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The coexistence of expiratory central airway collapse and diaphragmatic paralysis presents a diagnostic and treatment challenge. Both entities are underrecognized causes of dyspnea, cough, sputum production, and orthopnea. Optimal treatment must be individualized and is best achieved by a multidisciplinary team. We present a case of a patient with profound functional impairment from dyspnea and hypoxemia due to expiratory central airway collapse, complicated by bronchiectasis from recurrent respiratory infections, and diaphragmatic paralysis.

BACKGROUND Endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) is a safe and minimally invasive procedure for evaluating hilar and mediastinal lymph nodes. The reported sensitivity and specificity of EBUS-TBNA are 95% and 97%, respectively. A comparison of diagnostic sensitivity for lymph nodes suspected of lung cancer according to needle size in EBUS-TBNA is needed. OBJECTIVES To compare the diagnostic sensitivity of the 19-G, 21-G, 22-G and 25-G needles for lymph nodes suspected of non-small cell lung cancer (NSCLC) using EBUS-TBNA. METHODS A literature search from PubMed, EMBASE, LILACS, DOAJ and CENTRAL through October 2020 was performed by two reviewers. The extracted data were evaluated using STATA® and Open Meta Analyst software for meta-analysis with a binary method model to compare sensitivity, specificity and summary receiver operating characteristic curve for each needle size. RESULTS Fourteen studies including 1296 participants were considered for the analysis. The overall sensitivity of EBUS-TBNA was 88.2% (95% CI 84%, 91%) and 93% (95% CI 88%, 95%) for the 19-G needle, 87.6% (95% CI 79.6%, 92.8%) for the 21-G needle and 85% (95% CI 80%, 88%) for the 22-G needle. The overall sensitivity of EBUS-TBNA for diagnosing NSCLC was 88.3% (95% CI, 81%, 93%) and 92.9% (95% CI, 85%, 97%) for the 19-G needle, 89.4% (95% CI 79.4%, 94.8%) for the 21-G needle and 82.1% (95% CI 66%, 91%) for the 22-G needle. CONCLUSION The 19-G, 21-G and 22-G needles present a similarly high diagnostic sensitivity in EBUS-TBNA. The 19-G needle provided better sample adequacy for molecular and immunohistochemical testing, improving diagnostic yield in this subgroup.

Common respiratory symptoms, including dyspnea, cough, sputum production, and recurrent infections, frequently remain without a clear cause and may be the result of expiratory central airway collapse (ECAC). Establishing the diagnosis and appropriate treatment plan for patients with ECAC is challenging and benefits from a multidisciplinary approach. A coordinator role is crucial in this process to ensure optimal patient-centered outcomes. We describe the coordination of care in the process of diagnosing and treating ECAC. The coordinator leads the organization of the multiple services involved in the care of patients with ECAC, including pulmonary medicine, interventional pulmonology, radiology, and thoracic surgery, as well as hospital inpatient staff. From initial screening to evaluation and management with airway stents and corrective treatment with tracheobronchoplasty, the ECAC coordinator oversees the entire process of care for patients with ECAC.

BACKGROUND A transbronchial forceps lung biopsy performed in mechanically ventilated patients with respiratory failure of unknown etiology has significant uncertainty of diagnostic yield and safety along with sparse literature. This study investigated the complication rate of transbronchial biopsies in mechanically ventilated patients in the intensive care unit and its ability to obtain a diagnosis and change current therapy. METHODS PubMed, Ovid MEDLINE, and Ovid Cochrane Central Register of Controlled Trials databases were systematically searched for all publications of transbronchial lung biopsies in mechanically ventilated patients. We pooled the results of individual studies using random-effects meta-analysis models to achieve the summary proportions. RESULTS Of the identified 9 observational studies with a total of 232 patients undergoing a transbronchial biopsy, complications occurred in 67 patients [25.2%; 95% confidence interval (CI), 11.5%-42.0%; I2=70.0%]. Pneumothorax occurred in 24 patients (9.5%; 95% CI, 4.5%-16.2%; I2=15.9%) and bleeding in 18 patients (8.9%; 95% CI, 4.1%-15.3%; I2=0%). A diagnosis was given in 146 patients (62.9%; 95% CI, 56.0%-69.1%; I2=74.6%), with 103 of 210 patients (49.0%; 95% CI, 44.6%-55.1%; I2=74.9%) having a change in treatment. CONCLUSION The results of this meta-analysis suggest that a transbronchial forceps biopsy when performed in mechanically ventilated patients with respiratory failure of unclear etiology had a moderate complication rate. These biopsies resulted in varied diagnoses with a high rate of management change. Randomized controlled trials are necessary to identify the ideal patients to perform a transbronchial forceps biopsy on in the intensive care unit.

