Long-term results of sirolimus treatment in lymphangioleiomyomatosis: a single referral centre experience

Diagnòstic; Farmacoteràpia; Malalties del tracte respiratoriDiagnóstico; Farmacoterapia; Enfermedades del tracto respiratorioDiagnosis; Drug therapy; Respiratory tract diseasesThere are few published data on long-term treatment with sirolimus in lymphangioleiomyomatosis (LAM). The objective of this study was to describe the long-term effect of sirolimus in a series of LAM patients followed up in a referral centre, focusing on pulmonary function. We retrospectively reviewed a series of 48 patients with LAM diagnosed, followed up and treated with sirolimus in a single centre. Response to sirolimus was evaluated at 1 and 5 years. A negative sirolimus response was defined as an FEV1 decline greater than − 75 ml/year. A mixed-effects model was used to estimate the longitudinal changes in FEV1 (average slope), both as absolute (ml/year) and as predicted values (%predicted/year). From a total of 48 patients, 9 patients underwent lung transplantation and 4 died during the study. Mean (95% CI) FEV1 slope over 5 years was − 0.14 (− 26.13 to 25.85) ml/year in the whole LAM group, 42.55 (14.87 to 70.22) ml/year in the responder group, − 54.00 (− 71.60 to − 36.39) ml/year in the partial responder group and − 84.19 (− 113.5 to − 54.0) ml/year in the non-responder group. After 5 years of sirolimus treatment 59% had a positive response, 30% had a partial response and 11% had a negative response. Our study found that sirolimus treatment had a positive long-term effect on most LAM patients.E.R.L. received a pre-doctoral Grant from the Spanish Society of Pulmonology and Thoracic Surgery

Lymphangioleiomyomatosis: Searching for potential biomarkers

Biomarkers; Lymphangioleiomyomatosis; MetalloproteinasesBiomarcadores; Linfangioleiomiomatosis; MetaloproteinasasBiomarcadors; Limfangioleiomiomatosi; MetaloproteinasesBackground: Vascular endothelial growth factor-D (VEGF-D) is the most commonly used biomarker for diagnosing lymphangioleiomyomatosis (LAM). However, lung biopsy is often necessary as well; therefore, defining new biomarkers for LAM is crucial. The aim of this study was to describe the diagnostic accuracy of a variety of biomarkers. Methods: We assessed 13 analytes in serum related to extracellular matrix remodeling, lymphatic involvement and angiogenesis in a cohort of patients with LAM, comparing them with patients with other cystic lung diseases (OCLD) and healthy women. A scoring method based on the cut-point of each VEGF-D and metalloproteinase-2 (MMP-2) was used to evaluate the diagnostic performance of the marker combination. Results: A total of 97 subjects were recruited: 59 (61%) LAM patients, 18 (19%) OCLD patients, and 20 (20%) healthy female controls. MMP-2 was the only extracellular matrix remodeling biomarker able to differentiate LAM patients from OCLD and healthy patients. Serum MMP-2 was higher in LAM patients [median 578 (465–832) ng/ml] than in patients with OCLD and healthy controls [medians 360 (314–546) and 427 (365–513) ng/ml, respectively (p < 0.0001)]. The area under ROC curve (AUC) of MMP-2 was 0.785 and that of VEGF-D 0.815 (p = 0.6214). The sensitivity/specificity profiles of each biomarker (54/92% for MMP-2, 59/95% for VEGF-D) yielded a composite score (−6.36 + 0.0059 × VEGF-D + 0.0069 × MMP-2) with higher accuracy than each component alone (AUC 0.88 and sensitivity/specificity 79/87%). Conclusion: Combining MMP-2 and VEGF-D may increase diagnostic accuracy for LAM.This project was supported by the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR), grant number: PI 638/2018. The funders have no role in study design, data and analysis collection, decision to publish, or preparation of the manuscript

