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We propose and implement an optical technique to access the local temperature of an erbium doped crystal by probing the electron spin population under magnetic field. We reliably extract the sample temperature in the range 2-7 K. We additionally discuss the suitability of our method as a primary standard for cryogenic thermometry. By adding an auxiliary heating laser, we are able to measure the interface conductance between the dielectric crystal and the cold plate of the cryostat by exploring different cooling configurations., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Drug-induced interstitial lung disease (DI-ILD) is an increasingly common cause of morbidity and mortality as the list of culprit drugs continues to grow. Unfortunately, DI-ILD is difficult to study, diagnose, prove, and manage. This article attempts to raise awareness of the challenges in DI-ILD and discusses the current clinical landscape., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The COVID-19 pandemic increased the incidence of neuropsychiatric diseases. Proactive models of consultation-liaison psychiatry (CLP-p) could play a key role in the prevention and management of these diseases in a general hospital., Aim: To develop a protocol for implementing screening tools for neuropsychiatric symptoms in routine clinical practice., Material and Methods: Elements of the Plan-Do-Study-Act (PDSA) model were used to modify the Neuropsychiatric Surveillance protocol implemented at a clinical hospital during the COVID-19 pandemic by members of the hospital's CLP team., Results: A flowchart for active follow-up of neuropsychiatric symptoms during hospitalization is presented, with sequential management and referral flows, accompanied by suggestions for pre-discharge evaluation to define continuity of care actions. The COSMOS tool is also presented, designed for the detection of risk factors and actions for the prevention of neuropsychiatric diseases in general hospitals., Conclusions: The neuropsychiatric surveillance protocol facilitates early and timely interventions and establishes criteria for the continuity of post-discharge care. These changes could improve the quality of care in general hospitals and reduce the gap between mental and physical health.

Inflammatory bowel disease is associated with a wide spectrum of central, large, and small airway abnormalities, including bronchiectasis. The bronchiectasis associated with inflammatory bowel disease has a distinct phenotype, with marked inflammation and at times severe sterile bronchorrhea that can be responsive to inhaled corticosteroids., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The CUPID-Mo experiment at the Laboratoire Souterrain de Modane (France) is a demonstrator for CUPID, the next-generation ton-scale bolometric 0νββ experiment. It consists of a 4.2 kg array of 20 enriched Li&#95;{2}^{100}MoO&#95;{4} scintillating bolometers to search for the lepton-number-violating process of 0νββ decay in ^{100}Mo. With more than one year of operation (^{100}Mo exposure of 1.17  kg×yr for physics data), no event in the region of interest and, hence, no evidence for 0νββ is observed. We report a new limit on the half-life of 0νββ decay in ^{100}Mo of T&#95;{1/2}>1.5×10^{24}  yr at 90% C.I. The limit corresponds to an effective Majorana neutrino mass ⟨m&#95;{ββ}⟩<(0.31-0.54)  eV, dependent on the nuclear matrix element in the light Majorana neutrino exchange interpretation.

We present the first Ge-based constraints on sub-MeV/c^{2} dark matter (DM) particles interacting with electrons using a 33.4 g Ge cryogenic detector with a 0.53 electron-hole pair (rms) resolution, operated underground at the Laboratoire Souterrain de Modane. Competitive constraints are set on the DM-electron scattering cross section, as well as on the kinetic mixing parameter of dark photons down to 1  eV/c^{2}. In particular, the most stringent limits are set for dark photon DM in the 6 to 9  eV/c^{2} range. These results demonstrate the high relevance of Ge cryogenic detectors for the search of DM-induced eV-scale electron signals.

Approximately one third of patients with non-small-cell lung cancer (NSCLC) present with stage III or locally advanced NSCLC. These patients have historically been managed with chemoradiotherapy. However, outcomes for these patients remain poor, with a 5-year survival rate between 15% and 32%. Immune checkpoint inhibitors have revolutionized the treatment of patients with NSCLC. One such agent, durvalumab, a selective high-affinity human immunoglobulin G1 monoclonal antibody that blocks programmed cell death ligand 1 binding to programmed cell death protein 1 and cluster of differentiation 80, was recently approved in the consolidation setting after completion of definitive platinum-based chemoradiotherapy and has become the current standard of care for patients with stage III locally advanced NSCLC. Immune checkpoint blockade is associated with increased risk of immunotherapy-related adverse events, which can be managed most effectively when detected early, ideally in the context of a multidisciplinary approach. Pneumonitis represents the potentially most severe and life-threatening of all reported immunotherapy-related adverse events, but it is further complicated in the context of recent prior therapies also known to cause pulmonary toxicity, such as radiotherapy. However, there are major gaps in our ability to identify immunotherapy-related pneumonitis and distinguish it from radiation pneumonitis. This review aims to define the key steps in the detection, diagnosis, and treatment of immunotherapy-related pneumonitis., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

