacent to tumor tissue contained two distinct expression profiles that correlated with stromal cellularity, and shared similarities with soft tissue tumors with favorable outcome. Adjacent normal epithelium and stroma from breast cancer patients showed no significant association between expression profiles and standard clinical characteristics, but did cluster ER/PR/HER2-negative breast cancers with basal-like subtype expression profiles with poor prognosis. CONCLUSION: Our data reveal that morphologically normal tissue adjacent to breast carcinomas has not undergone significant gene expression changes when compared to breast reduction tissue, and provide an important gene expression dataset for comparative studies of tumor expression profiles

Excellent capability in degrading azo dyes by MgZn-based metallic glass powders

The lack of new functional applications for metallic glasses hampers further development of these fascinating materials. In this letter, we report for the first time that the MgZn-based metallic glass powders have excellent functional ability in degrading azo dyes which are typical organic water pollutants. Their azo dye degradation efficiency is about 1000 times higher than that of commercial crystalline Fe powders, and 20 times higher than the Mg-Zn alloy crystalline counterparts. The high Zn content in the amorphous Mg-based alloy enables a greater corrosion resistance in water and higher reaction efficiency with azo dye compared to crystalline Mg. Even under complex environmental conditions, the MgZn-based metallic glass powders retain high reaction efficiency. Our work opens up a new opportunity for functional applications of metallic glasses