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The TAM tyrosine kinases, Axl and MerTK, play an important role in rheumatoid arthritis (RA). Here, using a unique synovial tissue bioresource of patients with RA matched for disease stage and treatment exposure, we assessed how Axl and MerTK relate to synovial histopathology and disease activity, and their topographical expression and longitudinal modulation by targeted treatments. We show that in treatment-naive patients, high AXL levels are associated with pauci-immune histology and low disease activity and inversely correlate with the expression levels of pro-inflammatory genes. We define the location of Axl/MerTK in rheumatoid synovium using immunohistochemistry/fluorescence and digital spatial profiling and show that Axl is preferentially expressed in the lining layer. Moreover, its ectodomain, released in the synovial fluid, is associated with synovial histopathology. We also show that Toll-like-receptor 4-stimulated synovial fibroblasts from patients with RA modulate MerTK shedding by macrophages. Lastly, Axl/MerTK synovial expression is influenced by disease stage and therapeutic intervention, notably by IL-6 inhibition. These findings suggest that Axl/MerTK are a dynamic axis modulated by synovial cellular features, disease stage and treatment. The TAM tyrosine kinases, Axl and MerTK, have been implicated in rheumatoid arthritis (RA). Here, using a synovial tissue bioresource of patients with RA, the authors describe how Axl and MerTK expression and function are linked to synovial histopathology, disease activity, and therapeutic intervention with IL-6 inhibitors. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is one of the major causes of morbidity and mortality worldwide. Hospitalization due to acute exacerbations of COPD (AECOPD) is a relevant health problem both for its impact on disease outcomes and on health system resources. Severe AECOPD causing acute respiratory failure (ARF) often requires admission to an intensive care unit (ICU) with endotracheal intubation and invasive mechanical ventilation. AECOPD also acts as comorbidity in critically ill patients; this condition is associated with poorer prognoses. The prevalence reported in the literature on ICU admission rates ranges from 2 to 19% for AECOPD requiring hospitalization, with an in-hospital mortality rate of 20–40% and a re-hospitalization rate for a new severe event being 18% of the AECOPD cases admitted to ICUs. The prevalence of AECOPD in ICUs is not properly known due to an underestimation of COPD diagnoses and COPD misclassifications in administrative data. Non-invasive ventilation in acute and chronic respiratory failure may prevent AECOPD, reducing ICU admissions and disease mortality, especially when associated with a life-threating episode of hypercapnic ARF. In this review, we report on up to date evidence from the literature, showing how improving the knowledge and management of AECOPD is still a current research issue and clinical need. [ABSTRACT FROM AUTHOR]

Introduction: While selected clinical and laboratory findings are taken into account to find the best therapeutic strategies for chronic obstructive pulmonary disease (COPD), it is unknown whether the circadian rhythm of respiratory symptoms, a distinctive feature of COPD, affects the prescription pattern of pharmacological therapy. The main aim of this study was to verify whether the circadian rhythm of symptoms correlates with bronchodilating therapy prescribed to COPD patients as per clinical practice. A secondary objective was to assess the relationship between Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage and circadian rhythm of symptoms and health status. Methods: Five hundred sixty-six COPD patients were enrolled in the Italian multicenter STORICO study. Patients underwent a multidimensional assessment, and correlates of prescribed therapy were assessed through a multivariate multilevel model. Results: As expected, patients in GOLD D stage were more likely to receive triple inhaled therapy than GOLD A–C patients, but the circadian rhythm of symptoms, assessed by the nighttime, morning, and daytime symptoms of the COPD questionnaire, was unrelated to the prescription pattern. The multivariate model showed that emphysematous (EM) patients had a 50% increased risk compared with patients affected by chronic bronchitis (CB) of being prescribed long-acting β2-agonists (LABA)/long-acting muscarinic antagonist (LAMA) fixed-dose combination (FDC) instead of triple therapy [relative risk (RR) EM versus CB 1.50, 95% CI 1.11, 2.03]. Symptoms, mainly in the early morning and daytime, were highly prevalent, even in GOLD B stage (76%). Conclusion: Even if we cannot infer about causality of the symptoms–therapy relationship, based on the structured recording of circadian symptoms clearly shows that symptoms are poorly controlled as the circadian rhythm of symptoms does not correlate with the prescription pattern, and many patients are symptomatic both at daytime and by nighttime. Thus, therapy should be better tailored to the individual needs, with special attention to control nocturnal symptoms. Trial Registration: ClinicalTrials.gov identifier, NCT03105999. [ABSTRACT FROM AUTHOR]

Background/aims Although an increasing volume of research is emerging, rehabilitative treatment of patients with COVID-19 still continues to be a matter of great importance that must be explored further. The purpose of the present study was to describe the effects of inpatient rehabilitation in acute patients treated in a sub-intensive hospital setting during the COVID-19 pandemic. Methods A retrospective analysis was conducted based on the prospectively collected data of 192 patients with COVID-19 undergoing a physiotherapeutic regimen during their hospitalisation. Patients were admitted because of COVID-19-related pneumonia from the periods of 25 March-12 June 2020 and 2 November 2020-9 June 2021. This study investigated dyspnoea intensity using the modified Borg scale, motor function through the 1-minute sit-to-stand test, and daily walked distance. In a subset of 57 patients, handgrip strength and respiratory muscle function was also evaluated. Measurements were taken at baseline and discharge. Results Patients were classified according to the severity of their ratio of arterial oxygen partial pressure to fractional inspired oxygen (mean 225 ± 82 mmHg). At discharge to home or to another hospital facility, patients performed a mean of 12 repetitions (1-minute sit-to-stand test); dyspnoea intensity was 1.4 (modified Borg scale), and they were able to walk a mean distance of 266.7 metres. The mean handgrip strength of the dominant hand was 29.3 kg, the maximal inspiratory pressure was 43.5 cmH2O, and the maximal expiratory pressure was 59.1 cmH2O. Overall, significant differences before and after treatment were detected for all clinical variables. Dyspnoea improved by 0.7 points; walked distance by 200 metres; the number of repetitions at the 1-minute sit-to-stand test by 5.6; the handgrip strength by 1.2 kg (right hand) and 1.7 kg (left hand); maximal inspiratory pressure by 7.7 cmH2O; and maximal expiratory pressure by 9.5 cmH2O. Conclusions Patients obtained significant improvements in functional capacity, dyspnoea perception, handgrip strength and respiratory muscle function. In addition, the treatment was feasible and well tolerated by patients, and no adverse related events were observed in a sub-intensive care setting. [ABSTRACT FROM AUTHOR]