This dataset, produced through the Coordinated Ocean Wave Climate Project (COWCLIP) phase 2, represents the first coordinated multivariate ensemble of 21 st Century global wind-wave climate projections available (henceforth COWCLIP2.0). COWCLIP2.0 comprises general and extreme statistics of significant wave height (H S ), mean wave period (T m ), and mean wave direction (θ m ) computed over time-slices 1979-2004 and 2081-2100, at different frequency resolutions (monthly, seasonally and annually). The full ensemble comprising 155 global wave climate simulations is obtained from ten CMIP5-based state-of-the-art wave climate studies and provides data derived from alternative wind-wave downscaling methods, and different climate-model forcing and future emissions scenarios. The data has been produced, and processed, under a specific framework for consistency and quality, and follows CMIP5 Data Reference Syntax, Directory structures, and Metadata requirements. Technical comparison of model skill against 26 years of global satellite measurements of significant wave height has been undertaken at global and regional scales. This new dataset provides support for future broad scale coastal hazard and vulnerability assessments and climate adaptation studies in many offshore and coastal engineering applications.

The black-necked swan Cygnus melancoryphus is an aquatic herbivorous bird whose dietary habits depend on the dominance and accessibility of macrophyte banks in shallow areas of coastal and limnetic wetlands in southern South America. The swans from the Río Cruces wetland in southern Chile (ca. 39°S) feed mainly on the macrophyte Egeria densa from the water column between depths from less than 0,5 and 2,0 m. A micro- histological analysis of black-necked swan feces (N = 152) collected during six sampling occasions between 2012 and 2017 confirms the preferred consumption of E. densa and highlights the impact of temporal changes in the cover of these macrophytes on the swan's diet. The dietary composition of black-necked swans appears as a reliable proxy for temporal changes in the distribution of the most common aquatic macrophytes in the Río Cruces wetland. These results highlight the importance of preserving shallow wetlands as the habitat for aquatic macrophytes that provide the main food source for these herbivorous water birds., Competing Interests: There are no competing interests with anybody. The conclusions of this study are just those of the authors and should not be interpreted as representing other points of views or policies from the Arauco Company that provided funding for this study. That funding does not alter authors' adherence to PLOS ONE policies on sharing data and materials collected during this study.

Rationale: Immune checkpoint inhibitors (ICIs) have revolutionized cancer care but are associated with unique adverse events, including potentially life-threatening pneumonitis. The diagnosis of ICI-pneumonitis is increasing; however, the biological mechanisms, clinical and radiologic features, and the diagnosis and management have not been well defined. Objectives: To summarize evidence, identify knowledge and research gaps, and prioritize topics and propose methods for future research on ICI-pneumonitis. Methods: A multidisciplinary group of international clinical researchers reviewed available data on ICI-pneumonitis to develop and refine research questions pertaining to ICI-pneumonitis. Results: This statement identifies gaps in knowledge and develops potential research questions to further expand knowledge regarding risk, biologic mechanisms, clinical and radiologic presentation, and management of ICI-pneumonitis. Conclusions: Gaps in knowledge of the basic biological mechanisms of ICI-pneumonitis, coupled with a precipitous increase in the use of ICIs alone or combined with other therapies, highlight the importance in triaging research priorities for ICI-pneumonitis.

