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Journal: American journal of respiratory and critical care medicine


Cleaning tasks may imply exposure to chemical agents with potential harmful effects to the respiratory system, and increased risk of asthma and respiratory symptoms among professional cleaners and in persons cleaning at home has been reported. The long-term consequences of cleaning agents on respiratory health are, however, not well described.

Concepts: Pulmonology, Respiratory system, Mucus


Rationale: Critically ill patients frequently develop neuropsychological disturbances including acute delirium or memory impairment. The need for mechanical ventilation is as a risk factor for these adverse events, but a mechanism that links lung stretch and brain injury has not been identified. Objetives: To identify the mechanisms that lead to brain dysfunction during mechanical ventilation. Methods: Brains from mechanically ventilated mice were harvested, and signals of apoptosis and alterations in the Akt survival pathway studied. These measurements were repeated in vagotomized or haloperidol-treated mice, and in animals intracerebroventricullarly injected with selective dopamine-receptor blockers. Hippocampal slices were cultured and treated with micromolar concentrations of dopamine, with or without dopamine-receptor blockers. Finally, levels of dysbindin, a regulator of the membrane availability of dopamine receptors, were assessed in the experimental model and in brain samples from ventilated patients. Measurements and Main Results: Mechanical ventilation triggers hippocampal apoptosis as a result of type-2 dopamine receptor activation in response to vagal signaling. Activation of these receptors blocks the Akt/GSK3β prosurvival pathway and activates the apoptotic cascade, as demonstrated in vivo and in vitro. Vagotomy, systemic haloperidol or intracerebroventricular raclopride (a type-2 dopamine receptor blocker) ameliorated this effect. Moreover, ventilation induced a concomitant change in the expression of dysbindin-1C. These results were confirmed in brain samples from ventilated patients. Conclusions: These results prove the existence of a pathogenetic mechanism of lung stretch-induced hippocampal apoptosis that could explain the neurological changes in ventilated patients and may help to identify novel therapeutic approaches.

Concepts: Brain, Signal transduction, Traumatic brain injury, Second messenger system, Dopamine receptor, Antipsychotic, Dopamine, Haloperidol


Rationale: Increasing use of extracorporeal membrane oxygenation (ECMO) for acute respiratory failure may increase resource requirements and hospital costs. Better prediction of survival in these patients may improve resource utilisation, allow risk-adjusted comparison of center-specific outcomes and help clinicians to target patients most likely to benefit from ECMO. Objectives: To create a model for predicting hospital survival at initiation of ECMO for respiratory failure. Methods: Adult patients with severe acute respiratory failure treated by ECMO from 2000 to 2012 were extracted from the Extracorporeal Life Support Organization (ELSO) international registry. Multivariable logistic regression was used to create the Respiratory ECMO Survival Prediction score (RESP-score) using bootstrapping methodology with internal and external validation. Main results: Of the 2355 patients included in the study, 1338 patients (57%) were discharged alive from hospital. The RESP-score was developed using pre-ECMO variables independently associated with hospital survival on logistic regression which included: age, immunocompromised status, duration of mechanical ventilation prior to ECMO, diagnosis, central nervous system dysfunction, acute associated non-pulmonary infection, neuro-muscular blockade agents or nitric oxide use, bicarbonate infusion, cardiac arrest, PaCO2 and peak inspiratory pressure. The ROC curve analysis of the RESP score was c=0.74, 95% Confidence Interval (0.72 - 0.76). External validation, performed on 140 patients, exhibited excellent discrimination (c=0.92 [95%CI 0.89 - 0.97]). Conclusions: The RESP-score is a relevant and validated tool to predict survival for patients receiving ECMO for respiratory failure.

Concepts: Central nervous system, Nervous system, Regression analysis, Intensive care medicine, Prediction, Prediction interval, Extracorporeal, Extracorporeal membrane oxygenation


RATIONALE: Automated weaning has not been compared to a paper-based weaning protocol in North America. OBJECTIVE: We conducted a pilot randomized trial comparing Automated Weaning and Protocolized Weaning in critically ill adults to evaluate clinician compliance and acceptance of the study protocols, recruitment, and impact on outcomes. METHODS: From August 2007 to October 2009, we enrolled critically ill adults requiring > 24 hours of mechanical ventilation and at least partial reversal of the condition precipitating respiratory failure at 9 Canadian intensive care units. We randomized patients who tolerated at least 30 minutes of pressure support and either failed or were not yet ready to undergo a spontaneous breathing trial to Automated or Protocolized Weaning. Both groups utilized pressure support, included spontaneous breathing trials, used a common PEEP/FiO2 chart, sedation protocol and criteria for extubation, reintubation and noninvasive ventilation. RESULTS: We recruited 92 patients (49 Automated, 43 Protocolized) over 26 months. Adherence to assigned weaning protocols and extreme sedation scale scores fell within prespecified thresholds. Combined physician/RT and RN acceptance scores of the study weaning and sedation protocols, respectively, were not significantly different. Automated Weaning patients had significantly shorter median times to first successful breathing trial (1.0 vs. 4.0 d, p<0.0001), extubation (3.0 vs. 4.0 d, p=0.02), successful extubation (4.0 vs. 5.0 d, p=0.01) and underwent fewer tracheostomies and episodes of protracted ventilation. CONCLUSIONS: Compared to a standardized protocol, Automated Weaning was associated with promising outcomes that warrant further investigation. Minor protocol modifications may increase compliance, facilitate recruitment, and enhance feasibility.