For over 15 years, thoracic ultrasound has been applied in the evaluation of numerous lung diseases, demonstrating a variable diagnostic predictive power compared to traditional imaging techniques such as chest radiography and CT. However, in unselected pulmonary patients, there are no rigorous scientific demonstrations of the complementarity of thoracic ultrasound with traditional and standardized imaging techniques that use radiation. In this study 101 unselected pulmonary patients were evaluated blindly with ultrasound chest examinations during their hospital stay. Other instrumental examinations, carried out during hospitalization, were standard chest radiography, computed tomography (CT), and, when needed, radioisotopic investigation and cardiac catheterization. The operator who performed the ultrasound examinations was unaware of the anamnestic and clinical data of the patients. Diffuse fibrosing disease was detected with a sensitivity, specificity and diagnostic accuracy of 100%, 95% and 97%, respectively. In pleural effusions, ultrasound showed a sensitivity, specificity and diagnostic accuracy of 100%. In consolidations, the sensitivity, specificity and diagnostic accuracy were 83%, 98% and 93%, respectively. Low values of sensitivity were recorded for surface nodulations of less than one centimeter. Isolated subpleural ground glass densities were identified as White Lung with a sensitivity of 72% and a specificity of 86%. Only the associations Diffuse ultrasound findings/Definitive fibrosing disease, Ultrasound Consolidation/Definitive consolidation and non-diffuse ultrasound artefactual features/Definitive vascular pathology (pulmonary hypertension, embolism) were statistically significant with adjusted residuals of 7.9, 7 and 4.1, respectively. The obtained results show how chest ultrasound is an effective complementary diagnostic tool for the pulmonologist. When performed, as a complement to the patient's physical examination, it can restrict the diagnostic hypothesis in the case of pleural effusion, consolidation and diffuse fibrosing disease of the lung. [ABSTRACT FROM AUTHOR]

Background: Few studies have reported a double-step follow-up of patients after hospitalization for COVID-19. Objectives: We designed an observational double-step follow-up study with a clinical, functional, and radiological evaluation at 2 and 6 months after COVID-19. The primary outcome was to describe symptoms, spirometry, and 6-minute walking test (6MWT) at 2 and 6 months. Secondary outcomes were to identify if the lowest PaO2/FiO2 during hospitalization is related with functional and radiological evolution and to assess the correlation between radiological and functional abnormalities at 6 months. Methods: Symptoms, spirometry, and 6MWT were assessed at 2 and 6 months; arterial blood gas, chest x-ray, and lung ultrasound were performed at 2 months; body plethysmography, diffusing capacity for carbon monoxide (DLCO), and CT scan were performed at 6 months. Results: Sixty-four per cent and 42% of patients reported at least one symptom at 2 and 6 months, respectively. The most common 6-month functional alteration was DLCO impairment (57% of patients). An improvement of FEV1, FVC, and 6MWT was observed between 2 and 6 months (p < 0.001). Patients with PaO2/FiO2 <200 during hospitalization performed worse at 6MWT at 2 and 6 months (p < 0.05) and reported more extended radiological abnormalities at 6 months (p < 0.001) compared with patients with PaO2/FiO2>200. At 6 months, more extended radiological abnormalities were related with worse 6MWT, DLCO, and total lung capacity (p < 0.05). Discussion: DLCO and 6MWT impairment seem to be the functional hallmark of COVID-19 and are related with the severity of acute pneumonia. At 6 months, radiological abnormalities were related to functional impairment. [ABSTRACT FROM AUTHOR]

The author offers observation on the association between physical and respiratory exercise and thalassotherapy. Topics discussed include positive effects of thalassotherapy on lung diseases, aspects of exercise provided in different pulmonary settings explored by rehabilitation research, and possible reason for the lack of research on the association between physical and respiratory exercise and thalassotherapy.

Background: Pulmonary arterial hypertension (PAH) is characterized by the right ventricle (RV) remodeling and pulmonary endothelial dysfunction. We studied cardiac perfusion and innervation in PAH with a cadmium-zinc-telluride (CZT) scanner and lung uptake impairment of 123I-metaiodobenzylguanidine (123I-MIBG).Methods: In 13 patients with newly diagnosed PAH and 11 dilated cardiomyopathies (DCM, for comparative purposes), we assessed early and delayed 123I-MIBG uptake ratios of lung-to-mediastinum (L/M) and heart-to-mediastinum (H/M) on anterior planar images. A quantitative myocardial innervation with 123I-MIBG and perfusion with 99mTc-tetrofosmin using CZT-SPECT was performed. All patients underwent right heart catheterization.Results: Early and delayed L/M ratios in PAH were lower than DCM (1.47 ± 0.14 vs 1.98 ± 0.11 and 1.40 ± 0.13 vs 1.83 ± 0.09; P < .001), while early and delayed H/M were impaired but not different (1.73 ± 0.20 vs 1.65 ± 0.18 and 1.73 ± 0.27 vs 1.58 ± 0.19). RV perfusion and early innervation were significantly higher in PAH compared to DCM (68.4 ± 13.4 vs 28.6 ± 4.1 and 58.8 ± 9.3 vs 27 ± 2.2; P < .001); delayed RV innervation was not evaluable. RV/LV perfusion and innervation ratios were significantly related (R = 0.74; P < .0001) and had a significant correlation with clinical, hemodynamic, and morpho-functional parameters, including L/M ratios.Conclusion: Cardio-pulmonary scintigraphy through a perfusion and innervation study is feasible and may identify pulmonary vascular and RV remodeling, as in PAH. [ABSTRACT FROM AUTHOR]