Treatment of patients often includes the administration of medications and sometimes radiation. While the intent is to treat an underlying condition, in some cases, adverse effects occur due to these agents. Most of these adverse effects are mild, however, some can be severe and life-threatening. Furthermore, while these effects are often reversible upon cessation of exposure, especially if the inciting agent is recognized and withdrawn early, others might be permanent or even progressing. Most common histopathologic findings in drug-induced interstitial lung disease include nonspecific interstitial pneumonia (cellular and/or fibrotic), organizing pneumonia with or without bronchiolitis, eosinophilic pneumonia, pulmonary edema, diffuse alveolar damage, hypersensitivity pneumonitis, granulomatous interstitial lung disease, chronic bronchiolitis, and pulmonary hemorrhage. Pulmonary vascular changes or constrictive bronchiolitis can also occur. Drugs that are more commonly associated with lung toxicity include nitrofurantoin, amiodarone, and chemotherapeutic agents such as bleomycin and methotrexate. More recently introduced immune modulating agents including rituximab and immune checkpoint inhibitors such as anti-CTLA4, anti-PD-1 and anti-PD-L1 agents have also been associated with adverse effects in the lung. Radiation therapy to the chest can trigger acute or chronic lung toxicity. While newer radiation techniques are aimed to decrease and minimize side effects other risk factors such as additional chemotherapy, oxygen, and older age may be rising. Foreign substances such as talc, hydrogel, and medical devices such as hydrophilic polymer coated catheter may rarely also lead to pulmonary complications. It is important that clinicians and pathologists are aware of these potential adverse effects of drugs, radiation and medical devices and raise the possibility of drug-induced lung toxicity after exclusion of other differential diagnoses. It is the role of the clinician to provide the pathologist with an appropriate drug history. Early intervention to a drug-induced lung toxicity might prevent progression of side effects and permanent changes., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Doxorubicin Transdrug (DT), a nanoformulation of doxorubicin, was demonstrated to overcome the chemoresistance of hepatocellular carcinoma (HCC) in preclinical models. Its efficacy and safety were thus investigated in phase I and randomised phase II trials in unresectable HCC., Patients and Methods: Phase I was a single dose of DT through the hepatic intra-arterial (HIA) route, dose-escalating 3+3 trial, evaluating five-dose levels from 10 to 40 mg/m 2 with maximal tolerated dose (MTD) as primary endpoint. The multicentre phase II trial randomly assigned (2:1 ratio) patients to receive either 30 mg/m 2 of DT through HIA route every 4 weeks for up to three courses or best standard of care (BSC). Progression-free survival (PFS) rate at 3 months was the primary endpoint. Overall survival (OS) and disease control rate (DCR) were secondary endpoints., Results: In phase I, haematological and respiratory limited toxicities were reported at 35 and 40 mg/m 2 , giving MTD at 30 mg/m 2 . Partial response rate was 10%, and stable disease 70%. Phase II was discontinued due to three severe acute respiratory distress events in the DT group while 17 patients had received 30 mg/m 2 DT and 11 BSC. At 3 months, PFS was 64% (95% CI 31 to 89) vs 75% (95% CI 35 to 97), and DCR 35% vs 27% in DT and BSC, respectively (p=NS). Median OS was 32.6 months (95% CI 8.2 to 34.1) in DT group and 15 months (95% CI 8.0 to 18.8) in BSC group (p < 0.05)., Conclusion: DT increased OS in unresectable HCC but induced severe respiratory distress. Efficacy data deserve further investigation using a safer dosing and schedule regimen., Trial Registration Number: EUDRACT 2006-004088-77; Results., Competing Interests: Competing interests: PM: participant to boards and consultancy for Onxeo and Bayer; participant to boards for BMS. JPZ: honorary from Abbvie and consultancy for Gilead, BMS and Janssen. MB: consultancy for Bayer Pharma and Bristol-Myers Squibb; advisory board for Bayer Pharma and Bristol-Myers Squibb; received honoraria from Bayer Pharma and Sirtex. JT: honorary from Roche, Merck, Amgen, Celgene, Baxalta, Sanofi, Lilly and Sirtex. BV is an employee of Onxeo. PA is a shareholder of Onxeo and a patent owner.

Coastal communities throughout the world are exposed to numerous and increasing threats, such as coastal flooding and erosion, saltwater intrusion and wetland degradation. Here, we present the first global-scale analysis of the main drivers of coastal flooding due to large-scale oceanographic factors. Given the large dimensionality of the problem (e.g. spatiotemporal variability in flood magnitude and the relative influence of waves, tides and surge levels), we have performed a computer-based classification to identify geographical areas with homogeneous climates. Results show that 75% of coastal regions around the globe have the potential for very large flooding events with low probabilities (unbounded tails), 82% are tide-dominated, and almost 49% are highly susceptible to increases in flooding frequency due to sea-level rise.

Obstructive sleep apnoea (OSA) is characterized by repeated episodes of apnoea and hypopnoea during sleep. Little is known about the potential impact of therapy drugs on the underlying respiratory disorder. Any influence should be taken into account and appropriate action taken, including drug withdrawal if necessary. Here, we review drugs in terms of their possible impact on OSA; drugs which (1) may worsen OSA; (2) are unlikely to have an impact on OSA; (3) those for which data are scarce or contradictory; and (4) drugs with a potentially improving effect. The level of evidence is ranked according to three grades: A - randomized controlled trials (RCTs) with high statistical power; B - RCTs with lower power, non-randomized comparative studies and observational studies; C - retrospective studies and case reports. Our review enabled us to propose clinical recommendations. Briefly, agents worsening OSA or inducing weight gain, that must be avoided, are clearly identified. Drugs such as 'Z drugs' and sodium oxybate should be used with caution as the literature contains conflicting results. Finally, larger trials are needed to clarify the potential positive impact of certain drugs on OSA. In the meantime, some, such as diuretics or other antihypertensive medications, are helpful in reducing OSA-associated cardiovascular morbidity., (© 2016 The British Pharmacological Society.)

This paper reports on the development of a technology involving 100 Mo -enriched scintillating bolometers, compatible with the goals of CUPID, a proposed next-generation bolometric experiment to search for neutrinoless double-beta decay. Large mass ( ∼ 1 kg ), high optical quality, radiopure 100 Mo -containing zinc and lithium molybdate crystals have been produced and used to develop high performance single detector modules based on 0.2-0.4 kg scintillating bolometers. In particular, the energy resolution of the lithium molybdate detectors near the Q -value of the double-beta transition of 100 Mo (3034 keV) is 4-6 keV FWHM. The rejection of the α -induced dominant background above 2.6 MeV is better than 8 σ . Less than 10 μ Bq/kg activity of 232 Th ( 228 Th ) and 226 Ra in the crystals is ensured by boule recrystallization. The potential of 100 Mo -enriched scintillating bolometers to perform high sensitivity double-beta decay searches has been demonstrated with only 10 kg × d exposure: the two neutrino double-beta decay half-life of 100 Mo has been measured with the up-to-date highest accuracy as T 1 / 2 = [6.90 ± 0.15(stat.) ± 0.37(syst.)] × 10 18 years . Both crystallization and detector technologies favor lithium molybdate, which has been selected for the ongoing construction of the CUPID-0/Mo demonstrator, containing several kg of 100 Mo ., (© The Author(s) 2017.)