RATIONALE The use of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is currently recommended for staging non-small cell lung cancer (NSCLC) in centrally located tumors, tumors >3 cm, or with radiologic evidence of lymph node (LN) metastasis. Current guidelines do not recommend staging EBUS-TBNA in patients with stage I NSCLC who do not have any of the aforementioned conditions. OBJECTIVE We hypothesize that using EBUS-TBNA is useful for detecting occult metastasis in radiologic stage I NSCLC. METHODS In this single-center, retrospective study, charts of patients ≥18 years old who underwent staging EBUS-TBNA from January 2005 to May 2019 were reviewed. Only patients with combined positron-emission tomography and computed tomography (PET/CT) scans consistent with radiologic stage I NSCLC were included. Identified variables included: age, gender, personal history of any cancer, smoking history, tumor location, tumor centrality, tumor size, tumor PET activity, histopathologic type of NSCLC, and LN biopsy results. Patients whose LN samples showed a diagnosis other than NSCLC were excluded. The association between LN positivity, and each of the variables was assessed using Pearson's correlation for categorical variables, and logistic regression analysis for continuous variables. RESULTS From the 2,892 initially screened patients, 188 were included. Of those, 13 (6.9%; 95% CI, 4%-11%) had a malignancy-positive LN biopsy. The number needed to test (NNT) in order to detect one case of any occult metastasis was 15. Among the included variables, a significant association was found between LN positivity and tumor centrality, with central tumors found in 61.5% of patients with positive LN (n = 8) (p

Robotic assisted bronchoscopy represents a major turning point in bronchoscopic history. The management strategies to address significant airway bleeding in this “robotic era” are not well documented, and further guidance is required. We present a case report that exemplifies our approach and management strategy using a combined and simultaneous flexible/robotic bronchoscopy if this complication is encountered.

Currently, computed tomography-guided transthoracic biopsy (CTTB) is the most accurate diagnostic approach for pulmonary nodules suspected of malignancy. Traditional bronchoscopy has shown suboptimal diagnostic sensitivity, but the emergence of robotic-assisted bronchoscopy (RAB) has the potential to improve diagnostic accuracy, maximize diagnostic yield and complete mediastinal and hilar staging in a single procedure. We aim to assess the efficacy and diagnostic performance of RAB compared to CTTB for diagnosing pulmonary nodules suspected of lung cancer.A multicenter retrospective review of consecutive patients who underwent RAB and CTTB for evaluating pulmonary nodules from January 2019 to March 2021 at Mayo Clinic Florida and Mayo Clinic Rochester, United States. Clinical and demographic information, nodule characteristics, outcomes and complications were compared between RAB and CTTB.A total of 225 patients were included: 113 in the RAB group and 112 in the CTTB group. Overall diagnostic yield was 87.6% for RAB and 88.4% for CTTB. For malignant disease, RAB had a sensitivity of 82.1% and a specificity of 100%, CTTB had a sensitivity of 88.5% and a specificity of 100%. Complication rate was significantly higher for CTTB compared to RAB (17% vs. 4.4%; p = 0.002).RAB, when available, can be as accurate as CTTB for sampling pulmonary nodules with similar or reduced complications and should be considered as a means for nodule biopsy, particularly when mediastinal staging is also clinically warranted.

Introduction: Carbon dioxide (CO2) insufflation for endoscopies has been shown to be more comfortable and safe, but only in patients without underlying chronic obstructive pulmonary disease (COPD). The aim of this study was to show that using CO2 is safe in COPD patients. Methods: Patients were retrospectively identified who underwent extended endoscopic procedures during the time period of January 2012 to December 2017. Patients were included if they also had COPD. A matched control group without COPD was created during the same timeframe. All the patients were sedated with continuous monitoring of their CO2 levels by end-tidal CO2 (EtCO2). Results: One hundred and ten patients had COPD and underwent an extended endoscopic procedure. These patients had a higher severity of their comorbidities (American Society of Anesthesiologists class 3 or 4) (93.6% [95% confidence interval [CI], 87.4%–96.9%] vs. 60.3% [95% CI, 51.1%–69.0%]; P < 0.01) and an increase of co-existing obstructive sleep apnea (33.6% vs. 6.3%, P < 0.01). There was no difference in baseline EtCO2, but the peak EtCO2 and postprocedure EtCO2 were both significantly higher in the COPD group. The only postprocedural complication found was an inability to be extubated immediately following the procedure with subsequent need to hospitalize the patient, which occurred in three patients (2.8%; 95% CI, 0.9%–7.9%) in the COPD group and one (0.9%; 95% CI, 0.2%–4.9%) in the non-COPD group (P = 0.37). Conclusion: The present study, which was the only study looking at CO2 insufflation specifically in COPD patients, provides evidence that CO2 insufflation is safe in COPD despite a slight increase in EtCO2.

Background: Spiration Valve System (SVS) is an alternative for patients with severe heterogeneous emphysema; however, data about efficacy from randomized controlled trials (RCT) are unclear. Objectives: To explore both efficacy and safety of SVS in patients with severe emphysema and hyperinflation. Methods: We included PubMed, EMBASE, Coch­rane database. All searches were performed until August 2019. Only RCTs were included for analysis. Risk of bias was assessed using Cochrane risk of bias tool. A meta-analysis evaluated change in forced expiratory volume in 1 s (FEV1), 6-min walking test (6MWT), residual volume, modified medical research council (mMRC) and Saint George respiratory questionnaire (SGRQ), all-cause mortality, risk of pneumothorax, and risk of acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Quality of the evidence was rated using GRADE approach. Results: Four RCTs including 629 subjects were included. SVS showed an overall change of 0.03 L (–0.07 to 0.13, I2 = 90%) in the in FEV1 (L) and a 2.03% (–2.50 to 6.57, I2 = 96%) in the predicted FEV1 (%) compared to baseline; however, studies without collateral ventilation (CV) showed an improvement of 0.12 L (95% CI 0.09–0.015, I2 = 0%), This subgroup also reported better results in SGRQ –12.27 points (95% CI –15.84 to –8.70, I2 = 0%) and mMRC –0.54 (95% CI –0.74 to –0.33, I2 = 0%). We found no benefit in 6MWT mean difference = 4.56 m (95% CI –21.88 to 31.00, I2 = 73%). Relative risk of mortality was 2.54 (95% CI 0.81–7.96, I2 = 0%), for pneumothorax 3.3 (95% CI 0.61–18.12, I2 = 0%) and AECOPD 1.68 (95% CI 1.04–2.70, I2 = 0%). Conclusion: In patients with severe heterogeneous emphysema and hyperinflation without CV, SVS is an alternative that showed an improvement in pulmonary function, quality of life, and dyspnea score with an acceptable risk profile.

