Airway inflammation accelerates pulmonary exacerbations in cystic fibrosis.

Airway inflammation underlies cystic fibrosis (CF) pulmonary exacerbations. In a prospective multicenter study of randomly selected, clinically stable adolescents and adults, we assessed relationships between 24 inflammation-associated molecules and the future occurrence of CF pulmonary exacerbation using proportional hazards models. We explored relationships for potential confounding or mediation by clinical factors and assessed sensitivities to treatments including CF transmembrane regulator (CFTR) protein synthesis modulators. Results from 114 participants, including seven on ivacaftor or lumacaftor-ivacaftor, representative of the US CF population during the study period, identified 10 biomarkers associated with future exacerbations mediated by percent predicted forced expiratory volume in 1 s. The findings were not sensitive to anti-inflammatory, antibiotic, and CFTR modulator treatments. The analyses suggest that combination treatments addressing RAGE-axis inflammation, protease-mediated injury, and oxidative stress might prevent pulmonary exacerbations. Our work may apply to other airway inflammatory diseases such as bronchiectasis and the acute respiratory distress syndrome.

Improved Diagnosis through Diastolic Hyperemia-Free Ratio (DFR) over Fractional Flow Reserve (FFR) in Intermediate Coronary Lesions.

Objectives: To compare the fractional flow reserve (FFR) and diastolic hyperemia-free ratio (DFR) measurements in a population with intermediate coronary artery stenosis and improve the diagnosis. Background: Visual assessment of coronary artery stenosis severity, particularly in intermediate lesions, is prone to errors in decision-making. FFR provides a reliable assessment of functional severity in these cases but requires hyperemia induction by adenosine, which has side effects and increased cost. DFR is a novel hyperemia-independent index, which could be used as an alternative to adenosine-based hyperemia induction. Methods and Results: Between September 2019 to March 2020, 25 patients with 38 intermediate coronary stenotic lesions were included in the study. All patients underwent assessment of whole cycle Pd/Pa (ratio of distal coronary pressure to proximal aortic pressure), DFR and FFR. Mean whole cycle Pd/Pa, DFR and FFR were 0.93±0.06, 0.88±0.09, and 0.85±0.08, respectively. A significant positive correlation between DFR and FFR [r = 0.74; p<0.001] was observed. Receiver operating characteristic analysis showed an area under the curve of 0.90. DFR-only strategy with a treatment cut-off of ≤0.89 showed a diagnostic agreement with the FFR-only strategy in 74% of lesions, with a sensitivity of 54%, specificity of 82%, a positive predictive value of 60%, and a negative predictive value of 79%. Conclusions: Real-time DFR measurements show a clinically reliable correlation with FFR. Hence, using DFR is likely to avoid adenosine administration as well as reduce the cost and procedural time. Further studies with a larger sample size would be ideal to evaluate specific cut-off values and endpoints.

The receptor for advanced glycation end products (RAGE) is involved in mitochondrial function and cigarette smoke-induced oxidative stress.

The mechanisms underlying muscle dysfunction with Chronic Obstructive Pulmonary Disease (COPD) are poorly understood. Indirect evidence has recently suggested a role of Advanced Glycation End Products (AGEs) and their receptor (RAGE) in the pathophysiology of COPD. Accordingly, this study aimed to examine the redox balance and mitochondrial alterations in the skeletal muscle of a mouse model deficient in the receptor for AGE (RAGE-KO) and wild-type C57BL/6 exposed to cigarette smoke for 8-months using immunoblotting, spectrophotometry, and high-resolution respirometry. Cigarette smoke exposure increased by two-fold 4-HNE levels (P < 0.001), a marker of oxidative stress, and markedly downregulated contractile proteins, mitochondrial respiratory complexes, and uncoupling proteins levels (P < 0.001). Functional alterations with cigarette smoke exposure included a greater reliance on complex-I supported respiration (P < 0.01) and lower relative respiratory capacity for fatty acid (P < 0.05). RAGE knockout resulted in 47% lower 4-HNE protein levels than the corresponding WT control mice exposed to cigarette smoke (P < 0.05), which was partly attributed to increased Complex III protein levels. Independent of cigarette smoke exposure, RAGE KO decreased mitochondrial specific maximal respiration (P < 0.05), resulting in a compensatory increase in mitochondrial content measured by citrate synthase activity (P < 0.001) such that muscle respiratory capacity remained unaltered. Together, these findings suggest that knockout of RAGE protected the skeletal muscle against oxidative damage induced by 8 months of cigarette smoke exposure. In addition, this study supports a role for RAGE in regulating mitochondrial content and function and can thus serve as a potential therapeutic target.