Background and Objective: Nocturnal hypoventilation is now an accepted indication for the initiation of non-invasive ventilation. Nocturnal hypoventilation may be an under diagnosed condition in chronic respiratory failure. The most appropriate strategy to identify sleep hypoventilation is not yet clearly defined. In clinical practice, it is indirectly assessed using nocturnal pulse oximetry (NPO) and morning arterial blood gases (mABG). Even though continuous transcutaneous carbon dioxide partial pressure (TcPCO2 ) monitoring is theoretically superior to NPO plus mABG, it is not routinely used. We aimed to prospectively compare NPO plus mABG with nocturnal TcPCO2 for the detection of alveolar hypoventilation in a cohort of patients with chronic restrictive respiratory dysfunction., Methods: We assessed 80 recordings of mABG, nocturnal TcPCO2 and NPO in 72 consecutive patients with neuromuscular disease or thoracic cage disorders. Nocturnal hypoventilation was defined as a mean nightime TcPCO2 ≥50 mm Hg, and nocturnal hypoxaemia as ≥30% of the night with transcutaneous pulse oxygen saturation ≤90% and/or >5 consecutive minutes with transcutaneous pulse oxygen saturation ≤88%., Results: Amongst the 80 recordings, 25 of 76 (32.9%) without nocturnal hypoxaemia and 16 of 59 (27.1%) without hypercapnia on mABG showed nocturnal hypoventilation on TcPCO2 . Amongst recordings showing both normal NPO and mABG, 16 of 52 (30.8%) had a mean TcPCO2 ≥50 mm Hg. Nocturnal hypoxaemia was associated with nocturnal hypoventilation in all recordings. However, 5 of 21 (23.8%) recordings that showed an absence of nocturnal hypoventilation at the chosen threshold showed hypercapnia on mABG., Conclusion: Morning arterial blood gases and NPO alone or in combination underestimate nocturnal hypoventilation in patients with chronic restrictive respiratory dysfunction of extrapulmonary origin., (© 2016 Asian Pacific Society of Respirology.)

Bleomycin (BLM) is a potent anticancer drug used to treat different malignancies, mainly lymphomas, germ cell tumors, and melanomas. Unfortunately, BLM has major, dose-dependent, pulmonary toxicity that affects 20% of treated individuals. The most severe form of BLM-induced pulmonary toxicity is lung fibrosis. Deglyco-BLM is a molecule derived from BLM in which the sugar residue d-mannosyl-l-glucose disaccharide has been deleted. The objective of this study was to assess the anticancer activity and lung toxicity of deglyco-BLM. We compared the antitumor activity and pulmonary toxicity of intraperitoneally administrated deglyco-BLM and BLM in three rodent models. Pulmonary toxicity was examined in depth after intratracheal administration of both chemotherapeutic agents. The effect of both drugs was further studied in epithelial alveolar cells in vitro. We demonstrated in rodent cancer models, including a human Hodgkin's lymphoma xenograft and a syngeneic melanoma model, that intraperitoneal deglyco-BLM is as effective as BLM in inducing tumor regression. Whereas the antitumor effect of BLM was accompanied by a loss of body weight and the development of pulmonary toxicity, deglyco-BLM did not affect body weight and did not engender lung injury. Both molecules induced lung epithelial cell apoptosis after intratracheal administration, but deglyco-BLM lost the ability to induce caspase-1 activation and the production of ROS (reactive oxygen species), transforming growth factor-β1, and other profibrotic and inflammatory cytokines in the lungs of mice and in vitro. Deglyco-BLM should be considered for clinical testing as a less toxic alternative to BLM in cancer therapy., (Copyright © 2016, American Association for the Advancement of Science.)

A new survey coordinated by the French expert centres for rare pulmonary diseases investigated French pulmonologists' diagnostic and therapeutic practice for idiopathic pulmonary fibrosis (IPF) and explored changes since a previous survey in 2011-2012. From May 16 to August 30, 2014, 524 pulmonologists were contacted. Those following at least one patient with IPF were invited to complete a questionnaire administered by telephone or e-mail. 166 (31.7%) pulmonologists, 161 (97%) of whom had participated to the first survey, completed the questionnaire. Of those, 46% and 52%, respectively, discussed the cases with radiologists and pathologists. Out of 144 pulmonologists practicing outside of expert centres, 80% indicated referring patients to those centres. The 2013 French practical guidelines for IPF were known by 92% of pulmonologists involved in IPF, 96% of whom considered them appropriate for practice. The multidisciplinary discussion form for IPF diagnosis was known by 74% and considered appropriate by 94%. Diagnosis and management resulted from multidisciplinary discussion in 50% of the cases. About 58% of patients were diagnosed with "mild to moderate IPF" as defined by forced vital capacity ≥50% of the predicted value and diffusing capacity for carbon monoxide ≥35% of predicted. At the time of the survey, 31% of physicians were using pirfenidone to treat patients with "mild-to-moderately severe IPF" and 30% generally prescribed no treatment. Substantial improvement has occurred since the 2011-2012 survey with regard to knowledge of guidelines and proper management of IPF. Early diagnosis still needs to be improved through the network of expert centres., Competing Interests: can be found alongside this article at openres.ersjournals.com