Introduction Bronchoscopic lung volume reduction (BLVR) with endobronchial valves (EBVs) has emerged as an important treatment method for patients with severe chronic obstructive pulmonary disease (COPD). Acute exacerbations of COPD (AECOPD) are a frequent complication following BLVR with EBV. However, there is no consensus on the prevention of AECOPD. Objectives Our study aims to compare the outcomes of different prophylactic measures on the occurrence of AECOPD after BLVR with EBV. Methods We conducted a multicenter, retrospective study of patients who underwent BLVR with EBV at six different institutions. Emphasis was directed towards the specific practices aimed at preventing AECOPD: antibiotics, steroids, antibiotics plus steroids, or no prophylaxis. Subgroups were compared, and odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated. Results A total of 170 patients were reviewed. The rate of AECOPD was 21.2% for the full cohort. Patients who received prophylaxis had a significantly lower rate of AECOPD compared with those who did not (16.7% vs. 46.2%; p = 0.001). The rate was lowest in patients who received antibiotics alone (9.2%). There was no significant difference in the rate of AECOPD between patients who received steroids alone or antibiotics plus steroids, compared with the other subgroups. The OR for AECOPD was 4.3 (95% CI: 1.8-10.4; p = 0.001) for patients not receiving prophylaxis and 3.9 (95% CI: 1.5-10.1; p = 0.004) for prophylaxis other than antibiotics alone. Conclusions Administration of antibiotics after BLVR with EBV was associated with a lower rate of AECOPD. This was not observed with the use of steroids or in combination with antibiotics.

Objectives Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are the most commonly prescribed antihypertensives, with prior studies identifying a possible association between long-term use and increased rates of lung cancer. This study evaluated this potential association in a large population using propensity matching. Methods This was a population-based cohort study in a large healthcare system in three regions of the United States. Pairwise propensity score matching was performed using demographics and comorbidities. All of the adult patients in the healthcare system from January 1, 2000 to April 30, 2018 with at least 1 year of follow-up were included. Results In total, 3,253,811 patients with a median age of 59 (range 18-103) years were included. The ACEI group had a higher freedom from lung cancer versus controls at 15 years (98.47%, 95% confidence interval [CI] 98.41-98.54) versus 98.26%, (95% CI 98.20-98.33), whereas ARBs had similar rates versus controls at all time points. For patients diagnosed as having lung cancer, median all-cause survival was significantly higher in the ACEI (34.7 months, 95% CI 32.8-36.6) and ARB (30.9 months, 95% CI 28.1-33.8) groups than the control group (20.6 months, 95% CI 20.1-21.1). Conclusions This study showed lower rates of lung cancer with ACEI use and no difference in risk with ARBs. In addition, use of these medications was found to be associated with increased survival in those diagnosed as having lung cancer. This study supports the continued use of these medications without concern for increasing the risk of lung cancer.

Background Patients with chronic obstructive pulmonary disease (COPD) commonly have comorbidities which may impact both symptoms and prognosis. Endoscopic lung volume reduction (ELVR) with endobronchial valves (EBV) is an innovative, effective and safe treatment for patients with severe emphysema who remain symptomatic despite optimal medical therapy. Objectives To evaluate medical comorbidities associated with increased risk of complications after EBV procedure. Method This was a retrospective cohort review of patients with severe, heterogeneous emphysema who underwent Zephyr® EBV installation for ELVR. Demographics, baseline comorbidities, dyspnea scores, data regarding procedure, pulmonary function test, minimal clinically important difference and post-EBV complications were recorded. Results Of a total 82 participants, 24 were identified as having a post procedure complication. There was a significant difference in the incidence of type 2 diabetes mellitus (T2DM) at baseline (25%) in complication group compared with non-complication group (5.1%) (p value = 0.01). There was also a significant difference between baseline coronary artery disease (CAD) in those with (58.3%) or without (29.3%) complication (p = 0.01). Multivariate analysis of other covariables, identified associations of both CAD and T2DM with a heightened risk of complication (adjusted OR 4.19 CI: 1.23-14.2, p value = 0.02 and adjusted OR of 6.1 CI: 1.3-26.1, p value = 0.02 respectively). Conclusions Our study found that patients with severe, heterogeneous emphysema who undergo ELVR utilizing Zephyr® EBV and suffer complications during post-procedure period are more likely to have CAD or T2DM as baseline comorbidity. These data suggest that baseline CAD and T2DM might be predictive of increased risk of complications following ELVR with EBV.

