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Patient-reported outcome measures (PROMs), tools to assess patient self-report of health status, are now increasingly used in research, care and policymaking. While there are two well-developed disease-specific PROMs for interstitial lung diseases (ILD) and idiopathic pulmonary fibrosis (IPF), many unmet and urgent needs remain. In December 2019, 64 international ILD experts convened in Erice, Italy to deliberate on many topics, including PROMs in ILD. This review summarises the history of PROMs in ILD, shortcomings of the existing tools, challenges of development, validation and implementation of their use in clinical trials, and the discussion held during the meeting. Development of disease-specific PROMs for ILD including IPF with robust methodology and validation in concordance with guidance from regulatory authorities have increased user confidence in PROMs. Minimal clinically important difference for bidirectional changes may need to be developed. Cross-cultural validation and linguistic adaptations are necessary in addition to robust psychometric properties for effective PROM use in multinational clinical trials. PROM burden of use should be reduced through appropriate use of digital technologies and computerised adaptive testing. Active patient engagement in all stages from development, testing, choosing and implementation of PROMs can help improve probability of success and further growth.

Supported by the National Health and Medical Research Council Centre of Research Excellence in Pulmonary Fibrosis (GNT1116371), and by foundation partner, Boehringer Ingelheim, and program partners, Roche and Galapagos. Rationale : The interstitial lung disease (ILD) multidisciplinary meetings (MDM), composed of pulmonologists, radiologists, and pathologists, is integral to the rendering of an accurate ILD diagnosis. However, there is significant heterogeneity in the conduct of ILD MDMs, and questions regarding their best practices remain unanswered. Objectives : To achieve consensus among ILD experts on essential components of an ILD MDM. Methods : Using a Delphi methodology, semi-structured interviews with ILD experts were used to identify key themes and features of ILD MDMs. These items informed two subsequent rounds of online questionnaires that were used to achieve consensus among a broader, international panel of ILD experts. Experts were asked to rate their level of agreement on a five-point Likert scale. An a priori threshold for consensus was set at a median score 4 or 5 with an interquartile range of 0. Results : We interviewed 15 ILD experts, and 102 ILD experts participated in the online questionnaires. Five items and two exploratory statements achieved consensus on being essential for an ILD MDM following two questionnaire rounds. There was consensus that the presence of at least one radiologist, a quiet setting with a visual projection system, a high-quality chest high-resolution computed tomography, and a standardized template summarizing collated patient data are essential components of an ILD MDM. Experts also agreed that it would be useful for ILD MDMs to undergo an annual benchmarking process and a validation process by fulfilling a minimum number of cases annually. Twenty-seven additional features were considered to be either highly desirable or desirable features based on the degree of consensus. Although our findings on desirable features are similar to the current literature, several of these remain controversial and warrant further research. The study also showed an agreement among participants on several future concepts to improve the ILD MDM, such as performing regular self-assessments and conducting research into shared practices to develop an international expert guideline statement on ILD MDMs. Conclusions : This Delphi study showed consensus among international ILD experts on essential and desirable features of an ILD MDM. Our data represent an important step toward potential collaborative research into future standardization of ILD MDMs. Postprint

Permanent pacemaker implantation (PPI) represents a rare complication after cardiac surgery, with no uniform agreement on timing and no information on follow-up. A multi-center retrospective study was designed to assess pacemaker dependency (PMD) and long-term mortality after cardiac surgery procedures. Between 2004 and 2016, PPI-patients from 18 centers were followed. Time-to-event data were evaluated with semiparametric regression Cox models and semiparametric Fine and Gray model for competing risk framework. Of 859 (0.90%) PPI-patients, 30% were pacemaker independent (PMI) at 6 months. PMD showed higher mortality compared with PMI (10-year survival 80.1% +/- 2.6% and 92.2% +2.4%, respectively, log-rank p-value < 0.001) with an unadjusted hazard ratio for death of 0.36 (95% CI 0.20 to 0.65, p< 0.001 favoring PMI) and an adjusted hazard ratio of 0.19 (95% CI 0.08 to 0.45, p< 0.001 with PMD as reference). Crude cumulative incidence function of restored PMI rhythm at follow-up at 6 months, 1 year and 12 years were 30.5% (95% CI 27.3% to 33.7%), 33.7% (95% CI 30.4% to 36.9%) and 37.2% (95% CI 33.8% to 40.6%) respectively. PMI was favored by preoperative sinus rhythm with normal conduction (SR) (HR 2.37, 95% CI 1.65 to 3.40, p< 0.001), whereas coronary artery bypass grafting and aortic valve replacement were independently associated with PMD (HR 0.63, 95% CI 0.45 to 0.88, p = 0.006 and HR 0.807, 95% CI 0.65 to 0.99, p = 0.047 respectively). Time-to-implantation was not associated with increased rate of PMI. Although 30% of PPI-patients are PMI after 6 months, PMD is associated with higher mortality at long term. (C) 2020 The Author(s). Published by Elsevier Inc.

Neurological manifestations, such as encephalitis, meningitis, ischemic, and hemorrhagic strokes, are reported with increasing frequency in patients affected by Coronavirus disease 2019 (COVID-19). In children, acute ischemic stroke is usually multifactorial: viral infection is an important precipitating factor for stroke. We present a case of a child with serological evidence of SARS-CoV-2 infection whose onset was a massive right cerebral artery ischemia that led to a malignant cerebral infarction. The patient underwent a life-saving decompressive hemicraniectomy, with good functional recovery, except for residual hemiplegia. During rehabilitation, the patient also developed a lower extremity peripheral nerve neuropathy, likely related to a long-Covid syndrome.

Nine participants undergoing primary TKA submitted to spinal anesthesia, sedation, ultrasound-guided obturator and Femoral nerve Block analgesia, and photobiomodulation Therapy (FBMT) were evaluated regarding postoperative pain and morphine consumption. FBMT sessions were performed in the Immediate Postoperative period (IPO) and after 24 hours. Participants received 16.7±15 mg of morphine up to the third postoperative day. At IPO, mean pain score was 4.8 ± 3.2 and 5.6 ± 3.5, at rest and on movement, respectively. Photo biomodulation therapy can be considered an option for mitigating pain for patients undergoing TKA.