Background: BRAF and MEK are component of the MAPK/ERK pathway and inhibitors of these proteins have significantly improved the outcome of metastatic melanoma. We report for the first time two sequential episodes of pneumonitis presumably induced by trametinib (a MEK inhibitor) and vemurafenib (a BRAF inhibitor) in a 50 year-old man., Case Presentation: While receiving trametinib for a metastatic melanoma, the patient developed non-febrile acute respiratory failure in the context of bilateral ground-glass opacities and sub pleural reticulations on high resolution computed tomography. An excess of lymphocytes was found in the bronchoalveolar lavage fluid. Outcome was favorable after simple drug discontinuation. He subsequently developed a similar clinical-imaging picture 6 months into vemurafenib. A transthoracic lung biopsy disclosed interstitial lymphocytic infiltrate, poorly-formed granulomas with multinucleated giant cells and scattered eosinophils. Outcome was again favorable after simple drug discontinuation., Conclusion: These two episodes in the same patient suggest that MAPK/ERK inhibitors may cause interstitial lung disease and may exert cross toxicity. This side effect is of particular interest for physicians in charge of patients with melanoma but this drug family is currently under development for several other solid tumors.

Haemoptysis is a serious symptom with various aetiologies. Our aim was to define the aetiologies, outcomes and associations with lung cancer in the entire population of a high-income country.This retrospective multicentre study was based on the French nationwide hospital medical information database collected over 5 years (2008-2012). We analysed haemoptysis incidence, aetiologies, geographical and seasonal distribution and mortality. We studied recurrence, association with lung cancer and mortality in a 3-year follow-up analysis.Each year, ~15 000 adult patients (mean age 62 years, male/female ratio 2/1) were admitted for haemoptysis or had haemoptysis as a complication of their hospital stay, representing 0.2% of all hospitalised patients. Haemoptysis was cryptogenic in 50% of cases. The main aetiologies were respiratory infections (22%), lung cancer (17.4%), bronchiectasis (6.8%), pulmonary oedema (4.2%), anticoagulants (3.5%), tuberculosis (2.7%), pulmonary embolism (2.6%) and aspergillosis (1.1%). Among incident cases, the 3-year recurrence rate was 16.3%. Of the initial cryptogenic haemoptysis patients, 4% were diagnosed with lung cancer within 3 years. Mortality rates during the first stay and at 1 and 3 years were 9.2%, 21.6% and 27%, respectively.This is the first epidemiological study analysing haemoptysis and its outcomes in an entire population. Haemoptysis is a life-threatening symptom unveiling potentially life-threatening underlying conditions., (Copyright ©ERS 2015.)

Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by myofibroblast proliferation and extracellular-matrix accumulation. IPF typically starts in subpleural lung regions, and recent studies suggest that pleural mesothelial cells play a role in the onset of the disease. The transition of mesothelial cells into myofibroblasts (mesothelio-mesenchymal transition) is induced by the profibrotic cytokine, transforming growth factor (TGF)-β1, and is thought to play a role in the development and progression of IPF. The Mothers Against Decapentaplegic homolog (Smad)-dependent pathway is the main TGF-β1 pathway involved in fibrosis. αB-crystallin is constitutively expressed in the lungs, and is inducible by stress, acts as a chaperon, and is known to play a role in cell cytoskeleton architecture. We recently showed that the lack of αB-crystallin hampered TGF-β1 signaling by favoring Smad4 monoubiquitination and nuclear export. We demonstrate here, for the first time, that αB-crystallin is strongly overexpressed in the pleura of fibrotic lungs from patients with IPF and in rodent models of pleural/subpleural fibrosis. αB-crystallin-deficient mice are protected from pleural/subpleural fibrosis induced by the transient adenoviral-mediated overexpression of TGF-β1 or the intrapleural injection of bleomycin combined with carbon particles. We show that αB-crystallin inhibition hampers Smad4 nuclear localization in pleural mesothelial cells and the consequent characteristics of mesothelio-mesenchymal transition. αB-crystallin-deficient mesothelial cells fail to acquire the properties of myofibroblasts, thus limiting their migration in vivo and the progression of fibrosis in the lung parenchyma. In conclusion, our work demonstrates that αB-crystallin may be a key target for the development of specific drugs in the treatment of IPF.