Impairing RAGE signaling promotes survival and limits disease pathogenesis following SARS-CoV-2 infection in mice.

Cellular and molecular mechanisms driving morbidity following SARS-CoV-2 infection have not been well defined. The receptor for advanced glycation end products (RAGE) is a central mediator of tissue injury and contributes to SARS-CoV-2 disease pathogenesis. In this study, we temporally delineated key cell and molecular events leading to lung injury in mice following SARS-CoV-2 infection and assessed efficacy of therapeutically targeting RAGE to improve survival. Early following infection, SARS-CoV-2 replicated to high titers within the lungs and evaded triggering inflammation and cell death. However, a significant necrotic cell death event in CD45- populations, corresponding with peak viral loads, was observed on day 2 after infection. Metabolic reprogramming and inflammation were initiated following this cell death event and corresponded with increased lung interstitial pneumonia, perivascular inflammation, and endothelial hyperplasia together with decreased oxygen saturation. Therapeutic treatment with the RAGE antagonist FPS-ZM1 improved survival in infected mice and limited inflammation and associated perivascular pathology. Together, these results provide critical characterization of disease pathogenesis in the mouse model and implicate a role for RAGE signaling as a therapeutic target to improve outcomes following SARS-CoV-2 infection.

Implication of RAGE Polymorphic Variants in COPD Complication and Anti-COPD Therapeutic Potential of sRAGE.

Chronic obstructive pulmonary disease (COPD) is a slowly progressive and poorly reversible airway obstruction disease. It is caused either alone or in combination of emphysema, chronic bronchitis (CB), and small airways disease. COPD is thought to be a multi-factorial disorder in which genetic susceptibility, environmental factors and tobacco exposure could be doubly or simultaneously implicated. Available medicines against COPD include anti-inflammatory drugs, such as ß2-agonists and anticholinergics, which efficiently reduce airflow limitation but are unable to avert disease progression and mortality. Advanced glycation end products (AGE) and their receptors i.e. receptor for advanced glycation end products (RAGE) are some molecules that have been implicated in the complication of COPD. Several RAGE single nucleotide polymorphic (SNP) variants are produced by the mammalian cells. Based on the ethnicity some SNPs aggravate the COPD severity. Mammalian cells produce several alternative RAGE splice variants including a soluble RAGE (sRAGE) and an endogenous soluble RAGE (esRAGE). Both of these act as decoy receptor and thus may help to arrest the COPD complications. Several lines of evidences indicate a decreased level of sRAGE in the COPD subjects. One of the new strategies to reduce COPD complication may be sRAGE therapeutic administration to the COPD subjects. This comprehensive discussion sheds light on the role of RAGE and its polymorphic variants in the COPD complication along with sRAGE therapeutic significance in the COPD prevention.

Skeletal muscle mitochondrial adaptations induced by long-term cigarette smoke exposure.

Because patients with chronic obstructive pulmonary disease (COPD) are often physically inactive, it is still unclear whether the lower respiratory capacity in the locomotor muscles of these patients is due to cigarette smoking per se or is secondary to physical deconditioning. Accordingly, the purpose of this study was to examine mitochondrial alterations in the quadriceps muscle of 10 mice exposed to 8 mo of cigarette smoke, a sedentary mouse model of emphysema, and 9 control mice, using immunoblotting, spectrophotometry, and high-resolution respirometry in permeabilized muscle fibers. Mice exposed to smoke displayed a twofold increase in the oxidative stress marker, 4-HNE, (P < 0.05) compared with control mice. This was accompanied by significant decrease in protein expression of UCP3 (65%), ANT (58%), and mitochondrial complexes II-V (∼60%-75%). In contrast, maximal ADP-stimulated respiration with complex I and II substrates (CON: 23.6 ± 6.6 and SMO: 19.2 ± 8.2 ρM·mg-1·s-1) or octanoylcarnitine (CON: 21.8 ± 9.0 and SMO: 16.5 ± 6.6 ρM·mg-1·s-1) measured in permeabilized muscle fibers, as well as citrate synthase activity, were not significantly different between groups. Collectively, our findings revealed that sedentary mice exposed to cigarette smoke for 8 mo, which is typically associated with pulmonary inflammation and emphysema, exhibited a preserved mitochondrial respiratory capacity for various substrates, including fatty acid, in the skeletal muscle. However, the mitochondrial adaptations induced by cigarette smoke favored the development of chronic oxidative stress, which can indirectly contribute to augment the susceptibility to muscle fatigue and exercise intolerance.NEW & NOTEWORTHY It is unclear whether the exercise intolerance and skeletal muscle mitochondrial dysfunction observed in patients with COPD is due to cigarette smoke exposure, per se, or if they are secondary consequences to inactivity. Herein, while long-term exposure to cigarette smoke induces oxidative stress and an altered skeletal muscle phenotype, cigarette smoke does not directly contribute to mitochondrial dysfunction. With this evidence, we demonstrate the critical role of physical inactivity in cigarette smoke-related skeletal muscle dysfunction.