Bronchoscopy in thrombocytopenic patients remains a controversial topic as traditionally varying platelet thresholds have been stablished as “safe,” ranging from 20,000 to 50,000. A lower threshold may be safe for a routine airway inspection with bronchoalveolar lavage but will be far from safe for more invasive interventions such as needle biopsy, transbronchial biopsy, or cryo‐biopsy. Currently, a minimal platelet threshold during robotic‐assisted bronchoscopy (RAB) has not been established. In addition, the absolute platelet number does not guarantee appropriate platelet function. The literature regarding the safety of bronchoscopy and its bleeding risk, considering broader and more functional tests such as thromboelastography (TEG), is also lacking. We present our RAB approach to safely sample lung nodules in a patient with thrombocytopenia. Our precautionary strategy for high‐risk bleeding cases during RAB utilizing TEG and parallel flexible bronchoscopy with segmental balloon occlusion may be an appropriate technique to minimize bleeding risk., We present a precautionary strategy for high‐risk bleeding cases during robotic‐assisted bronchoscopy (RAB) utilizing thromboelastography and parallel flexible bronchoscopy with segmental balloon occlusion may be an appropriate technique to minimize bleeding risk.

Patients hospitalized for pneumonia are at high risk for mortality. Effective therapies are therefore needed. Recent randomized clinical trials suggest that systemic steroids can reduce the length of hospital stays among patients hospitalized for pneumonia. Furthermore, preliminary findings from a feasibility study demonstrated that early treatment with a combination of an inhaled corticosteroid and a bronchodilator can improve oxygenation and reduce risk of respiratory failure in patients at risk of acute respiratory distress syndrome. Whether such a combination administered early is effective in reducing acute respiratory failure (ARF) among patients hospitalized with pneumonia is unknown. Here we describe the ARREST Pneumonia (Arrest Respiratory Failure due to Pneumonia) trial designed to address this question. ARREST Pneumonia is a two-arm, randomized, double-blinded, placebo-controlled trial designed to test the efficacy of a combination of an inhaled corticosteroid and a β-agonist compared with placebo for the prevention of ARF in hospitalized participants with severe pneumonia. The primary outcome is ARF within 7 days of randomization, defined as a composite endpoint of intubation and mechanical ventilation; need for high-flow nasal cannula oxygen therapy or noninvasive ventilation for >36 hours (each alone or combined); or death within 36 hours of being placed on respiratory support. The planned enrollment is 600 adult participants at 10 academic medical centers. In addition, we will measure selected plasma biomarkers to better understand mechanisms of action. The trial is funded by the U.S. National Heart Lung and Blood Institute. Clinical trial registered with www.clinicaltrials.gov (NCT 04193878).

BACKGROUND: The clinical benefits of cardiopulmonary rehabilitation are extensive, including improvements in health-related quality of life, emotional condition, physical function, and overall mortality. The COVID-19 pandemic continues to have a negative impact on center-based cardiopulmonary rehabilitation. Justifiable concern exists that the exercise-related increase in pulmonary ventilation within the rehabilitation classes may lead to the generation of infectious respiratory particles. RESEARCH QUESTION: Is cardiopulmonary rehabilitation while wearing a procedural mask a particle-generating procedure? STUDY DESIGN AND METHODS: Data were collected prospectively at a cardiopulmonary rehabilitation facility with all patients wearing a procedural mask. Small (0.3-4.9 µm) and large (5-10 µm) particle generation was quantified using a light-scattering particle counter. Data were analyzed by time, exertion level, and number of participants. RESULTS: A total of 24 distinct patients attended two or more of the cardiopulmonary rehabilitation classes tested. Most of the patients were men (n = 16 [67%]) and were in rehabilitation because of cardiac disease. During the cardiopulmonary rehabilitation class, small and large micrometer-size particles increased with increasing class size. In classes with four patients or more, a significant increase was found from ambient levels in both small (four patients, P < .01; and five patients, P < .01) and large (four patients, P < .01; and five patients, P < .01) particle count that peaked at about 35 to 40 min during each class. INTERPRETATION: Using an airborne particle counter, we found significant exercise-related increases in both small and large micrometer-size particle generation during cardiopulmonary rehabilitation classes, with larger class sizes (ie, more patients), despite participants wearing a procedural mask.

COPD may cause profound dyspnea, functional impairment, and reduced quality of life. Available pharmacologic therapy provides suboptimal symptom improvement in many patients. Bronchoscopic lung volume reduction (BLVR), achieved with endobronchial valve placement, can effectively improve dyspnea and functional status in appropriately selected patients. Operationalizing a safe and effective BLVR program requires appropriate oversight, which can be achieved by a BLVR nurse coordinator (NC). By identifying and developing screening practices, coordinating multidisciplinary diagnostic evaluation, and establishing safe efficient patient flow throughout the entire care process, a BLVR NC can optimize patient care, safety, experience, efficiency, and overall outcomes. This article details the role of our NC to facilitate extrapolation to other institutions.