Electron Backscatter Diffraction (EBSD) has proven to be a useful tool for characterizing the crystallographic orientation aspects of microstructures at length scales ranging from tens of nanometers to millimeters in the scanning electron microscope (SEM). With the advent of high-speed digital cameras for EBSD use, it has become practical to use the EBSD detector as an imaging device similar to a backscatter (or forward-scatter) detector. Using the EBSD detector in this manner enables images exhibiting topographic, atomic density and orientation contrast to be obtained at rates similar to slow scanning in the conventional SEM manner. The high-speed acquisition is achieved through extreme binning of the camera-enough to result in a 5 × 5 pixel pattern. At such high binning, the captured patterns are not suitable for indexing. However, no indexing is required for using the detector as an imaging device. Rather, a 5 × 5 array of images is formed by essentially using each pixel in the 5 × 5 pixel pattern as an individual scattered electron detector. The images can also be formed at traditional EBSD scanning rates by recording the image data during a scan or can also be formed through post-processing of patterns recorded at each point in the scan. Such images lend themselves to correlative analysis of image data with the usual orientation data provided by and with chemical data obtained simultaneously via X-Ray Energy Dispersive Spectroscopy (XEDS)., (Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Pulmonary localized forms of Waldenström's macroglobulinemia are rare., Case Report: We report the observation of a 71-year-old woman with chronic cough and persisting alveolar opacities after several courses of antibiotics. Physical examination was unremarkable. Protein electrophoresis identified a monoclonal IgM in the serum. The lymphocyte immunophenotyping from the bronchoalveolar lavage was consistent with a B-cell lymphoma and Waldenström's macroglobulinemia was confirmed by the bone marrow biopsy. Chemotherapy with a combination of rituximab, fludarabine and cyclophosphamide improved the patient's symptoms and caused the pulmonary opacities to resolve. We discuss the various clinical and radiological pulmonary manifestations of this slowly progressive hematological condition., Conclusion: Pulmonary manifestations of Waldenström's macroglobulinemia result in various clinical and radiological patterns. A serum protein electrophoresis should be performed in cases of pleuropulmonary opacities persisting despite antibiotics., (Copyright © 2013 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Drug-induced infiltrative lung disease may manifest as variable clinical radiological patterns, including subacute or chronic interstitial pneumonia, pulmonary fibrosis, eosinophilic pneumonia, organising pneumonia, pulmonary edema, or sarcoidosis. A large amount of drugs have been incriminated, including those used in cardiovascular diseases (amiodarone, statins and angiotensin converting enzyme inhibitors), antibiotics (minocycline, nitrofurantoin), most of anticancer drugs (and especially chemotherapy and chest radiation), treatment of rheumatoid arthritis, as well as more recent drugs. A high index of suspicion is therefore required in any patient with infiltrative lung disease and the web-based tool www.pneumotox.com will help to list possible causative drugs. The following steps are necessary: history and timing of drug exposure, clinical and imaging pattern, exclusion of other causes of infiltrative lung disease, improvement following drug discontinuation. Rechallenge, dangerous, is not recommended.

Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by the proliferation of myofibroblasts and the accumulation of extracellular matrix (ECM) in the lungs. TGF-β1 is the major profibrotic cytokine involved in IPF and is responsible for myofibroblast proliferation and differentiation and ECM synthesis. αB-crystallin is constitutively expressed in the lungs and is inducible by stress, acts as a chaperone and is known to play a role in cell cytoskeleton architecture homeostasis. The role of αB-crystallin in fibrogenesis remains unknown. The principal signalling pathway involved in this process is the Smad-dependent pathway. We demonstrate here that αB-crystallin is strongly expressed in fibrotic lung tissue from IPF patients and in vivo rodent models of pulmonary fibrosis. We also show that αB-crystallin-deficient mice are protected from bleomycin-induced fibrosis. Similar protection from fibrosis was observed in αB-crystallin KO mice after transient adenoviral-mediated over-expression of IL-1β or TGF-β1. We show in vitro in primary epithelial cells and fibroblasts that αB-crystallin increases the nuclear localization of Smad4, thereby enhancing the TGF-β1-Smad pathway and the consequent activation of TGF-β1 downstream genes. αB-crystallin over-expression disrupts Smad4 mono-ubiquitination by interacting with its E3-ubiquitin ligase, TIF1γ, thus limiting its nuclear export. Conversely, in the absence of αB-crystallin, TIF1γ can freely interact with Smad4. Consequently, Smad4 mono-ubiquitination and nuclear export are favoured and thus TGF-β1-Smad4 pro-fibrotic activity is inhibited. This study demonstrates that αB-crystallin may be a key target for the development of specific drugs in the treatment of IPF or other fibrotic diseases., (Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Unlabelled: Since December 2009, chest physicians and allergologists in Burgundy have been able to call upon a medical indoor environment counsellor (MIEC). The consultations are free for the patient and are undertaken following a medical referal after systematic cutaneous prick tests., Aims: To describe the indications, the distribution of prescriptions and to measure the impact of the counsellor's visits on the first 100 patients at 6 months and on the physicians at 18 months., Method: Telephone interviews with the 67 physicians (whether prescribers or not) concerning their motivation and/or expectations, and with the first 100 patients concerning follow up of the recommendations., Results: Seventy percent of the physicians replied (n=47). The satisfaction of prescribers (n=22) was 8.42/10. The indications were rhinitis and a poorly controlled asthma. The requests concerned the search for dust mite (50%) and moulds (46%). Eighty-four percent of the physicians discussed the MIEC's report with the patients. The patients' symptoms were rhinitis (79%), asthma (57%) and conjunctivitis (33%). The Acarex test(®), performed in cases of positive prick tests to house dust mites (n=72), was strongly positive for 67 patients. Sixteen mould samples out of 21 were above the standard concentrations. Sixty-nine patients had followed the recommendations of the MIEC., Conclusion: The impact of the MIEC visits was perceived as positive by the physicians and the patients. The medico-economic impact warrants further evaluation., (Copyright © 2013 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Background: Case reports have suggested that the use of statins may be associated with an increase in the risk of interstitial lung disease (ILD)., Methods: Within a large cohort of users of respiratory medications identified in the Quebec health administrative databases during 1990-2005, we carried out a nested case-control analysis of the relationship between statins and the risk of ILD as defined by specialist visits or hospitalisations., Results: The cohort included over 1.4 million patients, of which 6665 possible or probable cases of ILD were identified during follow-up. These were compared with 26 660 controls matched for age, gender and calendar time. After adjustment for confounders and comorbid conditions, there was no association between current use of statins and risk of ILD (adjusted OR 0.99, 95% CI 0.91 to 1.08). The results were similar when any use of statins within the previous 1 or 2 years was considered or when the analysis was limited to more definite cases., Conclusions: This large cohort study did not find an association between statin use and the incidence of ILD.

Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by myofibroblast proliferation. Transition of epithelial/mesothelial cells into myofibroblasts [epithelial-to-mesenchymal transition (EMT)] occurs under the influence of transforming growth factor (TGF)-β1, with Snail being a major transcription factor. We study here the role of the heat-shock protein HSP27 in fibrogenesis and EMT. In vitro, we have up- and down-modulated HSP27 expression in mesothelial and epithelial cell lines and studied the expression of different EMT markers induced by TGF-β1. In vivo, we inhibited HSP27 with the antisense oligonucleotide OGX-427 (in phase II clinical trials as anticancer agent) in our rat subpleural/pulmonary fibrosis models. We demonstrate that HSP27 is strongly expressed during the fibrotic process in patients with IPF and in different in vivo models. We showed that HSP27 binds to and stabilizes Snail and consequently induces EMT. Conversely, HSP27 knockdown leads to Snail proteasomal degradation, thus inhibiting TGF-β1-induced EMT. Inhibition of HSP27 with OGX-427 efficiently blocks EMT and fibrosis development. Controls in vivo were an empty adenovirus that did not induce fibrosis and a control antisense oligonucleotide. The present work opens the possibility of a new therapeutic use for HSP27 inhibitors against IPF, for which there is no conclusively effective treatment.

Three weeks after single-lung transplantation for pulmonary fibrosis, a patient with high serum levels of de novo donor-specific antibodies received high-dose intravenous immunoglobulin (IVIG) infusion (scheduled dose: 2 g/kg on 2 days) to prevent antibody-mediated rejection. Within the first hours after completion of infusions, he experienced acute lung injury involving the transplanted lung. Given the clinical evolution and the absence of an alternative diagnosis, transfusion-related acute lung injury (TRALI) was diagnosed. The IVIG administered on each day was from the same batch. At day 110, because of an increase in the serum titers of donor-specific antibodies, IVIG therapy was reintroduced but from a different batch, with excellent clinical tolerance. The lung injury was explored biologically, but no mechanism was revealed. Given the increasing use of IVIG in solid-organ recipients, clinicians should be aware of possible TRALI after IVIG infusion., (© 2012 The Author(s). Vox Sanguinis © 2012 International Society of Blood Transfusion.)

Introduction: Atrophic polychondritis is a rare and serious disease characterised by multifocal inflammatory lesions of cartilage. The diagnosis, though urgent, is difficult when there is isolated tracheal involvement., Case Report: We report the case of a woman of 55 with recent, non-infectious febrile episodes accompanied by a steroid sensitive inflammatory syndrome. Auscultation, lung function tests and a thoracic CT scan suggested tracheobronchomalacia. Atrophic polychondritis was suspected without being confirmed on the basis of histological or biological tests; particularly as no other cartilaginous involvement was discovered. Laryngeal and tracheal hypermetabolism on a PET scan, performed in the absence of corticosteroid treatment, was also in favour of this diagnosis. One month after resumption of steroid treatment at increased dosage, this examination was normal. Secondarily, after careful reduction of steroids, the patient developed nasal chondritis, confirming the diagnosis of atrophic polychondritis., Conclusion: The PET scanner could be useful in the diagnosis of atrophic polychondritis in its isolated tracheobronchial form. Its place in the follow-up of this disease remains to be evaluated and should take account of the irradiation dose of this examination., (Copyright © 2012 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