Identification of Nrf2-responsive microRNA networks as putative mediators of myocardial reductive stress.

Although recent advances in the treatment of acute coronary heart disease have reduced mortality rates, few therapeutic strategies exist to mitigate the progressive loss of cardiac function that manifests as heart failure. Nuclear factor, erythroid 2 like 2 (Nfe2l2, Nrf2) is a transcriptional regulator that is known to confer transient myocardial cytoprotection following acute ischemic insult; however, its sustained activation paradoxically causes a reductive environment characterized by excessive antioxidant activity. We previously identified a subset of 16 microRNAs (miRNA) significantly diminished in Nrf2-ablated (Nrf2-/-) mouse hearts, leading to the hypothesis that increasing levels of Nrf2 activation augments miRNA induction and post-transcriptional dysregulation. Here, we report the identification of distinct miRNA signatures (i.e. "reductomiRs") associated with Nrf2 overexpression in a cardiac-specific and constitutively active Nrf2 transgenic (caNrf2-Tg) mice expressing low (TgL) and high (TgH) levels. We also found several Nrf2 dose-responsive miRNAs harboring proximal antioxidant response elements (AREs), implicating these "reductomiRs" as putative meditators of Nrf2-dependent post-transcriptional regulation. Analysis of mRNA-sequencing identified a complex network of miRNAs and effector mRNAs encoding known pathological hallmarks of cardiac stress-response. Altogether, these data support Nrf2 as a putative regulator of cardiac miRNA expression and provide novel candidates for future mechanistic investigation to understand the relationship between myocardial reductive stress and cardiac pathophysiology.

The emerging role of estrogen related receptorα in complications of non-small cell lung cancers.

Approximately 85% of lung cancer cases are recognized as non-small cell lung cancer (NSCLC) with a perilous (13-17%) 5-year survival in Europe and the USA. Although tobacco smoking has consistently emerged as the leading cause of NSCLC complications, its consequences are distinctly manifest with respect to sex bias, due to differential gene and sex hormone expression. Estrogen related receptor α (ERRα), a member of the nuclear orphan receptor superfamily is normally expressed in the lungs, and activates various nuclear genes without binding to the ligands, such as estrogens. In NSCLC ERRα expression is significantly higher compared with healthy individuals. It is well established ERα and ERß' have 93% and 60% identity in the DNA and ligand binding domains, respectively. ERα and ERRα have 69% (70% with ERRα-1) and 34% (35% with ERRα-1) identity, respectively; ERRα and ERRß' have 92 and 61% identity, respectively. However, whether there is distinctive ERRα interaction with mammalian estrogens or concurrent involvement in non-ER signalling pathway activation is not known. Relevant to NSCLC, ERRα promotes proliferation, invasion and migration by silencing the tumor suppressor proteins p53 and pRB, and accelerates G2-M transition during cell division. Epithelial to mesenchymal transition (EMT) and activation of Slug (an EMT associated transcription factor) are the prominent mechanisms by which ERRα activates NSCLC metastasis. Based on these observations, the present article focuses on the feasibility of antiERRα therapy alone and in combination with antiER as a therapeutic strategy for NSCLC complications.

Receptor for Advanced Glycation End Products (RAGE) and Its Polymorphic Variants as Predictive Diagnostic and Prognostic Markers of NSCLCs: a Perspective.