Poster Abstract

BackgroundThe impact of transcranial magnetic stimulation (TMS) on cortical neurons is currently hard to predict based on a priori biophysical and anatomical knowledge alone. This problem can hamper the reliability and reproducibility of protocols aimed at measuring electroencephalographic (EEG) responses to TMS.New MethodWe introduce and release a novel software tool to facilitate and standardize the acquisition of TMS-evoked potentials (TEPs). The tool, rt-TEP (real-time TEP), interfaces with different EEG amplifiers and offers a series of informative visualization modes to assess in real time the immediate impact of TMS on the underlying neuronal circuits.ResultsWe show that rt-TEP can be used to abolish or minimize magnetic and muscle artifacts contaminating the post-stimulus period thus affording a clear visualization and quantification of the amplitude of the early (Comparison with Existing MethodsThe ensemble of real-time visualization modes of rt-TEP are not implemented in any current commercial software and provide a key readout to titrate TMS parameters beyond the a priori information provided by anatomical models.ConclusionsReal-time optimization of stimulation parameters with rt-TEP can facilitate the acquisition of reliable TEPs with a high signal-to-noise ratio and improve the standardization and reproducibility of data collection across laboratories.Highlightsrt-TEP provides an immediate EEG readout to assess the quality of TEPs in real timert-TEP interfaces with most commercial EEG systemsInformative, real time visualization allows maximising the cortical impact of TMS while minimizing artifactsrt-TEP facilitates the acquisition of reliable TEPs with a high signal-to-noise ratio

Background: Shp1, a tyrosine-phosphatase-1 containing the Src-homology 2 (SH2) domain, is involved in inflammatory and immune reactions, where it regulates diverse signalling pathways, usually by limiting cell responses through dephosphorylation of target molecules. Moreover, Shp1 regulates actin dynamics. One Shp1 target is Src, which controls many cellular functions including actin dynamics. Src has been previously shown to be activated by a signalling cascade initiated by the cytosolic-phospholipase A2 (cPLA2) metabolite glycerophosphoinositol 4-phosphate (GroPIns4P), which enhances actin polymerisation and motility. While the signalling cascade downstream Src has been fully defined, the mechanism by which GroPIns4P activates Src remains unknown. Methods: Affinity chromatography, mass spectrometry and co-immunoprecipitation studies were employed to identify the GroPIns4P-interactors; among these Shp1 was selected for further analysis. The specific Shp1 residues interacting with GroPIns4P were revealed by NMR and validated by site-directed mutagenesis and biophysical methods such as circular dichroism, isothermal calorimetry, fluorescence spectroscopy, surface plasmon resonance and computational modelling. Morphological and motility assays were performed in NIH3T3 fibroblasts. Results: We find that Shp1 is the direct cellular target of GroPIns4P. GroPIns4P directly binds to the Shp1-SH2 domain region (with the crucial residues being Ser 118, Arg 138 and Ser 140) and thereby promotes the association between Shp1 and Src, and the dephosphorylation of the Src-inhibitory phosphotyrosine in position 530, resulting in Src activation. As a consequence, fibroblast cells exposed to GroPIns4P show significantly enhanced wound healing capability, indicating that GroPIns4P has a stimulatory role to activate fibroblast migration. GroPIns4P is produced by cPLA2 upon stimulation by diverse receptors, including the EGF receptor. Indeed, endogenously-produced GroPIns4P was shown to mediate the EGF-induced cell motility. Conclusions: This study identifies a so-far undescribed mechanism of Shp1/Src modulation that promotes cell motility and that is dependent on the cPLA2 metabolite GroPIns4P. We show that GroPIns4P is required for EGF-induced fibroblast migration and that it is part of a cPLA2/GroPIns4P/Shp1/Src cascade that might have broad implications for studies of immune-inflammatory response and cancer. [Figure not available: see fulltext.]

Background The World Health Organization (WHO) declared a global pandemic of Covid-19 on 11 March 2020. The lockdown caused a lifestyle changes: an increase in the use of mobile media devices (MMDs), sleep and psychiatric disorders, incorrect habits regarding food and physical activities. We investigate prevalence of admission for seizures at our emergency department (ED), during Italian lockdown, comparing with that of the same period of the previous year (2019), and the relationship with some lifestyle changes. Methods In this observational study, patients (4–14 years) with seizures that accessed at our ED, during Italian lockdown, were eligible. Non-epileptic events and febrile seizures were excluded. We describe two groups: patients with new-onset seizures and not. Moreover, a questionnaire concerning use of MMDs and sleep habits was administered. Results Fifty-seven patients were included; median age 8.03 years. Considering only paediatric medical emergencies, the prevalence of accesses for seizures was 2.6% (CI 95% 0.020–0.034), while the incidence was 0.94% (CI 95% 0.006–0.0149). There was a statistically significant difference with prevalence of previous years, χ2 102.21 (p = 0.0001). We also reported a difference in daily screen time (DST) (p = 0.001) and total sleep time (TST) (p = 0.045), in all population, between period pre- and during lockdown. A negative correlation between DST and seizures latency (Spearman’s ρ -0.426, p = 0.038) was found. In the two groups, the results were partially overlapping. Conclusions During lockdown period, we assisted to an increase of accesses for seizures. It is conceivable that a sleep time change and/or higher MMD use could act as triggers for seizures.

Fibrotic hypersensitivity pneumonitis is a complex interstitial lung disease that is not entirely understood. In its chronic and fibrotic form, hypersensitivity pneumonitis is one of the main mimickers of idiopathic pulmonary fibrosis (IPF). Distinguishing between these two conditions is challenging but is of particular clinical relevance. Two approved therapies are available for IPF, and a considerable number of clinical trials are now exploring newer pharmacological options. This impressive research effort is a consequence of new pathogenetic understanding, updated diagnostic criteria and a long history of pharmacological trials. Conversely, current knowledge gaps on pathogenesis of chronic hypersensitivity pneumonitis, coupled with lack of validated diagnostic criteria, make the management of this disease an unsolved clinical challenge. This also reflects the paucity of therapeutic clinical trials in this field. In this review, we describe the current evidence and the possible future options to approach this complex disease.

Surrogacy is an arrangement by which a surrogate mother bears a child for another couple or person, and is often thought of as a form of 'treatment' for couples (or even individuals) with fertility or sterility issues. Still, surrogacy entails ethical issues related to gender, fundamental human rights, exploitation and inequality.Starting from the Italian state of affairs, the authors have set out to briefly expound upon such complexities, taking into account relevant jurisprudence on the subject, with a particular focus on inter-country surrogacy and second-parent adoption, which can themselves engender significant legal dilemmas. When residents of countries where surrogacy is banned travel abroad and hire a surrogate, that may lead to considerable legal hurdles as well.In Italy and elsewhere, the courts have all too often had to fill the vacuum left by the lack of targeted legislation. The Italian Constitutional Court has recently urged lawmakers to enact new legislation to uphold the minor's best interests. In fact, while some countries recognise the surrogate as the legal parent, others ascribe parenthood to the commissioning parents. That discrepancy can lead to a 'clash of laws', resulting in children ending up stateless and unable to maintain an already established family relationship.Just like fundamental protection of human rights and public health, the regulation of revolutionary technologies that change the very notion of reproduction, parenthood, and human identity needs to be governed by uniform standards, shared at least by nations which espouse common core values.