Near-normal aerobic capacity in long-term survivors after lung transplantation

Lung transplant; Survivors; Aerobic capacityTrasplantaments de pulmó; Supervivents; Capacitat aeròbicaTrasplantes de pulmón; Supervivientes; Capacidad aeróbicaThe clinical course of lung transplantation (LT) is diverse: some patients present chronic lung allograft dysfunction (CLAD) and progressive decline in pulmonary function, but others maintain normal spirometric values and active lives. Objectives The aim of this study was to elucidate whether long-term LT survivors with normal spirometry achieve normal exercise capacity, and to identify predictive factors of exercise capacity. Methods This was a cross-sectional multicentre study, where bilateral LT recipients who survived at least 10 years after LT, with normal spirometry, no diagnosis of CLAD and modified Medical Research Council dyspnoea degree ≤2 underwent cardiopulmonary exercise testing (CPET). Results 28 LT recipients were included with a mean±sd age of 48.7±13.6 years. Oxygen uptake (V′O2) had a mean±sd value of 21.49±6.68 mL·kg−1·min−1 (75.24±15.6%) and the anaerobic threshold was reached at 48.6±10.1% of the V′O2max predicted. The mean±sd heart rate reserve at peak exercise was 17.56±13.6%. The oxygen pulse increased during exercise and was within normal values at 90.5±19.4%. The respiratory exchange ratio exceeded 1.19 at maximum exercise. The median (25–75th percentile) EuroQol-5D score was 1 (0.95–1), indicating a good quality of life. The median (25–75th percentile) International Physical Activity Questionnaire score was 5497 (4007–9832) MET-min·week−1 with 89% of patients reporting more than 1500 MET-min·week−1. In the multivariate regression models, age, sex and diffusing capacity of the lung for carbon monoxide remained significantly associated with V′O2max (mL·kg−1·min−1); haemoglobin and forced expiratory volume in 1 s were significantly associated with maximum work rate (watts), after adjusting for confounders. Conclusion We report for the first time near-normal peak V′O2 values during CPET and normal exercise capacity in long-term LT recipients without CLAD.Support statement: This study was financed by Instituto de Salud Carlos III (PI13/01076); the European Regional Development Fund (FEDER), FUCAP, Astellas, Novartis and Chiesi. Funding information for this article has been deposited with the Crossref Funder Registry.Ojanguren is a researcher supported by the “Pla Estratègic de Recerca i Innovació en Salut (PERIS)” 2016–2020 (SLT008/18/00108;G60594009)

Impaired Cytotoxic Response in PBMCs From Patients With COVID-19 Admitted to the ICU: Biomarkers to Predict Disease Severity

Infection by novel coronavirus SARS-CoV-2 causes different presentations of COVID-19 and some patients may progress to a critical, fatal form of the disease that requires their admission to ICU and invasive mechanical ventilation. In order to predict in advance which patients could be more susceptible to develop a critical form of COVID-19, it is essential to define the most adequate biomarkers. In this study, we analyzed several parameters related to the cellular immune response in blood samples from 109 patients with different presentations of COVID-19 who were recruited in Hospitals and Primary Healthcare Centers in Madrid, Spain, during the first pandemic peak between April and June 2020. Hospitalized patients with the most severe forms of COVID-19 showed a potent inflammatory response that was not translated into an efficient immune response. Despite the high levels of effector cytotoxic cell populations such as NK, NKT and CD8+ T cells, they displayed immune exhaustion markers and poor cytotoxic functionality against target cells infected with pseudotyped SARS-CoV-2 or cells lacking MHC class I molecules. Moreover, patients with critical COVID-19 showed low levels of the highly cytotoxic TCRγδ+ CD8+ T cell subpopulation. Conversely, CD4 count was greatly reduced in association to high levels of Tregs, low plasma IL-2 and impaired Th1 differentiation. The relative importance of these immunological parameters to predict COVID-19 severity was analyzed by Random Forest algorithm and we concluded that the most important features were related to an efficient cytotoxic response. Therefore, efforts to fight against SARS-CoV-2 infection should be focused not only to decrease the disproportionate inflammatory response, but also to elicit an efficient cytotoxic response against the infected cells and to reduce viral replication.This work was supported by the Coordinated Research Activities at the Centro Nacional de Microbiología (CNM, Instituto de Salud Carlos III) (COV20_00679) to promote an integrated response against SARS-CoV-2 in Spain (Spanish Ministry of Science and Innovation) that is coordinated by Dr. Inmaculada Casas (WHO National Influenza Center of the CNM); a generous donation provided by Chiesi España, S.A.U. (Barcelona, Spain); the Spanish Ministry of Economy and Competitiveness (PID2019-110275RB-I00); the Spanish AIDS Research Network RD16CIII/0002/0001 that is included in Acciόn Estratégica en Salud, Plan Nacional de Investigaciόn Científica, Desarrollo e Innovaciόn Tecnolόgica 2016-2020, Instituto de Salud Carlos III, European Region Development Fund (ERDF). The work of ML-H and SR-M is financed by NIH grant R01AI143567. The work of LH is supported by a pre-doctoral grant from Instituto de Salud Carlos III (FIS PI16CIII/00034-ISCIII-FEDER).S

Where myth and archaeology meet: Discovering the Gorgon Medusa's Lair.

Here we report the discovery of ceramic fragments that form part of a Gorgoneion, a ceramic image representation of the Gorgon Medusa. The fragments were found in a deep part of Gorham's Cave, well known to ancient mariners as a natural shrine, between the 8th and 2nd century BCE. We discuss the context of this discovery, both within the inner topography of the cave itself, and also the broader geographical context. The discovery is situated at the extreme western end of the Mediterranean Sea, where it meets the Atlantic Ocean. The location was known to ancient mariners as the northern Pillar of Herakles, which marked the end of the known world. We relate the discovery, and its geographical and chronological context, to Greek legends that situated the lair of the Gorgon sisters at a location which coincides with the physical attributes and geographical position of Gorham's Cave. We thus provide, uniquely, a geographical and archaeological context to the myth of Perseus and the slaying of the Gorgon Medusa

Comparison of seven prognostic tools to identify low-risk pulmonary embolism in patients aged <50 years

publishersversionPeer reviewe

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research