Aims: This study aimed to evaluate a novel echocardiographic algorithm for quantitative estimation of pulmonary artery wedge pressure (PAWP) and pulmonary vascular resistance (PVR) in patients with heart failure and pulmonary hypertension (PH) scheduled to right heart catheterization (RHC). Methods and results: In this monocentric study, 795 consecutive patients (427 men; age 68.4 ± 12.1 years) undergoing echocardiography and RHC were evaluated. Multiple regression analysis was performed to identify echocardiographic predictors of PAWP and PVR measured by RHC in the derivation group (the first 200 patients). The diagnostic accuracy of the model was then tested in the validation group (the remaining 595 patients). PH was confirmed by RHC in 507 (63.8%) patients, with 192 (24.2%) cases of precapillary PH, 248 (31.2%) of postcapillary PH, and 67 (8.4%) of combined PH. At regression analysis, tricuspid regurgitation maximal velocity, mitral E/e′ ratio, left ventricular ejection fraction, right ventricular fractional area change, inferior vena cava diameter, and left atrial volume index were included in the model (R = 0.8, P < 0.001). The model showed a high diagnostic accuracy in estimating elevated PAWP (area under the receiver operating characteristic curve = 0.97, 92% sensitivity, and 93% specificity, P < 0.001) and PVR (area under the receiver operating characteristic curve = 0.96, 89% sensitivity, and 92% specificity, P < 0.001), outperforming 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging recommendations (P < 0.001) and Abbas' equation (P < 0.001). Bland–Altman analysis showed satisfactory limits of agreement between echocardiography and RHC for PAWP (bias 0.7, 95% confidence interval −7.3 to 8.7) and PVR (bias −0.1, 95% confidence interval −2.2 to 1.9 Wood units), without indeterminate cases. Conclusions: A novel quantitative echocardiographic approach for the estimation of PAWP and PVR has high diagnostic accuracy in patients with heart failure and PH. [ABSTRACT FROM AUTHOR]

Background: Systemic Sclerosis (SSc) is a chronic autoimmune disease with a complex pathogenesis that includes vascular injury, abnormal immune activation, and tissue fibrosis. We provided a complete epidemiological characterization of SSc in the Tuscany region (Italy), considering prevalence and incidence, survival, comorbidities and drug prescriptions, by using a multi-database population-based approach. Cases of SSc diagnosed between 1st January 2003 and 31st December 2017 among residents in Tuscany were collected from the population-based Rare Diseases Registry of Tuscany. All cases were linked to regional health and demographic databases to obtain information about vital statistics, principal causes of hospitalization, complications and comorbidities, and drug prescriptions.Results: The prevalence of SSc in Tuscany population resulted to be 22.2 per 100,000, with the highest prevalence observed for the cases aged ≥ 65 years (33.2 per 100,000, CI 95% 29.6-37.3). In females, SSc was predominant (86.7% on the total) with an overall sex ratio F/M of 6.5. Nevertheless, males presented a more severe disease, with a lower survival and significant differences in respiratory complications and metabolic comorbidities. Complications and comorbidities such as pulmonary involvement (HR = 1.66, CI 95% 1.17-2.35), congestive heart failure (HR = 2.76, CI 95% 1.80-4.25), subarachnoid and intracerebral haemorrhage (HR = 2.33, CI 95% 1.21-4.48) and malignant neoplasms (HR = 1.63, CI 95% 1.06-2.52), were significantly associated to a lower survival, also after adjustment for age, sex and other SSc-related complications. Disease-modifying antirheumatic drugs, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors were the drugs with the more increasing prevalence of use in the 2008-2017 period.Conclusions: The multi-database approach is important in the investigation of rare diseases where it is often difficult to provide accurate epidemiological indicators. A population-based registry can be exploited in synergy with health databases, to provide evidence related to disease outcomes and therapies and to assess the burden of disease, relying on a large cohort of cases. Building an integrated archive of data from multiple databases linking a cohort of patients to their comorbidities, clinical outcomes and survival, is important both in terms of treatment and prevention. [ABSTRACT FROM AUTHOR]

Objectives: To explore the relevance of T-follicular-helper (Tfh) and pathogenic peripheral-helper T-cells (Tph) in promoting ectopic lymphoid structures (ELS) and B-cell mucosa-associated lymphoid tissue (MALT) lymphomas (MALT-L) in Sjögren's syndrome (SS) patients.Methods: Salivary gland (SG) biopsies with matched peripheral blood were collected from four centres across the European Union. Transcriptomic (microarray and quantitative PCR) analysis, FACS T-cell immunophenotyping with intracellular cytokine detection, multicolor immune-fluorescence microscopy and in situ hybridisation were performed to characterise lesional and circulating Tfh and Tph-cells. SG-organ cultures were used to investigate functionally the blockade of T-cell costimulatory pathways on key proinflammatory cytokine production.Results: Transcriptomic analysis in SG identified Tfh-signature, interleukin-21 (IL-21) and the inducible T-cell co-stimulator (ICOS) costimulatory pathway as the most upregulated genes in ELS+SS patients, with parotid MALT-L displaying a 400-folds increase in IL-21 mRNA. Peripheral CD4+CXC-motif chemokine receptor 5 (CXCR5)+programmed cell death protein 1 (PD1)+ICOS+ Tfh-like cells were significantly expanded in ELS+SS patients, were the main producers of IL-21, and closely correlated with circulating IgG and reduced complement C4. In the SG, lesional CD4+CD45RO+ICOS+PD1+ cells selectively infiltrated ELS+ tissues and were aberrantly expanded in parotid MALT-L. In ELS+SG and MALT-L parotids, conventional CXCR5+CD4+PD1+ICOS+Foxp3- Tfh-cells and a uniquely expanded population of CXCR5-CD4+PD1hiICOS+Foxp3- Tph-cells displayed frequent IL-21/interferon-γ double-production but poor IL-17 expression. Finally, ICOS blockade in ex vivo SG-organ cultures significantly reduced the production of IL-21 and inflammatory cytokines IL-6, IL-8 and tumour necrosis factor-α (TNF-α).Conclusions: Overall, these findings highlight Tfh and Tph-cells, IL-21 and the ICOS costimulatory pathway as key pathogenic players in SS immunopathology and exploitable therapeutic targets in SS. [ABSTRACT FROM AUTHOR]