Simultaneous administration of different vaccines is a strategy to increase the possibility to receive vaccines at appropriate age, safely and effectively, reducing the number of sessions and allowing a more acceptable integration of new vaccines into National Immunization Programs (NIPs). Co-administration can be performed when there are specific indications in the Summary of Product Characteristics (SmPC) of the vaccines; but, in absence of these indications, the practice is possible if there are no specific contraindications nor scientific evidence to discourage simultaneous administration. The aim of this work is to review the safety and efficacy of co-administration of the tetravalent measles, mumps, rubella, and varicella (MMRV) and the meningococcal C (Men C) conjugate vaccines after 12 months of age. Several studies demonstrated that MMRV and Men C conjugate vaccines can be administered concomitantly without a negative impact on the safety and immunogenicity of either vaccines, inducing highly immunogenic responses.

© 2019 John Wiley & Sons Ltd Aims and objectives: To review and synthesise research studies on surgical and medical inpatients’ perceptions on unmet nursing care needs. Background: Missed nursing care is a growing phenomenon that has been shown to adversely affect care outcomes—mainly in adult medical and surgical care settings. However, to date the aggregated and synthesised evidence of missed care comes from research that measures perceptions on missed care in surgical and medical settings from nurses, but not from the patients. Design: Scoping review. Methods: In September 2018, three databases were searched: MEDLINE/PubMed, CINAHL and SCOPUS and papers were selected using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Inclusion criteria were as follows: primary studies; published in peer-reviewed journals; in English or Italian; and regarding routine care provided to adult inpatients. Quality appraisal and a thematic analysis were conducted. Results: Of the 1541 abstracts initially identified, 44 papers were included. Five themes emerged: “communication,” “self-management, autonomy and education,” “personal sphere,” “essential physical care” and “emotional and psychological care.” The majority of the unmet needs were related to the “personal sphere” and “emotional and psychological care.” These unmet needs were not identified in previous literature on nurses’ perspectives of missed care. Also, physical care deficits like oral hygiene were identified. Conclusion: It is important to take into account patients’ perspectives. The themes focusing on patients’ personal sphere, and emotional and psychological care, underline how patients need nurses to pay more attention to their cultural background, consider the person as a whole and for nursing care to be holistic and respectful of patients’ dignity. Relevance to Clinical Practice: This study intends to raise awareness amongst nurses and policymakers about the importance of addressing missed nursing care and unmet patients’ needs in adult medical or surgical inpatient settings to ensure high-quality care and patient satisfaction.

The olive tree (Olea europaea L.) even though has both hermaphrodite and staminate flowers, it has mechanisms favoring the allogamy, being not advisable the monovarietals orchards planting. The pollination of olive trees is anemophilous, and produce a large amounts of pollen grains, dispersed throughout the atmosphere during the bloom. The economic viability of the olive oil is dependent of the fruit production and several factors can affect its fruit set. This study aimed understand the relationship of reproductive biology with fruit production in olive trees, in Southern Brazil. The study was carried out in a commercial olive grove located in Barra do Ribeiro (RS), whit seven year-old, in the years 2016-2017. The olive grove was formed for Koroneiki, Arbequina and Arbosana cultivars, spacing 5x7 m. It was evaluated the number of inflorescences per branch, number of flowers per inflorescence, number of hermaphrodite flowers, quality of pollen and the kind of pollination. ’Arbosana’ had the biggest number of flowers per inflorescence. ‘Arbequina’ had a higher percentage of hermaphrodite flowers than ‘Korneiki’ in both years, no differing of ‘Arbosana‘ in 2017. It has reduction of percentage of hermaphrodite flowers to ‘Koroneiki’ and ‘Arbequina’, in the second year. In the yeard 2017 there was reduction on the pollen viability, biggest in ‘Koroneiki’. Independent of cultivar, the open pollination provides bigger fructification. The fruit set in ‘Koroneiki’ was bigger than ‘Arbequina’. The measured parameters were not determinant for fruiting of the olive trees studied.

Background Guillain-Barre syndrome (GBS) is the broad term used to describe a number of related acute autoimmune neuropathies, which together form a continuous spectrum of variable and overlapping syndromes. Bifacial weakness with paresthesias (BFP) is a rare variant of GBS, characterized by isolated facial diplegia in the absence of ophthalmoplegia, ataxia, or limb weakness, and it is usually associated with distal limb paresthesias. Case description An 8-year-old boy was brought to our attention; because 5 days before coming to the hospital, he noticed he could no longer smile. Bilateral facial droop and inability to close both eyes were evident along with slight paresthesias at the hands and feet and gait disturbances. He progressively developed hypophonia, dysarthria, dysphagia associated with dysmetria, and limb ataxia. Nerve conduction studies showed a demyelinating polyneuropathy. Brain and spine magnetic resonance imaging (MRI) revealed contrast enhancement of both facial nerves and cauda equina nerve roots along with a hyperintense signal of the periaqueductal gray matter, superior cerebellar peduncles, and pontine tegmentum. Because BFP is not typically associated with other cranial neuropathies or ataxia, these clinical features along with peculiar MRI findings supported the diagnosis of "BFP plus." Finally, it can be speculated that this case configures a rare overlap between BFP and the other GBS variants, such as Bickerstaff encephalitis. Conclusions This atypical case underlines the potential role of MRI in contributing to refining the nosological classification of GBS spectrum and optimizing individual treatment, especially in children where unusual manifestations are not infrequent and neurological examination is more challenging.

Variants in SURF1, encoding an assembly factor of mitochondrial respiratory chain complex IV, cause Leigh syndrome (LS) and Charcot-Marie-Tooth type 4K in children and young adolescents. Magnetic resonance imaging (MRI) appearance of enlarged nerve roots with postcontrastographic enhancement is a distinctive feature of hypertrophic neuropathy caused by onion-bulb formation and it has rarely been described in mitochondrial diseases (MDs). Spinal nerve roots abnormalities on MRI are novel findings in LS associated with variants in SURF1. Here we report detailed neuroradiological and neurophysiologic findings in a child with LS and demyelinating neuropathy SURF1-related. Our case underlines the potential contributive role of spinal neuroimaging together with neurophysiological examination to identify the full spectrum of patterns in MDs. It remains to elucidate if these observations remain peculiar of SURF1 variants or potentially detectable in other MDs with peripheral nervous system involvement.

The main challenge in the clinical assessment of Psychogenic Non-Epileptic Seizures (PNES) is the lack of an electroencephalographic marker in the electroencephalography (EEG) readout. Although decades of EEG studies have focused on detecting cortical brain function underlying PNES, the principle of PNES remains poorly understood. To address this problem, electric potentials generated by large populations of neurons were collected during the resting state to be processed after that by Power Spectrum Density (PSD) for possible analysis of PNES signatures. Additionally, the integration of distributed information of regular and synchronized multi-scale communication within and across inter-regional brain areas has been observed using functional connectivity tools like Phase Lag Index (PLI) and graph-derived metrics. A cohort study of 20 PNES and 19 Healthy Control subjects (HC) were enrolled. The major finding is that PNES patients exhibited significant differences in alpha-power spectrum in brain regions related to cognitive operations, attention, working memory, and movement regulation. Noticeably, we observed that there exists an altered oscillatory activity and a widespread inter-regional phase desynchronization. This indicates changes in global efficiency, node betweenness, shortest path length, and small worldness in the delta, theta, alpha, and beta frequency bands. Finally, our findings look into new evidence of the intrinsic organization of functional brain networks that reflects a dysfunctional level of integration of local activity across brain regions, which can provide new insights into the pathophysiological mechanisms of PNES.