The administration of mammalian target of rapamycin (mTOR) inhibitors can give rise to a potentially life-threatening adverse event, often referred to as 'non-infectious pneumonitis' (NIP), which is characterized by non-infectious, non-malignant, and non-specific inflammatory infiltrates. Patients usually present with cough and/or dyspnoea. We provide a brief description of the mechanism of action of mTOR inhibitors and their overall safety in patients with metastatic renal cell carcinoma (mRCC) and review the literature on mTOR inhibitor-associated NIP in patients with solid tumours. The review was used to derive questions on the diagnosis, management, and monitoring of mRCC patients with NIP, and to develop a decision tree for use in routine clinical practise. A key recommendation was the subdivision of grade 2 NIP into grades 2a and 2b, where grade 2a is closer to grade 1 and grade 2b to grade 3. This subdivision is important because it takes into account the nature and severity of clinical symptoms potentially related to NIP, either the onset of new symptoms or the worsening of existing symptoms, and thus determines the type and frequency of follow-up. It also helps to identify a subgroup of patients in whom treatment, if effective, may be continued without dose adjustment.

Rationale: Noninfectious pneumonitis is a known class effect of mammalian target of rapamycin (mTOR) inhibitors., Objectives: To assess the incidence, radiographic patterns, management, and outcome of pneumonitis in patients with advanced renal cell carcinoma receiving everolimus., Methods: Clinical study data from 416 patients, randomized to receive everolimus versus placebo, were analyzed for adverse events of pneumonitis. Radiographic studies performed every 8 weeks were subject to a prospective, independent, blinded central review for the presence of findings indicative of pneumonitis., Measurements and Main Results: Of 274 patients receiving everolimus, clinical pneumonitis was suspected for 37 patients (13.5%) (none with placebo). Nine cases (3.3%) were grade 1 (asymptomatic), 18 (6.6%) were grade 2 (not interfering with daily living), and 10 (3.6%) were grade 3 (interfering with daily living or oxygen indicated). No grade 4 (life-threatening) pneumonitis was observed. Of the 10 patients with grade 3 pneumonitis, 5 had baseline radiological evidence of pneumonitis before everolimus therapy. Twenty of the 37 cases (54.0%) were reversible within the follow-up period; resolution followed dose reduction for 20 patients and treatment discontinuation in 10 patients. Corticosteroid therapy was initiated in 16 cases. Dedicated radiological review of available serial radiographic studies (245 patients receiving everolimus and 132 receiving placebo) found a higher percentage of new radiographic findings even in patients without a diagnosis of clinical pneumonitis who were receiving everolimus versus placebo (38.9 vs. 15.2%)., Conclusions: Early recognition, prompt intervention, and a conservative approach are important in managing the risk associated with noninfectious pneumonitis in association with everolimus. Clinical trial registered with www.clinicaltrials.gov (NCT 00410124).

The pathological changes in idiopathic pulmonary fibrosis (IPF) typically start in subpleural lung regions, a feature that is currently not explained. IPF, as well as bleomycin-induced lung fibrosis, are more common in smokers. We hypothesised that carbon particles, which are major components of cigarette smoke that are transported to alveoli and pleural surface, might be involved in the development of subpleural fibrosis through interaction with pleural mesothelial cells. Carbon particles were administered to mice in combination with bleomycin through intratracheal and/or intrapleural injection and fibrosis was assessed using histomorphometry. Carbon administered to the chest cavity caused severe pleural fibrosis in the presence of bleomycin, whereas bleomycin alone had no fibrogenic effect. The pleural response was associated with progressive fibrosis in subpleural regions, similar to IPF in humans. Matrix accumulation within this area evolved through mesothelial-fibroblastoid transformation, where mesothelial cells acquire myofibroblast characteristics. In contrast, carbon did not exaggerate bleomycin-induced pulmonary fibrosis after combined intratracheal administration. This represents a novel approach to induce a robust experimental model of pleural fibrosis. It also suggests that carbon particles might be involved as a cofactor in the initiation and/or progression of (subpleural) pulmonary and pleural fibrosis. Mesothelial cells appear to be critical contributors to this fibrotic process.

The rapid advance and falling costs of computing power and data storage during the last 40 years have greatly enhanced the data reduction speed and analytical capacity of energy dispersive spectroscopy (EDS) systems. At the same time, the solid state X-ray detector [until recently, the Si(Li) diode] has seen performance increases due to the use of advanced materials and processing techniques. In addition, the performance of the electronic components (field effect transistor, preamp, and pulse processor) of an EDS system has been constantly improved. These technology advances have resulted in improved spectral quality, excellent light element detection, and increased count rate performance. The results have been truly remarkable and driven by the needs of the analyst. This article will summarize the progress made in these areas in the last 40 years and make a brief reference to prospects for future development in EDS system performance.