Chronic obstructive pulmonary disease (COPD) is common and has significant morbidity and mortality as the fourth leading cause of death in the United States. In many patients, particularly those with emphysema, COPD is characterized by markedly increased residual volume contributing to exertional dyspnea. Current therapies have limited efficacy. Surgical resection of diseased areas of the lung to reduce residual volume was effective in identified subgroups but also had significant mortality in and suboptimal cost effectiveness. Lung-volume reduction, using bronchoscopic techniques, has shown substantial benefits in a broader patient population with less morbidity and mortality. This review is meant to spread the awareness about bronchoscopic lung-volume reduction and to promote its consideration and early referral for patients with advanced COPD and emphysema frequently encountered by both primary care physicians and specialists. A search was conducted on PubMed (MEDLINE), EMbase, and Cochrane library for original studies, using the following keywords: "lung-volume reduction." "endobronchial valves," "intrabronchial valves," "bronchoscopic lung-volume reduction," and "endoscopic lung-volume reduction." We included reports from systematic reviews, narrative reviews, clinical trials, and observational studies. Two reviewers evaluated potential references. A total of 27 references were included in our review. Included studies report experience in the diagnosis and bronchoscopic treatment for emphysema; case reports and non-English or non-Spanish studies were excluded.

• Brief description of lung cancer history, screening, and prognosis. • Discussion of curative intent treatment modalities including various types of systemic therapies, radiotherapy, and surgical resection. • Review of the complications associated with common treatment modalities. • Brief overview in defining treatment response to definitive therapy. • In depth review of the current clinical evidence and practices as well as upcoming modalities for surveillance imaging after curative intent lung cancer treatment.

Background: Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are the most commonly prescribed anti-hypertensives with prior studies identifying a possible association between long-term use and increased rates of lung cancer. This study evaluated the potential association between the use of ACEIs and/or ARBs and the development of lung cancer in a large population using propensity matching. Methods: This was a population-based cohort study in a large healthcare system in three regions of the US. All adult patients who entered the Mayo Clinic health system from January 1, 2000 to April 30, 2018 with at least one year of follow-up were included. Pairwise propensity score matching was performed using demographics and comorbidities. Findings: 3,253,811 patients with median age of 59 (range 18-103) years old were included. The ACEI group had a higher freedom from lung cancer versus controls at 5, 10, and 15 years [15 year: 98.47% (CI95: 98.41%-98.54%) vs. 98.26% (CI95: 98.20%-98.33%)] while ARB had similar rates versus controls at all time points. For patients diagnosed with lung cancer, median all-cause survival was significantly higher in the ACEI [34.7 months (CI 95: 32.8-36.6)] and ARB (30.9 months (CI95: 28.1-33.8)] groups than the control group (20.6 months (CI95: 20.1-21.1). Interpretation: This is the largest analysis of lung cancer risk with ACEI and ARBs using patient data from three regions of the United States. This study demonstrates a decreased risk of lung cancer with ACEI use, no difference in risk with ARBs, and no difference in the lung cancer subtypes with ACEI or ARB usage versus controls using propensity score matching. Additionally, ACEI and ARB use was found to be associated with increased survival in those diagnosed with lung cancer. This study supports the continued use of ACEIs without concern for increasing the risk of lung cancer. Funding Statement: Grant Number UL1 TR000135 from the NIH Clinical and Translational Award for the search engine and not awarded to any authors. Declaration of Interests: All authors (SH, MW, RB, YD, AL, CB, ZL, PJ, and NP) report no conflict of interest. Ethics Approval Statement: The Mayo Clinic Institutional Review Board approved this study

INTRODUCTION: Calcium/Calmodulin-dependent (Ca(2+)/CaM-dependent) regulation of protein signaling has long been recognized for its importance in a number of physiological contexts. Found in almost all eukaryotic cells, Ca(2+)/CaM-dependent signaling participates in muscle development, immune responses, cardiac myocyte function and regulation of neuronal connectivity. In excitatory neurons, dynamic changes in the strength of synaptic connections, known as synaptic plasticity, occur when calcium ions (Ca(2+)) flux through NMDA receptors and bind the Ca(2+)-sensor calmodulin (CaM). Ca(2+)/CaM, in turn, regulates downstream protein signaling in actin polymerization, receptor trafficking, and transcription factor activation. The activation of downstream Ca(2+)/CaM-dependent binding proteins (CBPs) is a function of the frequency of Ca(2+) flux, such that each CBP is preferentially “tuned” to different Ca(2+) input signals. We have recently reported that competition among CBPs for CaM binding is alone sufficient to recreate in silico the observed in vivo frequency-dependence of several CBPs. However, CBP activation may strongly depend on the identity and concentration of proteins that constitute the competitive pool; with important implications in the regulation of CBPs in both normal and disease states. METHODS: Here, we extend our previous deterministic model of competition among CBPs to include phosphodiesterases, AMPAR receptors that are important in synaptic plasticity, and enzymatic function of CBPs: cAMP regulation, kinase activity, and phosphatase activity. After rigorous parameterization and validation by global sensitivity analysis using Latin Hypercube Sampling (LHS) and Partial Rank Correlation Coefficients (PRCC), we explore how perturbing the competitive pool of CBPs influences downstream signaling events. In particular, we hypothesize that although perturbations may decrease activation of one CBP, increased activation of a separate, but enzymatically-related CBP could compensate for this loss, providing a homeostatic effect. RESULTS AND CONCLUSIONS: First we compare dynamic model output of two models: a two-state model of Ca(2+)/CaM binding and a four-state model of Ca(2+)/CaM binding. We find that a four-state model of Ca(2+)/CaM binding best captures the dynamic nature of the rapid response of CaM and CBPs to Ca(2+) flux in the system. Using global sensitivity analysis, we find that model output is robust to parameter variability. Indeed, although variations in the expression of the CaM buffer neurogranin (Ng) may cause a decrease in Ca(2+)/CaM-dependent kinase II (CaMKII) activation, overall AMPA receptor phosphorylation is preserved; ostensibly by a concomitant increase in adenylyl cyclase 8 (AC8)-mediated activation of protein kinase A (PKA). Indeed phosphorylation of AMPAR receptors by CaMKII and PKA is robust across a wide range of Ng concentrations, though increases in AMPAR phosphorylation is seen at low Ng levels approaching zero. Our results may explain recent counter-intuitive results in neurogranin knockout mice and provide further evidence that competitive tuning is an important mechanism in synaptic plasticity. These results may be readily translated to other Ca(2+)/CaM-dependent signaling systems in other cell types and can be used to suggest targeted experimental investigation to explain counter-intuitive or unexpected downstream signaling outcomes. Tamara Kinzer-Ursem is an Assistant Professor in the Weldon School of Biomedical Engineering. She received her B.S. in Bioengineering from the University of Toledo and her M.S. and Ph.D. degrees in Chemical Engineering from the University of Michigan, and her post-doctoral training in Molecular Neuroscience at the California Institute of Technology. Prior to joining Purdue she was the Head of R&D in Biochemistry at Maven Biotechnologies and Visiting Associate in Chemical Engineering at the California Institute of Technology. Research in the Kinzer-Ursem lab focuses on developing tools to advance quantitative descriptions of cellular processes and disease within three areas of expertise: 1) Using particle diffusivity measurements to quantify biomolecular processes. Particle diffusometry is being used as a sensitive biosensor to detect the presence of pathogens in environmental and patient samples. 2) Development of novel protein tagging technologies that are used to label proteins in vivo to enable quantitative description of protein function and elucidate disease mechanisms. 3) Computational modeling of signal transduction mechanisms to understand cellular processes. Using computational techniques, we have recently described “competitive tuning” as a mechanism that might be used to regulate information transfer through protein networks, with implications in cell behavior and drug target analysis.