Background: Interstitial lung diseases (ILDs) are often associated with rheumatic diseases. Their early diagnosis and management are not only difficult, but also crucial, because they are associated with major morbidity and mortality and can be the first cause of death in autoimmune rheumatic diseases (ARDs).Objectives: By using methodologies, such as Nominal Group Technique (NGT) and Delphi Survey, the aims of this study were (1) to measure consensus between pulmonologists, radiologists, and rheumatologists experienced in the management of ARD-ILD; (2) to highlight the importance of a multidisciplinary approach; and (3) to provide clinicians with a practical tool aimed at improving the prompt recognition and follow-up of ILD associated with ARDs and of any possible rheumatic conditions underlying ILD.Results: During the NGT round, the Steering Committee defined 57 statements to be used in the Delphi survey. A total of 78 experts participated in the Delphi survey, namely 28 pulmonologists, 33 rheumatologists, and 17 radiologists. During this round, consensus on agreement was reached in 47 statements, while disagreement was not reached in any statements. A secondary questionnaire was drafted by the Steering Committee to obtain clearer indications on ILD-ARD “red-flags” and follow-up. Delphi Panelists took part also in the second-questionnaire survey. Answers from both surveys were used to draft two checklists of “red flags” sign or symptom suggestive of ILD and ARD, respectively, and two checklists on identification and monitoring of rheumatoid arthritis (RA) and systemic sclerosis (SSc) ILD.Limitations: This study is a consensus work, which cannot produce empiric data, and is limited to the Italian scenario.Conclusions: This work showed a high level of agreement, but also shows some divergent opinions between different experts. This underlines the importance of a multidisciplinary approach. Eventually, we believe the drafted checklists can help clinicians in the diagnosis and follow-up of ILD-ARD.

The COVID-19 pandemic is impressively challenging the healthcare system. Several prognostic models have been validated but few of them are implemented in daily practice. The objective of the study was to validate a machine-learning risk prediction model using easy-to-obtain parameters to help to identify patients with COVID-19 who are at higher risk of death. The training cohort included all patients admitted to Fondazione Policlinico Gemelli with COVID-19 from March 5, 2020, to November 5, 2020. Afterward, the model was tested on all patients admitted to the same hospital with COVID-19 from November 6, 2020, to February 5, 2021. The primary outcome was in-hospital case-fatality risk. The out-of-sample performance of the model was estimated from the training set in terms of Area under the Receiving Operator Curve (AUROC) and classification matrix statistics by averaging the results of fivefold cross validation repeated 3-times and comparing the results with those obtained on the test set. An explanation analysis of the model, based on the SHapley Additive exPlanations (SHAP), is also presented. To assess the subsequent time evolution, the change in paO2/FiO2 (P/F) at 48 h after the baseline measurement was plotted against its baseline value. Among the 921 patients included in the training cohort, 120 died (13%). Variables selected for the model were age, platelet count, SpO2, blood urea nitrogen (BUN), hemoglobin, C-reactive protein, neutrophil count, and sodium. The results of the fivefold cross-validation repeated 3-times gave AUROC of 0.87, and statistics of the classification matrix to the Youden index as follows: sensitivity 0.840, specificity 0.774, negative predictive value 0.971. Then, the model was tested on a new population (n = 1463) in which the case-fatality rate was 22.6%. The test model showed AUROC 0.818, sensitivity 0.813, specificity 0.650, negative predictive value 0.922. Considering the first quartile of the predicted risk score (low-risk score group), the case-fatality rate was 1.6%, 17.8% in the second and third quartile (high-risk score group) and 53.5% in the fourth quartile (very high-risk score group). The three risk score groups showed good discrimination for the P/F value at admission, and a positive correlation was found for the low-risk class to P/F at 48 h after admission (adjusted R-squared = 0.48). We developed a predictive model of death for people with SARS-CoV-2 infection by including only easy-to-obtain variables (abnormal blood count, BUN, C-reactive protein, sodium and lower SpO2). It demonstrated good accuracy and high power of discrimination. The simplicity of the model makes the risk prediction applicable for patients in the Emergency Department, or during hospitalization. Although it is reasonable to assume that the model is also applicable in not-hospitalized persons, only appropriate studies can assess the accuracy of the model also for persons at home.

Background Invadopodia are actin-based cell-membrane protrusions associated with the extracellular matrix degradation accompanying cancer invasion. The elucidation of the molecular mechanisms leading to invadopodia formation and activity is central for the prevention of tumor spreading and growth. Protein tyrosine kinases such as Src are known to regulate invadopodia assembly, little is however known on the role of protein tyrosine phosphatases in this process. Among these enzymes, we have selected the tyrosine phosphatase Shp1 to investigate its potential role in invadopodia assembly, due to its involvement in cancer development. Methods Co-immunoprecipitation and immunofluorescence studies were employed to identify novel substrate/s of Shp1AQ controlling invadopodia activity. The phosphorylation level of cortactin, the Shp1 substrate identified in this study, was assessed by immunoprecipitation, in vitro phosphatase and western blot assays. Short interference RNA and a catalytically-dead mutant of Shp1 expressed in A375MM melanoma cells were used to evaluate the role of the specific Shp1-mediated dephosphorylation of cortactin. The anti-invasive proprieties of glycerophosphoinositol, that directly binds and regulates Shp1, were investigated by extracellular matrix degradation assays and in vivo mouse model of metastasis. Results The data show that Shp1 was recruited to invadopodia and promoted the dephosphorylation of cortactin at tyrosine 421, leading to an attenuated capacity of melanoma cancer cells to degrade the extracellular matrix. Controls included the use of short interference RNA and catalytically-dead mutant that prevented the dephosphorylation of cortactin and hence the decrease the extracellular matrix degradation by melanoma cells. In addition, the phosphoinositide metabolite glycerophosphoinositol facilitated the localization of Shp1 at invadopodia hence promoting cortactin dephosphorylation. This impaired invadopodia function and tumor dissemination both in vitro and in an in vivo model of melanomas. Conclusion The main finding here reported is that cortactin is a specific substrate of the tyrosine phosphatase Shp1 and that its phosphorylation/dephosphorylation affects invadopodia formation and, as a consequence, the ability of melanoma cells to invade the extracellular matrix. Shp1 can thus be considered as a regulator of melanoma cell invasiveness and a potential target for antimetastatic drugs.