Background: Assessment of intrinsic dynamic positive end-expiratory pressure (PEEPi,dyn) may be clinically important in stable patients with chronic obstructive pulmonary disease (COPD), but epidemiological data are scant. Objectives: The aim of our study was (i) to assess the PEEPi,dyn in a large population of stable patients with COPD and (ii) to evaluate the correlations with some noninvasive measurements routinely assessed. Method: Retrospective analysis of lung mechanics, dynamic volumes, arterial blood gases, dyspnoea by means of the Medical Research Council (MRC) scale, the COPD Assessment Test score, and maximal inspiratory/expiratory pressures in 87 hypercapnic and 62 normocapnic patients. Results: The mean PEEPi,dyn was significantly higher in hypercapnic than normocapnic patients (2.8 ± 2.2 vs. 1.9 ± 1.6 cm H2O, respectively, p = 0.0094). PEEPi,dyn did not differ according to Global Initiative for Chronic Obstructive Lung Disease stage, MRC score, or use or not of long-term oxygen therapy. There were significant although weak correlations between PEEPi,dyn and airway obstruction, hyperinflation, respiratory muscle function, arterial CO2 tension, and number of exacerbations/year. The transdiaphragmatic pressure was the strongest variable associated to PEEPi,dyn (R = 0.5713, p = 0.001). Conclusion: In stable patients with COPD, PEEPi,dyn is higher in hypercapnic patients and weakly correlated to noninvasive measures of lung and respiratory muscle function. [ABSTRACT FROM AUTHOR]

The application of ultrasound imaging to the diagnosis of lung diseases is nowadays receiving growing interest. However, lung ultrasound (LUS) is mainly limited to the analysis of imaging artifacts, such as B-lines, which correlate with a wide variety of diseases. Therefore, the results of LUS investigations remain qualitative and subjective, and specificity is obviously suboptimal. Focusing on the development of a quantitative method dedicated to the lung, in this work, we present the first clinical results obtained with quantitative LUS spectroscopy when applied to the differentiation of pulmonary fibrosis. A previously developed specific multifrequency ultrasound imaging technique was utilized to acquire ultrasound images from 26 selected patients. The multifrequency imaging technique was implemented on the ULtrasound Advanced Open Platform (ULA-OP) platform and an LA533 (Esaote, Florence, Italy) linear-array probe was utilized. RF data obtained at different imaging frequencies (3, 4, 5, and 6 MHz) were acquired and processed in order to characterize B-lines based on their frequency content. In particular, B-line native frequencies (the frequency at which a B-line exhibits the highest intensity) and bandwidth (the range of frequencies over which a B-line shows intensities within −6 dB from its highest intensity), as well as B-line intensity, were analyzed. The results show how the analysis of these features allows (in this group of patients) the differentiation of fibrosis with a sensitivity and specificity equal to 92% and 92%, respectively. These promising results strongly motivate toward the extension of the clinical study, aiming at analyzing a larger cohort of patients and including a broader range of pathologies. [ABSTRACT FROM AUTHOR]

Objective: Ectopic lymphoid structures (ELS) develop at sites of infection, autoimmunity, and cancer. In patients with Sjögren's syndrome (SS), ELS support autoreactive B cell activation and lymphomagenesis. Interleukin‐27 (IL‐27) is a key regulator of adaptive immunity and limits Th17 cell–driven pathology. We undertook this study to elucidate the role of IL‐27 in ELS formation and function in autoimmunity using a murine model of sialadenitis and in patients with SS. Methods: ELS formation was induced in wild‐type and Il27ra−/− mice via salivary gland (SG) cannulation of a replication‐deficient adenovirus in the presence or absence of IL‐17A neutralization. In SG biopsy samples, IL‐27–producing cells were identified by multicolor immunofluorescence microscopy. Lesional and circulating IL‐27 levels were determined by gene expression and enzyme‐linked immunosorbent assay. The in vitro effect of IL‐27 on T cells was assessed using fluorescence‐activated cell sorting and cytokine release. Results: In experimental sialadenitis, Il27ra−/− mice had larger and more hyperactive ELS (focus score; P < 0.001), increased autoimmunity, and an expanded Th17 response (P < 0.001), compared to wild‐type mice. IL‐17 blockade in Il27ra−/− mice suppressed the aberrant ELS response (B and T cell reduction against control; P < 0.01). SS patients displayed increased circulating IL‐27 levels (P < 0.01), and in SG biopsy samples, IL‐27 was expressed by DC‐LAMP+ dendritic cells in association with CD3+ T cells. Remarkably, in SS T cells (but not in T cells from patients with rheumatoid arthritis or healthy controls), IL‐27–mediated suppression of IL‐17 secretion was severely impaired and associated with an aberrant interferon‐γ release upon IL‐27 stimulation. Conclusion: Our data indicate that the physiologic ability of IL‐27 to limit the magnitude and function of ELS through control of Th17 cell expansion is severely impaired in SS patients, highlighting a defective immunoregulatory checkpoint in this condition. [ABSTRACT FROM AUTHOR]