Background Treatment of non‐small‐cell lung cancer (NSCLC) has been rapidly advancing over the last decade. Academic centers are considered equipped with better expertise. NSCLC outcome trends in novel therapeutic era and impact of initial treatment at academic centers have not been reported. Methods The National Cancer Database (NCDB) was used to identify NSCLC incident cases from 2004 to 2013. Overall survival (OS) was plotted by year of diagnosis and type of initial treatment center, accounting for several factors available in NCDB. Results A total of 1 150 722 NSCLC patients were included and separated by initial treatment center type (academic: 31.5%; nonacademic: 68.5%). Median follow‐up and OS for all patients were 11.8 months (range: 0‐133.6 months) and 13.1 months (95% CI: 13.08‐13.17), respectively. Median OS improved significantly for those diagnosed in 2010‐2013 (14.8 months [95% CI: 14.7‐14.9]) as compared to 2004‐2009 (12.4 months [95% CI: 12.3‐12.5]) (P

Ca2+/calmodulin-dependent protein kinase II (CaMKII) accounts for up to 2 percent of all brain protein and is essential to memory function. CaMKII activity is known to regulate dynamic shifts in the size and signaling strength of neuronal connections, a process known as synaptic plasticity. Increasingly, computational models are used to explore synaptic plasticity and the mechanisms regulating CaMKII activity. Conventional modeling approaches may exclude biophysical detail due to the impractical number of state combinations that arise when explicitly monitoring the conformational changes, ligand binding, and phosphorylation events that occur on each of the CaMKII holoenzyme’s subunits. To manage the combinatorial explosion without necessitating bias or loss in biological accuracy, we use a specialized syntax in the software MCell to create a rule-based model of a twelve-subunit CaMKII holoenzyme. Here we validate the rule-based model against previous experimental measures of CaMKII activity and investigate molecular mechanisms of CaMKII regulation. Specifically, we explore how Ca2+/CaM-binding may both stabilize CaMKII subunit activation and regulate maintenance of CaMKII autophosphorylation. Noting that Ca2+/CaM and protein phosphatases bind CaMKII at nearby or overlapping sites, we compare model scenarios in which Ca2+/CaM and protein phosphatase do or do not structurally exclude each other’s binding to CaMKII. Our results suggest a functional mechanism for the so-called “CaM trapping” phenomenon, wherein Ca2+/CaM may structurally exclude phosphatase binding and thereby prolong CaMKII autophosphorylation. We conclude that structural protection of autophosphorylated CaMKII by Ca2+/CaM may be an important mechanism for regulation of synaptic plasticity., Author summary In the hippocampus, dynamic fluctuation of the size and strength of neuronal connections is thought to underlie learning and memory processes. These fluctuations, called synaptic plasticity, are in-part regulated by the protein calcium/calmodulin-dependent kinase II (CaMKII). During synaptic plasticity, CaMKII becomes activated in the presence of calcium ions (Ca2+) and calmodulin (CaM), allowing it to interact enzymatically with downstream binding partners. Interestingly, activated CaMKII can phosphorylate itself, resulting in state changes that allow CaMKII to be functionally active independent of Ca2+/CaM. Phosphorylation of CaMKII at Thr-286/287 has been shown to be a critical component of learning and memory. To explore the molecular mechanisms that regulate the activity of CaMKII holoenzymes, we use a rule-based approach that reduces computational complexity normally associated with representing the wide variety of functional states that a CaMKII holoenzyme can adopt. Using this approach we observe regulatory mechanisms that might be obscured by reductive approaches. Our results suggest that CaMKII phosphorylation at Thr-286/287 may be stabilized by a mechanism in which CaM structurally excludes phosphatase binding at that site.