Medical guidelines on diagnosis and management of relevant diseases aim to recommend clinical practice while standardising patient care. However, evidence-based guideline development is laborious and challenging, the recommendations require nuanced wording, and the optimal approach remains controversial. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Funke-Chambour reports grants from roche, grants and personal fees from Boehringer Ingelheim, outside the submitted work;. Dr. Funke-Chambour reports grants from roche, grants and personal fees from Boehringer Ingelheim, outside the submitted work;. Conflict of interest: Dr. Albera reports personal fees from Roche, personal fees from Boheringer Ingelheim, personal fees from Fibrogen, personal fees from MSD, personal fees from Bayer, personal fees from GSK, grants from Roche, grants from Boheringer Ingelheim, during the conduct of the study;. Conflict of interest: Dr. Bendstrup reports grants, personal fees and non-financial support from Boehringer Ingelheim, grants, personal fees and non-financial support from Hoffmann la Roche, outside the submitted work;. Conflict of interest: Dr. Costabel reports personal fees and non-financial support from Boehringer, personal fees and non-financial support from Roche, personal fees from Fibrogen, personal fees from Pliant Therapeutics, personal fees from Bristol-Myers Squibb, personal fees from Astra Zeneca, personal fees from Novartis, outside the submitted work;. Conflict of interest: Dr. Grutters has nothing to disclose. Conflict of interest: Dr. Harari reports personal fees from Roche, grants and personal fees from Actelion and Boehringer Ingelheim, outside the submitted work;. Conflict of interest: Dr. Johannson reports personal fees, non-financial support and other from Boehringer-Ingelheim, personal fees from Hoffman-La Roche Ltd., grants from The Chest Foundation, grants from University of Calgary Cumming School of Medicine, personal fees from Blade Therapeutics, personal fees from Theravance, personal fees and non-financial support from Three Lakes Foundation, grants from UCB Biopharma SPRL, grants from Pulmonary Fibrosis Society of Calgary, outside the submitted work;. Conflict of interest: Dr. Kreuter reports grants and personal fees from Boehringer Ingelheim, grants and personal fees from Roche, personal fees from Galapagos, outside the submitted work;. Conflict of interest: Dr. Strambu reports personal fees from Boehringer Ingelheim, personal fees from Boehringer Ingelheim, personal fees from Roche Pharma, personal fees from Astra Zeneca, personal fees from Novartis, personal fees from Galapagos, outside the submitted work;. Conflict of interest: Dr. Vancheri reports grants and personal fees from Roche, grants and personal fees from Boehringer Ingelheim, outside the submitted work;. Conflict of interest: Dr. Varone reports personal fees from Boehringer Ingelheim and Roche, outside the submitted work. Conflict of interest: Dr. Vitulo has nothing to disclose. Conflict of interest: Dr. wuyts reports grants from roche, grants from Boehringer Ingelheim, outside the submitted work and payed to my institution;. Conflict of interest: Dr. Martinez reports personal fees, non-financial support and other from AtraZeneca, other from Afferent/Merck, personal fees, non-financial support and other from Boheringer Ingelheim, other from Bristol Myers Squibb, other from Chiesi, personal fees and non-financial support from Canadian Respiratory Society, personal fees and non-financial support from CME Outfitters, personal fees and non-financial support from CSL Behring, personal fees from Dartmouth University, personal fees from France Foundation, personal fees from Gala, personal fees and non-financial support from Genentech, grants, personal fees, non-financial support and other from GlaxoSmithKline, personal fees and non-financial support from Inova Fairfax, personal fees and non-financial support from MDMagazine, personal fees and non-financial support from NYP Methodist Hospital Brooklyn, personal fees and non-financial support from Miller Communications, personal fees and non-financial support from National Association for Continuing Education, other from Nitto, personal fees and non-financial support from Novartis, personal fees from New York University, personal fees and non-financial support from Patara/Respivant, personal fees from Pearl, personal fees and non-financial support from Peer View, personal fees from Physicians Education Resource, personal fees from ProMedior, personal fees and non-financial support from Rare Diseases Healthcare Communications, personal fees from Rockpointe Communications, personal fees and non-financial support from Sanofi/Regeneron, other from Biogen, personal fees and non-financial support from Sunovion, personal fees and non-financial support from Teva, other from twoXR, personal fees from University of Birmingham Alabama, personal fees from UpToDate, non-financial support from Veracyte, personal fees from Vindico, personal fees and non-financial support from WebMD/MedScape, non-financial support and other from Zambon, non-financial support from ProTerrix Bio, personal fees from IQVIA, outside the submitted work;. Conflict of interest: Dr. Raghu reports personal fees and other from Boerhinger Ingelheim, Roche, Respivant and Veracyte ;other from Avalyn, BMS, Biogen, Blade therapeutics Bellerophan, Fibrogen, Gilead, Genentech, Nitto, Promedior, and grants from NIH, outside the submitted work.

Arsenite induces many critical effects associated with the formation of reactive oxygen species (ROS) through different mechanisms. We focused on the Ca2+-dependent mitochondrial superoxide (mitoO2-.) formation and addressed questions on the effects of low concentrations of arsenite on the mobilization of the cation from the endoplasmic reticulum and the resulting mitochondrial accumulation. Using various differentiated and undifferentiated cell types uniquely expressing the inositol-1, 4, 5-triphosphate receptor (IP3R), or both the IP3R and the ryanodine receptor (RyR), we determined that expression of this second Ca2+ channel is an absolute requirement for mitoO2-. formation and for the ensuing mitochondrial dysfunction and downstream apoptosis. In arsenite-treated cells, RyR was recruited after IP3R stimulation and agonist studies indicated that in these cells RyR is in close apposition with mitochondria. It was also interesting to observe that arsenite fails to promote mitochondrial Ca2+ accumulation, mitoO2-. formation, mitochondrial toxicity in RyR-devoid cells, in which the IP3R is in close contact with the mitochondria. We therefore conclude that low dose arsenite-induced mitoO2- formation and the resulting mitochondrial dysfunction and toxicity, are prerequisite of cell types expressing the RyR in close apposition with mitochondria.