Lung ultrasound imaging is a fast-evolving field of application for ultrasound technologies. However, most diagnoses are currently performed with imaging protocols that assume a quasi-homogeneous speed of sound in the volume of interest. When applied to the lung, due to the presence of air, this assumption is unrealistic. Consequently, diagnoses are often based on imaging artifacts and thus qualitative and subjective. In this paper, we present an image formation protocol that is capable of capturing the frequency dependence of well-known artifacts (B-lines) and visualizing it in real time, ultimately providing a quantitative assessment of the signals received from the lung. Previous in vitro studies have shown the potential of B-lines native-frequency for the characterization of bubbly medium, but this paper presents the first results on clinical data. The image formation process has been designed to work on lung tissue, and ultrasound images generated with four orthogonal bands centered at 3, 4, 5 and 6 MHz can be acquired and displayed in real time. Results show that B-lines can be characterized on the basis of their native frequency in vivo and open the way toward real-time quantitative lung ultrasound imaging. [ABSTRACT FROM AUTHOR]

Objectives IL-36 agonists are pro-inflammatory cytokines involved in the pathogenesis of psoriasis. However, their role in the pathogenesis of arthritis and treatment response to DMARDs in PsA remains uncertain. Therefore, we investigated the IL-36 axis in the synovium of early, treatment-naïve PsA, and for comparison RA patients, pre- and post-DMARDs therapy. Methods Synovial tissues were collected by US-guided biopsy from patients with early, treatment-naïve PsA and RA at baseline and 6 months after DMARDs therapy. IL-36 family members were investigated in synovium by RNA sequencing and immunohistochemistry, and expression levels correlated with DMARDs treatment response ex vivo. Additionally, DMARDs effects on IL-36 were investigated in vitro in fibroblast-like synoviocytes. Results PsA synovium displayed a reduced expression of IL-36 antagonists, while IL-36 agonists were comparable between PsA and RA. Additionally, neutrophil-related molecules, which drive a higher activation of the IL-36 pathway, were upregulated in PsA compared with RA. At baseline, the synovial expression of IL-36α was significantly higher in PsA non-responders to DMARDs treatment, with the differential expression being sustained at 6 months post-treatment. In vitro , primary PsA-derived fibroblasts were more responsive to IL-36 stimulation compared with RA and, importantly, DMARDs treatment increased IL-36 expression in PsA fibroblasts. Conclusion The impaired balance between IL-36 agonists–antagonists described herein for the first time in PsA synovium and the decreased sensitivity to DMARDs in vitro may explain the apparent lower efficacy of DMARDs in PsA compared with RA. Exogenous replacement of IL-36 antagonists may be a novel promising therapeutic target for PsA patients. [ABSTRACT FROM AUTHOR]

In standard B mode imaging, a set of ultrasound pulses is used to reconstruct a 2-D image even though some of the assumptions needed to do this are not fully satisfied. For this reason, ultrasound medical images show numerous artifacts which physicians recognize and evaluate as part of their diagnosis since even one artifact can provide clinical information. Understanding the physical mechanisms at the basis of the formation of an artifact is important to identify the physiopathological state of the biological medium which generated the artifact. Ultrasound lung images are a significant example of this challenge since everything that is represented beyond the thickness of the chest wall ($\approx ~2$ cm) is artifactual information. A convincing physical explanation of the genesis of important ultrasound lung artifacts does not exist yet. Physicians simply base their diagnosis on a correlation observed over the years between the manifestation of some artifacts and the occurrence of particular lung pathologies. In this article, a plausible genesis of some important lung artifacts is suggested. [ABSTRACT FROM AUTHOR]

Background: Persistent hypercapnia after COPD exacerbation is associated with excess mortality and early rehospitalization. High Flow Nasal cannula (HFNC), may be theoretically an alternative to long-term noninvasive ventilation (NIV), since physiological studies have shown a reduction in PaCO2 level after few hours of treatment. In this clinical study we assessed the acceptability of HFNC and its effectiveness in reducing the level of PaCO2 in patients recovering from an Acute Hypercapnic Respiratory Failure (AHRF) episode. We also hypothesized that the response in CO2 clearance is dependent on baseline level of hypercapnia.Methods: Fifty COPD patients recovering from an acute exacerbation and with persistent hypercapnia, despite having attained a stable pH (i.e. pH > 7,35 and PaCO2 > 45 mmHg on 3 consecutive measurements), were enrolled and treated with HFNC for at least 8 h/day and during the nighttime RESULTS: HFNC was well tolerated with a global tolerance score of 4.0 ± 0.9. When patients were separated into groups with or without COPD/OSA overlap syndrome, the "pure" COPD patients showed a statistically significant response in terms of PaCO2 decrease (p = 0.044). In addition, the subset of patients with a lower pH at enrolment were those who responded best in terms of CO2 clearance (score test for trend of odds, p = 0.0038).Conclusions: HFNC is able to significantly decrease the level of PaCO2 after 72 h only in "pure" COPD patients, recovering from AHRF. No effects in terms of CO2 reduction were found in those with overlap syndrome. The present findings will help guide selection of the best target population and allow a sample size calculation for future long-term randomized control trials of HFNC vs NIV.Trial Registration: This study is registered with www. clinicaltrials.gov with identifier number NCT03759457. [ABSTRACT FROM AUTHOR]

Introduction: Multiple organ failure has been considered a contraindication for noninvasive ventilation (NIV). Materials and methods: We described the outcome of Do‐not‐Intubate (DNI) patients with acute respiratory failure, treated with NIV and, subsequently, necessitating renal replacement therapy (RRT). Results and discussion: Seven patients admitted to our Respiratory Intensive Care Unit, developed Acute Kidney Injury (AKI) during NIV treatment and received RRT for 12.8 ± 8 days together with NIV. All the patients but one, discontinued renal support because they regained a satisfactory urinary output; nevertheless mortality rate was high (71%). Conclusion: Our data suggest that RRT could be feasible together with NIV. RRT was associated with an acute improvement in renal function but did not modify the mortality rate. [ABSTRACT FROM AUTHOR]