Dyspnea, cough, sputum production, and recurrent respiratory infections are frequently encountered clinical concerns leading patients to seek medical care. It is not unusual for a well-defined etiology to remain elusive or for the therapeutics of a presumed etiology to be incompletely effective. Either scenario should prompt consideration of central airway pathology as a contributor to clinical manifestations. Over the past decade, recognition of dynamic central airway collapse during respiration associated with multiple respiratory symptoms has become more commonly appreciated. Expiratory central airway collapse may represent the answer to this diagnostic void. Expiratory central airway collapse is an underdiagnosed disorder that can coexist with and mimic asthma, chronic obstructive pulmonary disease, and bronchiectasis. Awareness of expiratory central airway collapse and its spectrum of symptoms is paramount to its recognition. This review includes clear definitions, diagnostics, and therapeutics for this challenging condition. We performed a narrative review through the PubMed (MEDLINE) database using the following MeSH terms: airway collapse, tracheobronchomalacia, tracheomalacia, and bronchomalacia. We include reports from systematic reviews, narrative reviews, clinical trials, and observational studies from 2005 to 2020. Two reviewers evaluated potential references. No systematic reviews were found. A total of 28 references were included into our review. Included studies report experience in the diagnosis and/or treatment of dynamic central airway collapse; case reports and non-English or non-Spanish studies were excluded. We describe the current diagnostic dilemma, highlighting the role of dynamic bronchoscopy and tracheobronchial stent trial; outline the complex therapeutic options (eg, tracheobronchoplasty); and present future directions and challenges.

Background: The coronavirus disease 2019 (COVID-19) has been identified in over 110 million people with no studies comparing pre-infection pulmonary function to post-infection. This study's aim was to compare pre-infection and post-infection pulmonary function tests (PFT) in COVID-19 infected patients to better delineate between preexisting abnormalities and effects of the virus. Methods: This was a retrospective multi-center cohort study. Patients were identified based on having COVID-19 and a pre- and post-infection PFT within one year of infection during the time period of March 1, 2020 to November 10, 2020. Findings: There was a total of 80 patients, with an even split in gender; the majority were white (n = 70, 87·5%) and never smokers (n = 42, 52·5%). The majority had mild to moderate COVID-19 disease (n = 60, 75·1%) with 25 (31·2%) requiring hospitalization. There was no difference between the pre- and post-PFT data, specifically with the forced vital capacity (FVC) (p = 0·52), forced expiratory volume in 1 s (FEV1)(p = 0·96), FEV1/FVC(p = 0·66), total lung capacity (TLC) (p = 0·21), and diffusion capacity (DLCO)(p = 0·88). There was no difference in the PFT when analyzed by hospitalization and disease severity. After adjusting for potential confounders, interstitial lung disease (ILD) was independently associated with a decreased FEV1 (-2·6 [95% CI, -6·7 to - 1·6] vs. -10·3 [95% CI, -17·7 to -2·9]; p = 0·03) and an increasing age (p = 0·01) and cystic fibrosis (-1·1 [95% CI, -4·5 to- 2·4] vs. -36·5 [95% CI, -52·1 to -21·0]; p

Background: In chronic obstructive pulmonary disease (COPD), body mass index (BMI) is significantly lower in the emphysema-dominant type. Endoscopic lung volume reduction (ELVR) is an innovative way of treating severe emphysema. However, the specific associations of low BMI values and outcomes of ELVR is not well-studied. Objectives: We evaluated associations between initial BMI and changes in major outcomes after endobronchial valve (EBV) placement in patients with heterogeneous severe emphysema. Methods: In a retrospective cohort study, patients were divided into 2 groups based on their baseline BMI (higher BMI ≥21 kg/m2 [n = 18] and lower BMI 2 [n = 63]). Demographics, procedure data, pulmonary function test and 6-min-walk test (6MWT), dyspnea score (according to the modified Medical Research Council [mMRC] scale), BODE (BMI, airflow obstruction, dyspnea, exercise capacity) index, and complications were recorded. After 6 months, changes in variables (dWeight and dBMI) were recorded. Results: Comparing the 2 groups, we found the following: a dWeight of –2.34 kg and +3.39 kg (p value 2, in the higher BMI and lower BMI group, respectively (p value 1), 6MWT, mMRC score, and BODE index were not statistically significant. The most common complication was pneumothorax. The lower BMI group experienced more complications than the higher BMI group (40 vs. 24%). Conclusion: Baseline BMI is relevant when selecting candidates for ELVR. Our results show that the COPD patients with a lower BMI gained a significant amount of weight, thus increasing their BMI after the procedure. The rate of complications was higher in the lower BMI group. These findings should alert physicians and encourage nutritional assessment in this population.

Pleural disease often affects critically ill patients and is usually related to trauma (including accidental perforation) or infection. Pneumothorax, a potentially life-threatening condition, requires early clinical recognition and sometimes urgent treatment. General intensivists often encounter pneumothorax after a procedure such as catheter placement. Neurointensivists often encounter pneumothorax after polytrauma or recent tunneling of a ventriculoperitoneal catheter.