PURPOSE OF REVIEW: Non-small cell lung cancers (NSCLCs) account for ~ 85% of all lung cancers, and 5-year survival in Europe and the USA is ~ 13-17%. In this review, we focus on the significance of Receptor for Advanced Glycation End products (RAGE) as a diagnostic or post-therapeutic prognostic marker for various forms of NSCLCs. RECENT FINDINGS: The lungs have the highest levels of basal RAGE expression in mammals. The physiologic RAGE in lungs may be involved in adhesion and spreading of AT-1 cells and maintenance of pulmonary homeostasis. However, high level expression of RAGE complicates various diseases including acute lung injury. In NSCLCs, while a number of studies report decreased RAGE expression, inferring a protective role, others suggest that RAGE expression may contribute to NSCLC pathogenesis. Genetic polymorphisms of RAGE are reportedly associated with NSCLC development and complications. RAGE and its polymorphic variants may be useful diagnostic or post-therapeutic prognostic markers of NSCLCs.

Recent Advances in Curcumin Treated Non-Small Cell Lung Cancers: An Impetus of Pleiotropic Traits and Nanocarrier Aided Delive ry.

Characterized by the abysmal 18% five year survival chances, non-small cell lung cancers (NSCLCs) claim more than half of their sufferers within the first year of being diagnosed. Advances in biomedical engineering and molecular characterization have reduced the NSCLC diagnosis via timid screening of altered gene expressions and impaired cellular responses. While targeted chemotherapy remains a major option for NSCLCs complications, delayed diagnosis, and concurrent multi-drug resistance remain potent hurdles in regaining normalcy, ultimately resulting in relapse. Curcumin administration presents a benign resolve herein, via simultaneous interception of distinctly expressed pathological markers through its pleiotropic attributes and enhanced tumor cell internalization of chemotherapeutic drugs. Studies on NSCLC cell lines and related xenograft models have revealed a consistent decline in tumor progression owing to enhanced chemotherapeutics cellular internalization via co-delivery with curcumin. This presents an optimum readiness for screening the corresponding effectiveness in clinical subjects. Curcumin is delivered to NSCLC cells either (i) alone, (ii) in stoichiometrically optimal combination with chemotherapeutic drugs, (iii) through nanocarriers, and (iv) nanocarrier co-delivered curcumin and chemotherapeutic drugs. Nanocarriers protect the encapsulated drug from accidental and non-specific spillage. A unanimous trait of all nanocarriers is their moderate drug-interactions, whereby native structural expressions are not tampered. With such insights, this article focuses on the implicit NSCLC curative mechanisms viz-a-viz, free curcumin, nanocarrier delivered curcumin, curcumin + chemotherapeutic drug and nanocarrier assisted curcumin + chemotherapeutic drug delivery.

Ravaging SARS-CoV-2: rudimentary diagnosis and puzzling immunological responses.

INTRODUCTION: In December 2019, the first COVID-19 case, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was reported in Wuhan, China. The SARS-CoV-2 rapidly disseminated throughout the world via community spread, acquiring pandemic status with significant fatality. OBSERVATIONS: Rapid SARS-CoV-2 diagnosis was soon perceived critical for arresting community spread and effective therapy development. Human SARS-CoV-2 infection can be diagnosed either by nucleic acid identification or specific antibody detection. Contrary to nucleic acid identification confirmed active SARS-CoV-2 infection; antibody detection confirms a past infection, even in asymptomatic subjects. SARS-CoV-2 specific antibodies augment the ability to effectively counter the virus. A crucial hurdle limiting the steadfast implementation of antibody detection is the time required for threshold B lymphocyte population generation. This process is dependent on precise antigen recognition and MHC class I molecules presentation. CONCLUSIONS: Thus, nucleic acid and antibody dependent tests complement each other in identifying human SARS-CoV-2 infection and shaping up subsequent immunological responses. This article discusses the complimentary association of nucleic acid identification (corresponding to an active infection) and antibody testing (the yester CoV-2 infection vulnerability) as the diagnostic and screening measures of SARS-CoV-2 infection. Highlights Nucleic acid (RNA) identification and specific antibody detection against SARS-CoV-2 are the noted diagnostic mechanisms for screening human SARS-CoV-2 infection. While nucleic acid identification screens prevailing SARS-CoV-2 infection, detection of SARS-CoV-2 specific antibodies signifies a past infection, even in asymptomatic subjects. Antibodies against SARS-CoV-2 provide a potential therapeutic option via transfer from antibody rich plasma of a recovered subject to an infected individual. Nucleic acid identification may not absolutely confirm the infection because of frequent SARS-CoV-2 genome mutations and possible technical errors, while specific antibody detection also needs at least (8-14) days for detectable screening of B-cell generated antibodies. Nucleic acid and antibody tests are complementary to each other as an early stage diagnostic assay for SARS-CoV-2 infection and possible therapy (antibodies). Sufferers with a high clinical suspicion but negative RT-PCR screening could be examined via combined imaging and repeated swab test.