Oxygen therapy through a high-flow nasal cannula is thought to improve the work of breathing and the comfort of patients with acute bronchiolitis. It is widely used in hospital wards and critical care of pediatric patients. However, there is uncertainty on the magnitude of the effect on critical and important outcomes in these patients.The objective of this review is to evaluate the available evidence on the use of oxygen administered through high-flow cannula versus low-flow oxygen for the treatment of acute bronchiolitis in children under two years of age.We carried out a systematic review and a meta-analysis following the PRISMA standards for reporting. The search was carried out in electronic databases by two researchers independently. The evidence was summarized using the GRADE methodology.Six randomized and non-randomized clinical trials were included, including 1867 individuals younger than 24 months of age with acute bronchiolitis in pediatric emergency, hospitalization, and intensive care services. Mortality was not reported in the included studies. Treatment failure occurred in 108/933 in the high flow group and 233/934 in the low flow group (relative risk: 0.46; 95% confidence interval: 0.35 to 0.62), which shows 11.7% less treatment failure (95% confidence interval between 7.9% and 14.5% less) in the high flow group with a number needed to treat of 7.5 (95% confidence interval 6 to 10) with moderate certainty in the evidence.The use of humidified and heated oxygen with high flow compared to oxygen at low flow is probably associated with decreased treatment failure in children younger than two years with acute bronchiolitis. There is uncertainty about the effect on hospitalization days and clinical progression.La terapia con oxígeno a través de cánula nasal de alto flujo actuaría mejorando el trabajo de la respiración y el confort de los pacientes con bronquiolitis aguda. Su uso se encuentra ampliamente difundido en distintas áreas de internación y cuidados críticos de pacientes pediátricos. Sin embargo, existe incertidumbre en la magnitud del efecto en desenlaces críticos e importantes en estos pacientes.Evaluar la evidencia disponible acerca del uso de oxígeno administrado a través de cánulas de alto flujo, frente a oxígeno a bajo flujo para el tratamiento de la bronquiolitis aguda en menores de dos años.Realizamos una revisión sistemática y metanálisis siguiendo los estándares PRISMA para el reporte de la misma. La búsqueda fue realizada en bases de datos electrónicas por dos investigadores de forma independiente. La evidencia fue resumida utilizando la metodología GRADE.Se incluyeron seis ensayos clínicos aleatorizados y no aleatorizados, incluyendo 1867 individuos menores de 24 meses de edad con bronquiolitis aguda en servicios de emergencias, internación y cuidados intensivos pediátricos. La mortalidad no fue reportada en los estudios incluidos. El fracaso del tratamiento ocurrió en 108/933 en el grupo alto flujo y 233/934 en el grupo bajo flujo (riesgo relativo: 0,46; intervalo de confianza 95%: 0,35 a 0,62), lo que muestra 11,7% menos fracaso de tratamiento (intervalo de confianza 95%: entre 7,9% y 14,5% menos) en el grupo alto flujo con un número necesario a tratar de 7,5 (de 6 a 10) con moderada certeza en la evidencia.La utilización de oxígeno humidificado y calentado con alto flujo en comparación con el oxígeno a bajo flujo probablemente se asocie con una disminución del fracaso de tratamiento en niños menores de dos años con bronquiolitis aguda. Existe incertidumbre en el efecto sobre los días de internación y puntajes clínicos de progresión.

Rib fractures are common injuries associated with significant morbidity and mortality, largely due to pulmonary complications. Despite equivocal effectiveness data, incentive spirometers are widely utilized to reduce pulmonary complications in the postoperative setting. Few studies have evaluated the effectiveness of incentive spirometry after rib fracture. Multiple investigations have demonstrated incentive spirometry to be an important screening tool to identify high-risk rib fracture patients who could benefit from aggressive, multidisciplinary pulmonary complication prevention strategies. This review evaluates the epidemiology of rib fractures, their associated pulmonary complications, along with the evidence for optimizing their clinical management through the use of incentive spirometry, multimodal analgesia, and surgical fixation.

Transcranial magnetic stimulation (TMS) excites neurons in the cortex, and neural activity can be simultaneously recorded using electroencephalography (EEG). However, TMS-evoked EEG potentials (TEPs) do not only reflect transcranial neural stimulation as they can be contaminated by artifacts. Over the last two decades, significant developments in EEG amplifiers, TMS-compatible technology, customized hardware and open source software have enabled researchers to develop approaches which can substantially reduce TMS-induced artifacts. In TMS-EEG experiments, various physiological and external occurrences have been identified and attempts have been made to minimize or remove them using online techniques. Despite these advances, technological issues and methodological constraints prevent straightforward recordings of early TEPs components. To the best of our knowledge, there is no review on both TMS-EEG artifacts and EEG technologies in the literature to-date. Our survey aims to provide an overview of research studies in this field over the last 40 years. We review TMS-EEG artifacts, their sources and their waveforms and present the state-of-the-art in EEG technologies and front-end characteristics. We also propose a synchronization toolbox for TMS-EEG laboratories. We then review subject preparation frameworks and online artifacts reduction maneuvers for improving data acquisition and conclude by outlining open challenges and future research directions in the field.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the novel coronavirus disease 2019 (COVID-19) pandemic, which spread throughout the world. Acute hypoxemic respiratory failure is the most dangerous complication of COVID-19 pneumonia. To date, no specific therapeutic drugs or vaccines have been proven efficacious. Ventilatory support is still a significant challenge for physicians facing COVID-19. The mechanisms underlying hypoxemia in those patients are not fully understood, but a new physiopathology model has been proposed. Oxygen therapy should be delivered to patients with mild to moderate hypoxemia. More severe patients could benefit from other treatments (high-flow nasal cannula, noninvasive ventilation or intubation, and invasive ventilation). Given the rapid evolution of COVID-19, there has been a paucity of the high-quality data that typically inform clinical practice guidelines from professional societies, and a worldwide consensus is still lacking. This chapter aims to illustrate the potentials of ventilatory support as therapeutic options for adult and pediatric patients affected by COVID-19 pneumonia.

Introduction The novel coronavirus SARS-Cov-2 can infect the respiratory tract causing a spectrum of disease varying from mild to fatal pneumonia, and known as COVID-19. Ongoing clinical research is assessing the potential for long-term respiratory sequelae in these patients. We assessed the respiratory function in a cohort of patients after recovering from SARS-Cov-2 infection, stratified according to PaO2/FiO2 (p/F) values. Method Approximately one month after hospital discharge, 86 COVID-19 patients underwent physical examination, arterial blood gas (ABG) analysis, pulmonary function tests (PFTs), and six-minute walk test (6MWT). Patients were also asked to quantify the severity of dyspnoea and cough before, during, and after hospitalization using a visual analogic scale (VAS). Seventy-six subjects with ABG during hospitalization were stratified in three groups according to their worst p/F values: above 300 (n = 38), between 200 and 300 (n = 30) and below 200 (n = 20). Results On PFTs, lung volumes were overall preserved yet, mean percent predicted residual volume was slightly reduced (74.8 ± 18.1%). Percent predicted diffusing capacity for carbon monoxide (DLCO) was also mildly reduced (77.2 ± 16.5%). Patients reported residual breathlessness at the time of the visit (VAS 19.8, p Conclusion Approximately one month after hospital discharge, patients with COVID-19 can have residual respiratory impairment, including lower exercise tolerance. The extent of this impairment seems to correlate with the severity of respiratory failure during hospitalization.