Background The Coronavirus pandemic has a high mortality rate in patients that are mechanically ventilated, which has led to an ever increasing interest in noninvasive forms of oxygenation. The use of these devices has the theoretical risk of increased exposure risk because of possible particulate generation. This study aimed to quantify the particulate generation associated with different oxygen devices. Methods This was a prospective single center study conducted during September 2020 using ten healthy adult volunteers. Testing was conducted in a negative pressure hospital room using a light scattering particle counter. The oxygen devices used were a nasal cannula, an OxyMask™, a non-rebreathing mask, and a high flow system. Particle measurements were obtained at baseline in the room and then with each oxygen delivery device and pre-specified oxygen flow rates. These measurements were obtained different distances from the volunteer with their mouth open. A Wilcoxon/Kruskal-Wallis test was performed on each separate oxygen modality with all flow rates as one model. Results The particle concentrations were slightly non-significantly increased with the OxyMask™ and non-rebreathing mask at the closest distance measured. As the distance increased, these counts decreased closer to ambient levels. The nasal cannula and high flow nasal cannula particle counts were not significantly different from ambient measurements at either distance. Conclusion Nasal cannula, OxyMask™, non-rebreathing mask, and high flow oxygen did not generate any additional aerosols or droplets above a baseline room measurement, but further studies are necessary to determine infectious risk.

A number of neurological disorders arise from perturbations in biochemical signaling and protein complex formation within neurons. Normally, proteins form networks that when activated produce persistent changes in a synapse’s molecular composition. In hippocampal neurons, calcium ion (Ca2+) flux through N-methyl-D-aspartate (NMDA) receptors activates Ca2+/calmodulin signal transduction networks that either increase or decrease the strength of the neuronal synapse, phenomena known as long-term potentiation (LTP) or long-term depression (LTD), respectively. The calcium-sensor calmodulin (CaM) acts as a common activator of the networks responsible for both LTP and LTD. This is possible, in part, because CaM binding proteins are “tuned” to different Ca2+ flux signals by their unique binding and activation dynamics. Computational modeling is used to describe the binding and activation dynamics of Ca2+/CaM signal transduction and can be used to guide focused experimental studies. Although CaM binds over 100 proteins, practical limitations cause many models to include only one or two CaM-activated proteins. In this work, we view Ca2+/CaM as a limiting resource in the signal transduction pathway owing to its low abundance relative to its binding partners. With this view, we investigate the effect of competitive binding on the dynamics of CaM binding partner activation. Using an explicit model of Ca2+, CaM, and seven highly-expressed hippocampal CaM binding proteins, we find that competition for CaM binding serves as a tuning mechanism: the presence of competitors shifts and sharpens the Ca2+ frequency-dependence of CaM binding proteins. Notably, we find that simulated competition may be sufficient to recreate the in vivo frequency dependence of the CaM-dependent phosphatase calcineurin. Additionally, competition alone (without feedback mechanisms or spatial parameters) could replicate counter-intuitive experimental observations of decreased activation of Ca2+/CaM-dependent protein kinase II in knockout models of neurogranin. We conclude that competitive tuning could be an important dynamic process underlying synaptic plasticity., Author summary Learning and memory formation are likely associated with dynamic fluctuations in the connective strength of neuronal synapses. These fluctuations, called synaptic plasticity, are regulated by calcium ion (Ca2+) influx through ion channels localized to the post-synaptic membrane. Within the post-synapse, the dominant Ca2+ sensor protein, calmodulin (CaM), may activate a variety of downstream binding partners, each contributing to synaptic plasticity outcomes. The conditions at which certain binding partners most strongly activate are increasingly studied using computational models. Nearly all computational studies describe these binding partners in combinations of only one or two CaM binding proteins. In contrast, we combine seven well-studied CaM binding partners into a single model wherein they simultaneously compete for access to CaM. Our dynamic model suggests that competition narrows the window of conditions for optimal activation of some binding partners, mimicking the Ca2+-frequency dependence of some proteins in vivo. Further characterization of CaM-dependent signaling dynamics in neuronal synapses may benefit our understanding of learning and memory formation. Furthermore, we propose that competitive binding may be another framework, alongside feedback and feed-forward loops, signaling motifs, and spatial localization, that can be applied to other signal transduction networks, particularly second messenger cascades, to explain the dynamical behavior of protein activation.

Pulmonary amyloidosis is a rare disease that incorporates deposition of amyloid microfibril material in the lung parenchyma. The condition generally presents as an indolent subacute-to-chronic pulmonary disease and requires tissue biopsy to establish the diagnosis. Nodular pulmonary amyloidosis, a subtype of pulmonary amyloidosis, is characterised by special radiographic and pathological features. While the disease can be associated with inflammatory conditions; its association with mucosal-associated lymphoid tissue (MALT lymphoma) is unusual and carries management challenges. Herein, we illustrate a case study of nodular pulmonary amyloidosis associated with underlying MALT lymphoma in a patient with known systemic lupus erythematosus. The aim of this article is to share the management experience of this complex condition with the medical community and to conduct an up-to-date literature review on nodular pulmonary amyloidosis.

In this report we discuss two cases of patients with Pulmonary Arterial Hypertension. Both patients were evaluated and were recommended therapy according to current acceptable guidelines. Despite these recommendations, each patient sought on their own accord, additional therapy in the form of stem cell therapy. They subsequently received an infusion of stem cells into their pulmonary circulation. Objective and subjective measures were followed prior to and following infusion. After a review of each case we briefly discuss the decisions a physician must face when a patient seeks therapies not proven safe or effective by a governing authority.