NRF2 loss recapitulates heritable impacts of paternal cigarette smoke exposure.

Paternal cigarette smoke (CS) exposure is associated with increased risk of behavioral disorders and cancer in offspring, but the mechanism has not been identified. Here we use mouse models to investigate mechanisms and impacts of paternal CS exposure. We demonstrate that CS exposure induces sperm DNAme changes that are partially corrected within 28 days of removal from CS exposure. Additionally, paternal smoking is associated with changes in prefrontal cortex DNAme and gene expression patterns in offspring. Remarkably, the epigenetic and transcriptional effects of CS exposure that we observed in wild type mice are partially recapitulated in Nrf2-/- mice and their offspring, independent of smoking status. Nrf2 is a central regulator of antioxidant gene transcription, and mice lacking Nrf2 consequently display elevated oxidative stress, suggesting that oxidative stress may underlie CS-induced heritable epigenetic changes. Importantly, paternal sperm DNAme changes do not overlap with DNAme changes measured in offspring prefrontal cortex, indicating that the observed DNAme changes in sperm are not directly inherited. Additionally, the changes in sperm DNAme associated with CS exposure were not observed in sperm of unexposed offspring, suggesting the effects are likely not maintained across multiple generations.

Reductive stress impairs myogenic differentiation.

Myo-satellite cells regenerate and differentiate into skeletal muscle (SM) after acute or chronic injury. Changes in the redox milieu towards the oxidative arm at the wound site are known to compromise SM regeneration. Recently, we reported that abrogation of Nrf2/antioxidant signaling promotes oxidative stress and impairs SM regeneration in C57/Bl6 mice. Here, we investigated whether the activation of intracellular Nrf2 signaling favors antioxidant transcription and promotes myoblast differentiation. Satellite cell-like C2C12 myoblasts were treated with sulforaphane (SF; 1.0 & 5.0 µM) to activate Nrf2/antioxidant signaling during proliferation and differentiation (i.e. formation of myotubes/myofibers). SF-mediated Nrf2 activation resulted in increased expression of Nrf2-antioxidants (e.g. GCLC and G6PD) and augmented the production of reduced glutathione (GSH) leading to a reductive redox state. Surprisingly, this resulted in significant inhibition of myoblast differentiation, as observed from morphological changes and reduced expression of MyoD, Pax7, and Myh2, due to reductive stress (RS). Furthermore, supplementation of N-acetyl-cysteine (NAC) or GSH-ester or genetic knock-down of Keap1 (using siRNA) also resulted in RS-driven inhibition of differentiation. Interestingly, withdrawing Nrf2 activation rescued differentiation potential and formation of myotubes/myofibers from C2C12 myoblasts. Thus, abrogation of physiological ROS signaling through over-activation of Nrf2 (i.e. RS) and developing RS hampers differentiation of muscle satellite cells.

Reductive Stress Causes Pathological Cardiac Remodeling and Diastolic Dysfunction.

Aims: Redox homeostasis is tightly controlled and regulates key cellular signaling pathways. The cell's antioxidant response provides a natural defense against oxidative stress, but excessive antioxidant generation leads to reductive stress (RS). This study elucidated how chronic RS, caused by constitutive activation of nuclear erythroid related factor-2 (caNrf2)-dependent antioxidant system, drives pathological myocardial remodeling. Results: Upregulation of antioxidant transcripts and proteins in caNrf2-TG hearts (TGL and TGH; transgenic-low and -high) dose dependently increased glutathione (GSH) redox potential and resulted in RS, which over time caused pathological cardiac remodeling identified as hypertrophic cardiomyopathy (HCM) with abnormally increased ejection fraction and diastolic dysfunction in TGH mice at 6 months of age. While the TGH mice exhibited 60% mortality at 18 months of age, the rate of survival in TGL was comparable with nontransgenic (NTG) littermates. Moreover, TGH mice had severe cardiac remodeling at ∼6 months of age, while TGL mice did not develop comparable phenotypes until 15 months, suggesting that even moderate RS may lead to irreversible damages of the heart over time. Pharmacologically blocking GSH biosynthesis using BSO (l-buthionine-SR-sulfoximine) at an early age (∼1.5 months) prevented RS and rescued the TGH mice from pathological cardiac remodeling. Here we demonstrate that chronic RS causes pathological cardiomyopathy with diastolic dysfunction in mice due to sustained activation of antioxidant signaling. Innovation and Conclusion: Our findings demonstrate that chronic RS is intolerable and adequate to induce heart failure (HF). Antioxidant-based therapeutic approaches for human HF should consider a thorough evaluation of redox state before the treatment.