Concepts: Epidemiology, Medical terms, Randomized controlled trial, Intensive care medicine, Mechanical ventilation, Failure, Sedation, Spontaneous breathing trial


RATIONALE: Occupational co-exposure to asbestos and other fibers or particles could modify the carcinogenicity of asbestos with regard to pleural mesothelioma. OBJECTIVES: To estimate associations between pleural mesothelioma and occupational mineral wool and silica exposure and to study the impact of occupational co-exposure on the risk of pleural mesothelioma. METHODS: 1,199 male cases and 2,379 controls were included in a French pooled case-control study. Complete job histories were collected and occupational exposure to asbestos, mineral wool (MW), and silica were assessed by three French job exposure matrices. Unconditional logistic regression models adjusted for age, birth date, and occupational asbestos exposure were used to estimate odds ratios (OR) and 95% confidence intervals. MEASUREMENTS AND MAIN RESULTS: A significant association between mesothelioma and MW exposure was observed after adjustment for occupational asbestos exposure. OR for subjects exposed to less than 0.01 f/ml-y was 1.6 (95% CI: 1.2-2.1) and increased to 2.5 (95% CI: 1.8-3.4) for subjects exposed to more than 0.32 f/ml-y. All ORs for silica exposure were around the null. Co-exposure to either asbestos and MW or asbestos and silica seemed to increase the risk of pleural mesothelioma. ORs were 17.6 (95% CI: 11.8-26.2) and 9.8 (95% CI: 4.2-23.2) for subjects exposed to both asbestos and MW and for subjects exposed to both asbestos and silica, respectively, compared to 4.3 (95% CI: 1.9-9.8) for occupational asbestos exposure alone. CONCLUSION: Our results are in favour of an increased risk of pleural mesothelioma for subjects exposed to both asbestos and MW or asbestos and silica.

Concepts: Regression analysis, Logit, Logistic regression, Epidemiology, Cancer, Mesothelioma, Asbestos, Mineral wool


ABSTRACT RATIONALE: Bacterial colonization of neonatal airways with the pathogenic bacterial species M. catarrhalis, S. pneumoniae and H. influenzae is associated with later development of childhood asthma. OBJECTIVE: To study a possible association between the immune signature of the upper airways and colonization with pathogenic bacterial strains in healthy neonates. Method: 20 cytokines and chemokines were quantified in vivo in the airway mucosal lining fluid of 662 neonates from the COPSAC2010 birth cohort. Colonization of the hypopharynx with M. catarrhalis, S. pneumoniae, H. influenzae and S. aureus was assessed simultaneously. The association between immune signatures and bacterial colonization or non-colonized controls was analyzed utilizing conventional statistical methods supplemented by a multivariate approach for pattern identification. MEASUREMENTS AND MAIN RESULTS: Colonization with M. catarrhalis and H. influenzae induced a mixed Th1/Th2/Th17-type response with high levels of IL-1β (M. catarrhalis P= 2.2x10-12, H. influenzae P= 7.1x10-10), TNF-α (M. catarrhalis P= 1.5x10-9, H. influenzae P= 5.9x10-7) and MIP-1β (M. catarrhalis P= 1.6x10-11, H. influenzae P= 2.7x10-7). S. aureus colonization demonstrated a Th17-promoting profile with elevated IL-17 levels (P=1.6x10-24). S. pneumoniae colonization was not significantly associated with any of the mediators. CONCLUSION: M. catarrhalis and H. influenzae colonization of the airways of asymptomatic neonates is associated with an inflammatory immune response profile of the airway mucosa which may result in chronic inflammation.

Concepts: Immune system, Inflammation, Bacteria, Microbiology, Pneumonia, Infection, Pathogen, Pathogenic bacteria


Over 25 million American children breathe polluted air on diesel school buses. Emission reduction policies exist but the health impacts to individual children have not been evaluated.

Concepts: Petroleum, Pollution, Biofuel, School bus, Air pollution, Chicago, Bus, Diesel engine


Tuberculosis (TB), a chronic infectious disease of global importance, is facing the emergence of drug-resistant strains with few new drugs to treat the infection. Pulmonary cavitation, the hallmark of established disease, is associated with very high bacillary burden. Cavitation may lead to delayed sputum culture conversion, emergence of drug resistance, and transmission of the infection. The host immunological reaction to M. tuberculosis is implicated in driving the development of TB cavities. TB is characterized by a matrix degrading phenotype in which the activity of proteolytic matrix metalloproteinases (MMPs) is relatively unopposed by the specific tissue inhibitors of metalloproteinases (TIMPs). Proteases, in particular MMPs, secreted from monocyte-derived cells, neutrophils and stromal cells, are involved in both cell recruitment and tissue damage and may cause cavitation. MMP activity is augmented by pro-inflammatory chemokines and cytokines, is tightly regulated by complex signalling paths and causes matrix destruction. MMP concentrations are elevated in human TB and are closely associated with clinical and radiological markers of lung tissue destruction. Immunomodulatory therapies targeting MMPs in preclinical and clinical trials are potential adjuncts to TB treatment. Strategies targeting patients with cavitatory TB have the potential to improve cure rates and reduce disease transmission.

Concepts: Medicine, Epidemiology, Infectious disease, Lung, Infection, Tuberculosis, Matrix metalloproteinase, Tissue inhibitor of metalloproteinases


There are no studies on ICS withdrawal in patients on long-term triple therapy in the absence of frequent exacerbations.


Nintedanib and pirfenidone slow the progression of IPF, but the disease continues to progress. More data are needed on the safety and efficacy of combination therapy with nintedanib and add-on pirfenidone.

Concepts: Idiopathic pulmonary fibrosis