A neoprene wetsuit is widely used to reduce thermal dispersion during diving. Recent observations have pointed out that elastic recoil of the wetsuit might have significant compressive effects, able to affect water and electrolyte homeostasis during both dry and immersed conditions. The aim of this study was to evaluate the possible cardiovascular and respiratory effects of the neoprene wetsuit in dry conditions in a sample of experienced divers. Twenty-four (24) healthy divers were evaluated by Doppler-echocardiography and by spirometry in basal conditions and while wearing a full neoprene wetsuit. During wetsuit conditions, we observed a significant decrease in heart rate (-5%; p<0.05) and cardiac output (-12%; p<0.05), and a significant increase in total peripheral resistances (15%; p<0.05). Moreover, a significant reduction of right ventricular early diastolic filling was observed (-15%; p<0.05). As concerns pulmonary function, a significant reduction of vital capacity (-2%; p<0.001) and expiratory reserve volume (-25%; p<0.001), and a significant increase of inspiratory capacity (9%; p<0.001) and tidal volume (25%; p<0.05) were observed. These data support the hypothesis that neoprene elastic recoil, possibly due to a compression exerted on chest, might affect systemic circulation (decreasing cardiac output and impairing right ventricular filling) and respiratory function. [ABSTRACT FROM AUTHOR]

In neutrophils (but also in eosinophils and in mast cells), different inflammatory stimuli induce histone deimination, chromatin decondensation, and NET formation. These web-like structures that trap and kill microbes contain DNA, cationic granule proteins, and antimicrobial peptides, but the most abundant proteins are core histones. Histones contained in NETs have been deiminated, and arginines are converted in citrullines. While deimination is a physiological process amplified in inflammatory conditions, only individuals carrying genetic predisposition to develop rheumatoid arthritis (RA) make antibodies to deiminated proteins. These antibodies, collectively identified as anti-citrullinated proteins/peptides antibodies (ACPA), react with different deiminated proteins and display partially overlapping specificities. In this paper, we will summarize current evidence supporting the role of NETosis as critical mechanism in the breach of tolerance to self-antigens and in supporting expansion and differentiation of autoreactive cells. In fact, several lines of evidence connect NETosis with RA: RA unstimulated synovial fluid neutrophils display enhanced NETosis; sera from RA patients with Felty's syndrome bind deiminated H3 and NETs; a high number of RA sera bind deiminated H4 contained in NETs; human monoclonal antibodies generated from RA synovial B cells decorate NETs and bind deiminated histones. In RA, NETs represent on one side an important source of autoantigens bearing posttranslational modifications and fueling the production of ACPA. On the other side, NETs deliver signals that maintain an inflammatory milieu and contribute to the expansion and differentiation of ACPA-producing B cells. [ABSTRACT FROM AUTHOR]

The present study describes the case of a 45-year-old man diagnosed with metastatic lung adenocarcinoma, which harbored a deletion within exon 19 of the epidermal growth factor receptor (EGFR) gene. The patient was subsequently treated with gefitinib (250 mg/day orally from May 2013 to March 2014), but developed acquired resistance to the drug following 11 months of treatment. Tumor burden molecular analysis was performed on a tumor rebiopsy and plasma sample, and histological analysis was also performed on the tumor rebiopsy. A small cell transformation retaining the original EGFR mutation was detected in the tumor rebiopsy, while the T790M mutation together with the activating ex19del mutation were identified only in the plasma sample. The patient was treated with cytotoxic chemotherapy (off-label schedule with epirubicin 80 mg/mq and paclitaxel 160 mg/mq every 21 days for 6 cycles) and radiation (50.4 Gy administered in 28 fractions of 1.8 Gy once daily for 5.5 weeks) specific for small cell lung cancer, and may also have benefitted from treatment with a third generation T790M-specific EGFR-TKI. To better describe the mechanisms of resistance to TKI inhibitors and to optimize therapeutic regimens, the simultaneous analysis of tumor biopsies and circulating tumor DNA should be considered. [ABSTRACT FROM AUTHOR]

Background: Estimating COPD occurrence is perceived by the scientific community as a matter of increasing interest because of the worldwide diffusion of the disease. We aimed to estimate COPD prevalence by using administrative databases from a city in central Italy for 2002–2006, improving both the sensitivity and the reliability of the estimate. Methods: Multiple sources were used, integrating the hospital discharge register (HDR), clinical charts, spirometry and the cause-specific mortality register (CMR) in a longitudinal algorithm, to reduce underestimation of COPD prevalence. Prevalence was also estimated on the basis of COPD cases confirmed through spirometry, to correct misclassification. Estimating such prevalence relied on using coefficients of validation, derived as the positive predictive value (PPV) for being an actual COPD case from clinical and spirometric data at the Institute of Clinical Physiology of the National Research Council. Results: We found that sensitivity of COPD prevalence increased by 37%. The highest estimate (4.43 per 100 residents) was observed in the 5-year period, using a 3-year longitudinal approach and combined data from three sources. We found that 17% of COPD cases were misclassified. The above estimate of COPD prevalence decreased (3.66 per 100 residents) when coefficients of validation were applied. The PPV was 80% for the HDR, 82% for clinical diagnoses and 91% for the CMR. Conclusions: Adjusting the COPD prevalence for both underestimation and misclassification of the cases makes administrative data more reliable for epidemiological purposes. [ABSTRACT FROM AUTHOR]