A new coronavirus respiratory disease (COVID-19) caused by the SARS-CoV-2 virus, surprised the entire world, producing social, economic, and health problems. The COVID-19 triggers a lung infection with a multiple proinflammatory cytokine storm in severe patients. Without effective and safe treatments, COVID-19 has killed thousands of people, becoming a pandemic. Stem cells has been suggested as a therapy for lung related diseases. In particular, mesenchymal stem cells (MSCs) have been successfully tested in some clinical trials in patients with COVID-19. The encouraging results positioned MSCs as a possible cell therapy for COVID-19. The amniotic membrane from human placenta at term is a valuable stem cell source, including human amniotic epithelial cells (hAECs) and human mesenchymal stromal cells (hAMSCs). Interestingly, amnion cells have immunoregulatory, regenerative, and anti-inflammatory properties. Moreover, hAECs and hAMSCs have been used both in preclinical studies and in clinical trials against respiratory diseases. They have reduced the inflammatory response and restored the pulmonary tissue architecture in lung-injury in vivo models. Here, we review the existing data about the stem cells use for COVID-19 treatment, including the ongoing clinical trials. We also consider the non-cellular therapies that are being applied. Finally, we discuss the human amniotic membrane cells use in patients who suffer from immune/inflammatory lung diseases and hypothesize their possible use as a successful treatment against COVID-19. Fil: Riedel, Rodrigo Nicolas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Pérez Pérez, Antonio. Universidad de Sevilla; España Fil: Sánchez Margalet, Victor S. Universidad de Sevilla; España Fil: Varone, Cecilia Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Maymo, Julieta Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina

COVID-19, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, showed higher severity and lethality in male older adults . There are currently no specific treatments. Studies are evaluating the efficacy of monoclonal antibodies against interleukin-6 receptor. Here we present the case of a 98-years old man admitted to our COVID-Hospital with acute respiratory failure. Comprehensive geriatric assessment showed no signs of frailty. First-line therapy with hydroxychloroquine and anticoagulants was not effective. Patient was administered intravenous monoclonal antibodies, and he showed remarkable clinical improvement. This case suggests that age alone should not preclude access to new therapeutic approaches. Comprehensive, multisciplinary, multidomain approaches are needed to develop patient-tailored treatments against COVID-19.

Background Coronary artery ectasia (CAE) is a relatively frequent finding in patient with ST-elevation myocardial infarction (STEMI) who undergo emergent coronary angiography. However, the long-term outcome of STEMI patients with CAE as compared to Non-CAE has been poorly investigated. Purpose To compare the baseline features and outcome of patients with and without CAE in the clinical setting of STEMI. Methods All patients with STEMI who underwent emergent coronary angiography from January 2012 to December 2017 at our Institution were retrospectively enrolled. Baseline demographic, clinical, instrumental, angiographic and percutaneous coronary intervention (PCI) findings were collected for patients with and without CAE. The study outcome measures were recurrent myocardial infarction (MI) and all-cause death. The propensity score weighting (PSW) technique was used to take into account for potential selection bias in treatment assignment between CAE and Non-CAE groups. Results The study included 534 patients with STEMI (mean age 62.9±12.0 years), 154 were CAE and 380 Non-CAE. The two groups were significantly different in terms of sex (90.9% in CAE vs 72,6% in Non-CAE, p The survival free from recurrent MI was lower, although not statistically significant, in CAE vs. Non-CAE patients (3.1/100 person/years vs. 4.8/100 person/years; Log-Rank = 0.068). After PSW, an optimal balance was obtained as demonstrated by a standardized mean difference Conclusions Patient with STEMI and angiographic evidence of CAE have a different clinical profile compared to Non-CAE. In this analysis focused on STEMI patients, CAE was associated with a higher risk of recurrent MI at long-term follow-up. Funding Acknowledgement Type of funding source: None

Inflammatory responses are elicited through lipid products of phospholipase A2 activity that acts on the membrane phospholipids, including the phosphoinositides, to form the pro-inflammatory arachidonic acid and, in parallel, the glycerophosphoinositols. Here, we investigate the role of the glycerophosphoinositol in inflammatory response. We show that it is part of a negative-feedback loop that limits pro-inflammatory and pro-thrombotic responses in human monocytes stimulated with lipopolysaccharide. This inhibition is exerted both on the signaling cascade initiated by the lipopolysaccharide with the glycerophosphoinositol-dependent decrease in IKKalpha/beta, p38, JNK and Erk1/2 kinases phosphorylation and at the nuclear level with decreased NF-kappaB translocation and binding to inflammatory gene promoters. In a model of endotoxaemia in the mouse, treatment with glycerophosphoinositol reduced TNF-alpha synthesis, which supports the concept that glycerophosphoinositol inhibits the de-novo synthesis of pro-inflammatory and pro-thrombotic compounds and might thus have a role as an endogenous mediator in the resolution of inflammation. As indicated, this effect of glycerophosphoinositol can also be exploited in the treatment of the manifestations of severe inflammation, by exogenous administration of the compound.

Background Idiopathic pulmonary fibrosis (IPF) is a complex disease with a highly variable clinical course and generally poor prognosis. Classified as a rare disease, significant increases in incidence have been recorded worldwide in recent years. Left untreated IPF is extremely debilitating with substantial personal, social and economic implications. Objectives To discuss how IPF is diagnosed and managed in real life clinical practice with particular reference to Italy and to determine how new and effective therapies can be incorporated into a patient-centred management approach in order to improve the lives of patients with IPF. Outcomes Barriers to early diagnosis are discussed. Cited reasons for delays in diagnosing IPF in Italy include: inherent difficulties in diagnosis; lack of knowledge/awareness of the condition among point-of-contact healthcare professionals; delays in referral to centres of excellence and underestimation of symptoms by both patients and healthcare workers. Valid therapeutic options with demonstrated efficacy in slowing the decline in lung function are now available for patients with IPF. The ASCEND trial confirmed the effects of pirfenidone, approved for the treatment of IPF on the basis of the four phase III trials. Nintedanib, a tyrosine kinase inhibitor that targets the PDGF receptors α/β, FGF receptors 1 to 3, and VEGF receptors 1–3, is approved in the USA and the EU for the treatment of IPF. The TOMORROW and the INPULSIS placebo controlled trials in patients with IPF confirm the efficacy and safety of nintedanib and recent interim analyses endorse its long-term effects in slowing disease progression. Conclusions The importance of early and accurate diagnosis of IPF cannot be underestimated and it is the duty of all healthcare professionals to be vigilant to the symptoms of IPF and to involve a multidisciplinary team in diagnosing and managing IPF early in the course of disease.