Prospective multicenter randomized patient recruitment and sample collection to enable future measurements of sputum biomarkers of inflammation in an observational study of cystic fibrosis.

BACKGROUND: Biomarkers of inflammation predictive of cystic fibrosis (CF) disease outcomes would increase the power of clinical trials and contribute to better personalization of clinical assessments. A representative patient cohort would improve searching for believable, generalizable, reproducible and accurate biomarkers. METHODS: We recruited patients from Mountain West CF Consortium (MWCFC) care centers for prospective observational study of sputum biomarkers of inflammation. After informed consent, centers enrolled randomly selected patients with CF who were clinically stable sputum producers, 12 years of age and older, without previous organ transplantation. RESULTS: From December 8, 2014 through January 16, 2016, we enrolled 114 patients (53 male) with CF with continuing data collection. Baseline characteristics included mean age 27 years (SD = 12), 80% predicted forced expiratory volume in 1 s (SD = 23%), 1.0 prior year pulmonary exacerbations (SD = 1.2), home elevation 328 m (SD = 112) above sea level. Compared with other patients in the US CF Foundation Patient Registry (CFFPR) in 2014, MWCFC patients had similar distribution of sex, age, lung function, weight and rates of exacerbations, diabetes, pancreatic insufficiency, CF-related arthropathy and airway infections including methicillin-sensitive or -resistant Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia complex, fungal and non-tuberculous Mycobacteria infections. They received CF-specific treatments at similar frequencies. CONCLUSIONS: Randomly-selected, sputum-producing patients within the MWCFC represent sputum-producing patients in the CFFPR. They have similar characteristics, lung function and frequencies of pulmonary exacerbations, microbial infections and use of CF-specific treatments. These findings will plausibly make future interpretations of quantitative measurements of inflammatory biomarkers generalizable to sputum-producing patients in the CFFPR.

RAGE is a Critical Mediator of Pulmonary Oxidative Stress, Alveolar Macrophage Activation and Emphysema in Response to Cigarette Smoke.

The receptor for advanced glycation end products (RAGE), a cell membrane receptor, recognizes ligands produced by cigarette smoke (CS) and has been implicated in the pathogenesis of COPD. We demonstrate that deletion or pharmacologic inhibition of RAGE prevents development of CS-induced emphysema. To identify molecular pathways by which RAGE mediates smoking related lung injury we performed unbiased gene expression profiling of alveolar macrophages (AM) obtained from RAGE null and C57BL/6 WT mice exposed to CS for one week or four months. Pathway analysis of RNA expression identified a number of genes integral to the pathogenesis of COPD impacted by the absence of RAGE. Altered expression of antioxidant response genes and lung protein 4-HNE immunostaining suggest attenuated oxidative stress in the RAGE null mice despite comparable CS exposure and lung leukocyte burden as the WT mice. Reduced endoplasmic reticulum stress in response to CS exposure also was observed in the AM from RAGE null mice. These findings provide novel insight into the sources of oxidative stress, macrophage activation, and the pathogenesis of lung disease due to CS exposure.

Single intervention for a reduction in portable chest radiography (pCXR) in cardiovascular and surgical/trauma ICUs and associated outcomes.