Reportedly, patients with scleroderma-related pulmonary hypertension (SSc-PAH) respond poorly to new vasoactive drugs (NVD). Forty-nine SSc-PAH patients underwent right heart catheterization (RHC) and, according to NVD availability, divided as follows: Group 1 ( n = 23, from 1999 to 2004, poor availability), and Group 2 ( n = 26, from 2005 to 2010, good availability). Before diagnostic RHC, NVD had been given to 30 % of the patients in Group 1, and 58 % of those in Group 2 ( p = 0.049). At diagnosis, patients in Group 1 had greater heart dilatation ( p < 0.01), higher mean pulmonary artery pressure ( p < 0.05), lower pulmonary artery capacitance ( p < 0.05), and lower carbon monoxide lung diffusing capacity (DLco, p < 0.05) than those in Group 2. At a median follow-up time of 15.5 months, DLco further decreased in Group 1 ( p < 0.05), whereas cardiac index increased in Group 2 ( p < 0.05). At 36 months of follow-up, 72.4 % of the patients in Group 2 were still alive as opposed to 30.4 % in Group 1 ( p = 0.02). In multivariate analysis, DLco and mixed venous oxygen saturation (SvO) were independent predictors of survival. A value of DLco <7.2 mL/mmHg/min was associated with a hazard ratio (HR) of 5.3 ( p < 0.001); for SvO <63.8 %, the HR was 3.7 ( p < 0.01).NVD have beneficial effects in patients with SSc-PAH. Both DLco and SvO are predictors of survival and may assist in planning treatment. [ABSTRACT FROM AUTHOR]

Aims: Radiological inappropriateness in medical imaging leads to loss of resources and accumulation of avoidable population cancer risk. Aim of the study was to audit the appropriateness rate of different cardiac radiological examinations. Methods and Principal Findings: With a retrospective, observational study we reviewed clinical records of 818 consecutive patients (67±12 years, 75% males) admitted from January 1-May 31, 2010 to the National Research Council – Tuscany Region Gabriele Monasterio Foundation cardiology division. A total of 940 procedures were audited: 250 chest x-rays (CXR); 240 coronary computed tomographies (CCT); 250 coronary angiographies (CA); 200 percutaneous coronary interventions (PCI). For each test, indications were rated on the basis of guidelines class of recommendation and level of evidence: definitely appropriate (A, including class I, appropriate, and class IIa, probably appropriate), uncertain (U, class IIb, probably inappropriate), or inappropriate (I, class III, definitely inappropriate). Appropriateness was suboptimal for all tests: CXR (A = 48%, U = 10%, I = 42%); CCT (A = 58%, U = 24%, I = 18%); CA (A = 45%, U = 25%, I = 30%); PCI (A = 63%, U = 15%, I = 22%). Top reasons for inappropriateness were: routine on hospital admission (70% of inappropriate CXR); first line application in asymptomatic low-risk patients (42% of CCT) or in patients with unchanged clinical status post-revascularization (20% of CA); PCI in patients either asymptomatic or with miscellaneous symptoms and without inducible ischemia on non-invasive testing (36% of inappropriate PCI). Conclusion and Significance: Public healthcare system – with universal access paid for with public money – is haemorrhaging significant resources and accumulating avoidable long-term cancer risk with inappropriate cardiovascular imaging prevention. [ABSTRACT FROM AUTHOR]

Patients with inoperable chronic thromboembolic pulmonary hypertension (Inop-CTEPH) treated with conventional therapy have a poor survival. We compare the 3-year survival between those treated with conventional therapy and those treated with conventional therapy and a combination of novel drugs. We also evaluate the clinical course. A total of 34 Inop-CTEPH consecutive patients were evaluated from 1991 to 2009 including right heart catheterization (RHC) and perfusion lung scan (PLS): 7 underwent surgical treatment while 27 were confirmed inoperable. Of these 27 patients, 12 evaluated from 1991 to 2003 (Group 1) were treated with conventional therapy and 15 evaluated from 2004 to 2009 (Group 2) were treated with conventional and novel therapies. At baseline, no group difference emerged at RHC. Based on clinical course, novel drugs and oxygen supplementation were given to patients of Group 2. Seven of these who had worse clinical course repeated RHC and four of them also PLS during therapy. Those without repeat RHC had baseline pulmonary artery mean pressure and brain natriuretic peptide (NT-proBNP) lower and mixed venous saturation (SvO) and exercise test higher ( p = 0.022, 0.015, 0.044 and 0.003, respectively). During therapy, those with repeat RHC had total pulmonary vascular resistance reduced ( p = 0.012), base excess increased ( p = 0.002) and significant redistribution of pulmonary blood flow at PLS. At the 3-year follow-up, survival was 86% in Group 2 and 31% in Group 1 ( p = 0.031). In Inop-CTEPH patients, the clinical course may help to select drugs and the level of oxygen supply that can improve hemodynamics, gas exchange and long-term survival. [ABSTRACT FROM AUTHOR]

Objectives: The development of technologically advanced, expensive techniques has progressively reduced the value of chest X-ray in clinical practice for the assessment of left ventricular (LV) dilatation and dysfunction. Although controversial data are reported on the role of this widely available technique in cardiac assessment, it is known that the cardio-thoracic ratio is predictive of risk of progression in the NYHA Class, hospitalization, and outcome in patients with LV dysfunction. This study aimed to evaluate the reliability of the transverse diameter of heart shadow [TDH] by chest X-ray for detecting LV dilatation and dysfunction as compared to Magnetic Resonance Imaging (MRI) performed for different clinical reasons. Materials and Methods: In 101 patients, TDH was measured in digital chest X-ray and LV volumes and ejection fraction (EF) by MRI, both exams performed within 2 days. Results: A direct correlation between TDH and end-diastolic volumes (r = .75, P<0.0001) was reported. TDH cut-off values of 14.5 mm in females identified LV end-diastolic volumes >150 mL (sensitivity: 82%, specificity: 69%); in males a cut-off value of 15.5 mm identified LV end-diastolic volumes >210 mL (sensitivity: 84%; specificity: 72%). A negative relation was found between TDH and LVEF (r = -.54, P<0.0001). The above cut-off values of TDH discriminated patients with LV systolic dysfunction -- LVEF <35% (sensitivity and specificity: 67% and 57% in females; 76% and 59% in males, respectively). Conclusions: Chest X-ray may still be considered a reliable technique in predicting LV dilatation by the accurate measurement of TDH as compared to cardiac MRI. Technologically advanced, expensive, and less available imaging techniques should be performed on the basis of sound clinical requests. [ABSTRACT FROM AUTHOR]