Background and objective In clinical practice, a working diagnosis of IPF may be performed to provide effective antifibrotic treatment to patients who cannot undergo SLB. In this study, we compared the disease course across IPF diagnostic categories in a real-life clinical setting to clarify the appropriateness of a working diagnosis of IPF and treatment initiation in these patients. Methods Longitudinal data from IPF patients receiving antifibrotic treatment (pirfenidone or nintedanib) were retrospectively collected at three tertiary centres in Italy. Univariate and multivariate analyses were performed to compare time to death and to a composite endpoint of disease progression between two diagnostic subgroups, that is, patients with UIP on HRCT and/or SLB, and patients with possible UIP and no histological confirmation. Results A total of 249 IPF patients were included in the analysis. Among patients with a possible UIP pattern on HRCT, 41 (55%) were prescribed antifibrotic treatment (either nintedanib or pirfenidone) despite absence of histological confirmation. This group demonstrated similar mortality and disease progression as compared to patients with a definite diagnosis of IPF as per diagnostic guidelines (log-rank test P = 0.771 and P = 0.139, respectively). Such findings were confirmed on multivariate analysis (HR: 1.19, 95% CI: 0.49-2.89, P = 0.7 for death; HR: 1.42, 95% CI: 0.83-2.44, P = 0.201 for disease progression). Conclusion In patients receiving antifibrotics following a working diagnosis of IPF, disease progression rates were similar to patients with a confident diagnosis of IPF according to consensus guidelines, supporting the rationale for treatment initiation in these patients by expert multidisciplinary teams.

Introduction: Idiopathic Pulmonary Fibrosis (IPF) is a fibrotic interstitial lung disease (ILD) with unknown pathogenesis and poor prognosis. Unpredictable events defined as Acute Exacerbations (AE-IPF) may be experienced up to one in five IPF patients. The hallmark is a rapid respiratory failure not fully explained by heart failure/infections and associated with new lung infiltrates. Guidelines recommended treatment with steroids despite a lack of solid evidence. Aims: To compare survival of AE-IPF patients treated with methylprednisolone to those not treated with steroids. Methods: Retrospective analysis of IPF patients admitted to the pulmonary ward from 1 Jan 2014 through 15 Jan 2020. A case-by-case record review was performed. Survival was analyzed using Cox regression and Kaplan-Meier. Results: We admitted 119 ILD patients due and 73 (61.3%) had IPF. We analyzed 26 (35.6%) AE-IPF subjects. Males were predominant (80.1%) with a mean age of 73.2 years and mostly smokers (63.2%). We administered steroid in 12 subjects (46.2%). 10 AE-IPFs died during hospitalization. No association between steroid and mortality was identified either during in-hospital stay (HR 0.81; CI 0.21-3.10; p=0.76). Conclusions: We found no association between corticosteroid use and improved survival in subjects with AE-IPF. Large, controlled-studies are needed to address this unsolved problem. To date, the decision to use steroids remains difficult

Viral-induced exacerbation of asthma remains a major cause of hospitalization and mortality. New human-relevant models of the airways are urgently needed to understand how respiratory infections may trigger asthma attacks and to advance treatment development. Here, we describe a new human-relevant model of rhinovirus-induced asthma exacerbation that recapitulates viral infection of asthmatic airway epithelium and neutrophil transepithelial migration, and enables evaluation of immunomodulatory therapy. Specifically, a microengineered model of fully differentiated human mucociliary airway epithelium was stimulated with IL-13 to induce a T-helper cell type 2 asthmatic phenotype and infected with live human rhinovirus 16 (HRV16) to reproduce key features of viral-induced asthma exacerbation. We observed that the infection with HRV16 replicated key hallmarks of the cytopathology and inflammatory responses observed in human airways. Generation of a T-helper cell type 2 microenvironment through exogenous IL-13 stimulation induced features of asthmatic airways, including goblet cell hyperplasia, reduction of cilia beating frequency, and endothelial activation, but did not alter rhinovirus infectivity or replication. High-resolution kinetic analysis of secreted inflammatory markers revealed that IL-13 treatment altered IL-6, IFN-λ1, and CXCL10 secretion in response to HRV16. Neutrophil transepithelial migration was greatest when viral infection was combined with IL-13 treatment, whereas treatment with MK-7123, a CXCR2 antagonist, reduced neutrophil diapedesis in all conditions. In conclusion, our microengineered Airway Lung-Chip provides a novel human-relevant platform for exploring the complex mechanisms underlying viral-induced asthma exacerbation. Our data suggest that IL-13 may impair the hosts' ability to mount an appropriate and coordinated immune response to rhinovirus infection. We also show that the Airway Lung-Chip can be used to assess the efficacy of modulators of the immune response.

Multidisciplinary team (MDT) discussion is the gold standard in the management of interstitial lung disease (ILD). The rheumatologist is not routinely involved in MDT, even if up to 20% of ILD are related to systemic autoimmune rheumatic diseases (SARD). The study aims to assess the agreement and its variation over time between rheumatologists and pulmonologists in the screening of SARD and between rheumatologists and an MDT extended to rheumatologists (eMDT) in evaluating the progression of SARD. We computed the agreement between the pulmonologist and rheumatologist in the identification of red flags for SARDs of 81 ILD cases and between the rheumatologist alone and eMDT in the confirmation of 70 suspected SARD-ILD progressions. The agreement between rheumatologists and pulmonologists was moderate for the detection of autoimmunity test positivity (&kappa, = 0.475, p &lt, 0.001) and family history of SARD (&kappa, = 0.491, p &lt, 0.001) and fair for the identification of extrapulmonary symptoms (&kappa, = 0.225, p = 0.064) or routine laboratory abnormalities consistent with SARD. The average agreement between the rheumatologist and eMDT in the identification of ILD progression was moderate (&kappa, = 0.436, p &lt, 0.001). The class of agreement improved from the first to the third semester. The average agreement with the rheumatologist ranged from fair to moderate, suggesting that a shared evaluation of SARD-ILD in eMDT could improve the diagnostic work-up and the evaluation of ILD progression.

SummarySolid tumors are often characterized by a hypoxic microenvironment which contributes, through the hypoxia-inducible factor HIF-1, to the invasion-metastasis cascade. Endoplasmic reticulum (ER) stress also leads tumor cells to thrive and spread by inducing a transcriptional and translational program, the Unfolded Protein Response (UPR), aimed at restoring ER homeostasis. We studied ERO1 alpha (henceforth ERO1), a protein disulfide oxidase with the tumor-relevant characteristic of being positively regulated by both ER stress and hypoxia. Analysis of the redox secretome indicated that pro-angiogenic HIF-1 targets, were blunted in ERO1-devoid breast cancer cells under hypoxic conditions. ERO1 deficiency reduced tumor cell migration and lung metastases by impinging on tumor angiogenesis, negatively regulating the upstream ATF4/CHOP branch of the UPR and selectively impeding oxidative folding of angiogenic factors, among which VEGF-A. Thus, ERO1 deficiency acted synergistically with the otherwise feeble curative effects of anti-angiogenic therapy in aggressive breast cancer murine models and it might be exploited to treat cancers with pathological HIF-1-dependent angiogenesis. Furthermore, ERO1 levels are higher in the more aggressive basal breast tumors and correlate inversely with the disease- and metastasis-free interval of breast cancer patients. Thus, taking advantage of our in vitro data on ERO1-regulated gene products we identified a gene set associated with ERO1 expression in basal tumors and related to UPR, hypoxia, and angiogenesis, whose levels might be investigated in patients as a hallmark of tumor aggressiveness and orient those with lower levels toward an effective anti-angiogenic therapy.