PURPOSE: Studies suggest that "on-demand" radiography is equivalent to daily routine with regard to adverse events. In these studies, provider behavior is controlled. Pragmatic implementation has not been studied. MATERIALS AND METHODS: This was a quasi-experimental, pre-post intervention study. Medical directors of two intervention ICUs requested pCXRs be ordered on an on-demand basis at one time point, without controlling or monitoring behavior or providing follow-up. RESULTS: A total of 11,994 patient days over 18months were included. Combined characteristics: Age: 56.7, 66% male, 96% survival, APACHE II 14 (IQR: 11-19), mechanical ventilation (MV) (occurrences)/patient admission: mean 0.7 (SD: 0.6; range: 0-5), duration (hours) of MV: 21.7 (IQR: 9.8-81.4) and ICU LOS (days): 2.8 (IQR: 1.8-5.6). Average pCXR rate/patient/day before was 0.93 (95% CI: 0.89-0.96), and 0.73 (95% CI: 0.69-0.77) after. Controlling for severity, daily pCXR rate decreased by 21.7% (p<0.001), then increased by about 3%/month (p=0.044). There was no change in APACHE II, mortality, and occurrences or duration of MV, unplanned re-intubations, ICU LOS. CONCLUSIONS: In critically ill adults, pCXR reduction can be achieved in cardiothoracic and trauma/surgical patients with a pragmatic intervention, without adversely affecting patient care, outside a controlled study.

Impact of Laboratory Charge Display Within the Electronic Health Record Across an Entire Academic Medical Center: Results of a Randomized Controlled Trial.

OBJECTIVES: To determine the impact of systemwide charge display on laboratory utilization. METHODS: This was a randomized controlled trial with a baseline period and an intervention period. Tests were randomized to a control arm or an active arm. The maximum allowable Medicare reimbursement rate was displayed for tests in the active arm during the intervention period. Total volume of tests in the active arm was compared with those in the control arm. Residents were surveyed before and after the intervention to assess charge awareness. RESULTS: Charge display had no effect on order behavior. This result held for patient type (inpatient vs outpatient) and for insurance category (commercial, government, self-pay). Residents overestimated the charges of tests both before and after the intervention. Many residents failed to notice the charge display in the computerized order entry system. CONCLUSIONS: The impact of charge display depends on context. Charge display is not always effective.

Chronic Endurance Exercise Impairs Cardiac Structure and Function in Middle-Aged Mice with Impaired Nrf2 Signaling.

Nuclear factor erythroid 2 related factor 2 (Nrf2) signaling maintains the redox homeostasis and its activation is shown to suppress cardiac maladaptation. Earlier we reported that acute endurance exercise (2 days) evoked antioxidant cytoprotection in young WT animals but not in aged WT animals. However, the effect of repeated endurance exercise during biologic aging (WT) characterized by an inherent deterioration in Nrf2 signaling and pathological aging (pronounced oxidative susceptibility-Nrf2 absence) in the myocardium remains elusive. Thus, the purpose of our study was to determine the effect of chronic endurance exercise-induced cardiac adaptation in aged mice with and without Nrf2. Age-matched WT and Nrf2-null mice (Nrf2-/-) (>22 months) were subjected to 6 weeks chronic endurance exercise (25 meter/min, 12% grade). The myocardial redox status was assessed by expression of antioxidant defense genes and proteins along with immunochemical detection of DMPO-radical adduct, GSH-NEM, and total ubiquitination. Cardiac functions were assessed by echocardiography and electrocardiogram. At sedentary state, loss of Nrf2 resulted in significant downregulation of antioxidant gene expression (Nqo1, Ho1, Gclm, Cat, and Gst-α) with decreased GSH-NEM immuno-fluorescence signals. While Nrf2-/- mice subjected to CEE showed an either similar or more pronounced reduction in the transcript levels of Gclc, Nqo1, Gsr, and Gst-α in relation to WT littermates. In addition, the hearts of Nrf2-/- on CEE showed a substantial reduction in specific antioxidant proteins, G6PD and CAT along with decreased GSH, a pronounced increase in DMPO-adduct and the total ubiquitination levels. Further, CEE resulted in a significant upregulation of hypertrophy genes (Anf, Bnf, and ß-Mhc) (p < 0.05) in the Nrf2-/- hearts in relation to WT mice. Moreover, the aged Nrf2-/- mice exhibited a higher degree of cardiac remodeling in association with a significant decrease in fractional shortening, pronounced ST segment, and J wave elevation upon CEE compared to age-matched WT littermates. In conclusion, our findings indicate that while the aged WT and Nrf2 knockout animals both exhibit hypertrophy after CEE, the older Nrf2 knockouts showed ventricular remodeling coupled with profound cardiac functional abnormalities and diastolic dysfunction.