The article discusses a study which investigated the effect of hypoxic and hyperbaric stress on pulmonary gas exchange in breath-hold divers. Pulmonary diffusing capacity to carbon monoxide (DLCO) and nitric oxide, haemoglobin and haematocrit were estimated in six elite divers. DLCO indicated a relative elevation at two minutes in five subjects and a tendency to drop at 25 minutes compared to pre-dive. The study concluded that an early but transient elevation in DLCO in five divers may reflect the main shift in blood volume during a breath-hold dive.

Ectopic lymphoid structures (ELS) can develop in rheumatoid arthritis (RA) synovial tissue, but the precise pathways of B cell activation and selection are not well understood. Here, we identify a synovial B cell population characterized by co-expression of a family of orphan nuclear receptors (NR4A1-3), which is highly enriched in RA synovial tissue. A transcriptomic profile of NR4A synovial B cells significantly overlaps with germinal center light zone B cells and an accrual of somatic hypermutation that correlates with loss of naive B cell state. NR4A B cells co-express lymphotoxins α and β and IL-6, supporting functions in ELS promotion. Expanded and shared clones between synovial NR4A B cells and plasma cells and the rapid upregulation with BCR stimulation point to in situ differentiation. Together, we identify a dynamic progression of B cell activation in RA synovial ELS, with NR4A transcription factors having an important role in local adaptive immune responses. [Display omitted] • Single-cell analysis of RA synovium reveals a unique NR4A+ B cell population • NR4A+ B cells express ELS chemotactic factors and a GC RNA profile • NR4A+ B cells display a continuum of SHM that correlates with loss of naive status • Evidence of clonal expansion and sharing between NR4A+ B cells and PCs in synovium Meednu et al. identify a B cell population in the RA synovium with upregulation of the NR4A gene family. The population displays a continuum of somatic hypermutation—pointing to in situ activation—with NR4A expression a readout of antigen stimulation and pathological B cell responses. [ABSTRACT FROM AUTHOR]

Background: Alveolar volume measured according to the American Thoracic Society-European Respiratory Society (ATS-ERS) guidelines during the single breath diffusion test can be underestimated when there is maldistribution of ventilation. Therefore, the alveolar volume calculated by taking into account the ATS-ERS guidelines was compared to the alveolar volume measured from sequentiallly collected samples of the expired volume in two groups of individuals: COPD patients and healthy individuals. The aim of this study was to investigate the effects of the maldistribution of ventilation on the real estimate of alveolar volume and to evaluate some indicators suggestive of the presence of maldistribution of ventilation. Methods: Thirty healthy individuals and fifty patients with moderate-severe COPD were studied. The alveolar volume was measured either according to the ATS-ERS guidelines or considering the whole expired volume subdivided into five quintiles. An index reflecting the non-uniformity of the distribution of ventilation was then derived (DeltaVA/VE). Results: Significant differences were found when comparing the two measurements and the alveolar volume by quintiles appeared to have increased progressively towards residual volume in healthy individuals and much more in COPD patients. Therefore, DeltaVA/VE resulted in an abnormal increase in COPD. Conclusion: The results of our study suggest that the alveolar volume during the single breath diffusion test should be measured through the collection of a sample of expired volume which could be more representative of the overall gas composition, especially in the presence of uneven distribution of ventilation. Further studies aimed at clarifying the final effects of this way of calculating the alveolar volume on the measure of DLCO are needed. DeltaVA/VE is an index that can help assess the severity of inhomogeneity in COPD patients. [ABSTRACT FROM AUTHOR]

Pulmonary embolism remains a challenging diagnostic problem. We developed a simple diagnostic strategy based on combination of assessment of the pretest probability with perfusion lung scan results to reduce the need for pulmonary angiography. We studied 390 consecutive patients (78% in-patients) with suspected pulmonary embolism. The pretest probability was rated low (<10%), intermediate (>10%, ≤50%), moderately high (>50%, ≤90%) or high (>90%) according to a structured clinical model. Perfusion lung scans were independently assigned to one of four categories: normal; near-normal; abnormal, suggestive of pulmonary embolism (wedge-shaped perfusion defects); abnormal, not suggestive of pulmonary embolism (perfusion defects other than wedge shaped). Pulmonary embolism was diagnosed in patients with abnormal scans suggestive of pulmonary embolism and moderately high or high pretest probability. Patients with normal or near-normal scans and those with abnormal scans not suggestive of pulmonary embolism and low pretest probability were deemed not to have pulmonary embolism. All other patients were allocated to pulmonary angiography. Patients in whom pulmonary embolism was excluded were left untreated. All patients were followed up for 1 year. Pulmonary embolism was diagnosed non-invasively in 132 patients (34%), and excluded in 191 (49%). Pulmonary angiography was required in 67 patients (17%). The prevalence of pulmonary embolism was 41% (n=160). Patients in whom pulmonary embolism was excluded had a thrombo-embolic risk of 0.4% (95% confidence interval: 0.0%–2.8%). Our strategy permitted a non-invasive diagnosis or exclusion of pulmonary embolism in 83% of the cases (95% confidence interval: 79%–86%), and appeared to be safe. [ABSTRACT FROM AUTHOR]