Search

Diabetes is a rare, but potentially life‐threatening, adverse event of immune checkpoint inhibitors that requires prompt recognition and treatment. It usually occurs in the first 3 months of treatment and is typically related to programmed cell death‐1 antibodies, alone or in combined therapy. It has rarely been described developing after immunotherapy cessation. We present a 51‐year‐old man with metastatic melanoma, who developed acute‐onset diabetes 52 days after combined immunotherapy cessation with nivolumab and ipilimumab, and 25.6 months after receiving the first dose. He presented with acute hyperglycemic symptoms, ketosis, complete insulin depletion and negative autoimmunity, fulfilling the criteria of fulminant type 1 diabetes. The patient had previously developed hypophysitis with isolated adrenocorticotropic hormone deficiency during immunotherapy. We describe a case of late‐onset fulminant type 1 diabetes developing after immunotherapy cessation. Patient education and active follow up after immunotherapy discontinuation are crucial to warrant a timely intervention., We describe a case of immunotherapy‐related type 1 diabetes developing after combined immunotherapy cessation. The patient developed fulminant type 1 diabetes >2 years after the first immunotherapy dose, and had previously developed immune‐related hypophysitis.

Background Silicosis is associated with an increased risk of developing systemic autoimmune rheumatic disease (SARD). The prognostic implications of this association are poorly characterized. The aim of this study was to determine the prevalence of SARD and autoimmune markers in a cohort of patients with exposure to silica and assess their impact on prognosis. Method We performed a prospective observational study of all patients attending the dedicated silicosis clinic of our pulmonology unit between 2009 and December 2017. Diagnosis was confirmed by a rheumatologist according to Spanish Rheumatology Society criteria. Autoimmune markers, pulmonary function tests, radiological progression, visits to the emergency department and primary care center, and hospital admissions for respiratory causes, and mortality were analyzed. Results Overall, 489 cases of silicosis and 95 cases of exposure were studied. In total, 54 (11.0%) patients with silicosis had SARD: 12 (2.4%) rheumatoid arthritis, 10 (2.0%) systemic lupus erythematosus, 10 (2.0%) systemic sclerosis, 3 (0.6%) Sjogren syndrome, 2 (0.4%) vasculitis associated with anti-neutrophil cytoplasmic antibodies (ANCA +), 6 (1.2%) psoriatic arthritis, 3 (0.6%) ankylosing spondylitis, and 8 (1.6%) other autoimmune diseases with no special features. The patients with SARD visited the emergency room more often (63.0% vs. 42.5%; p = 0.004), and progressed more rapidly (22.2 vs. 11.7%; p = 0.030). Conclusions The presence of systemic rheumatic autoimmune diseases involves radiological progression and a higher clinical impact.

Resumen Introduccion La silicosis se asocia con aumento del riesgo de padecer alguna de las enfermedades reumatologicas autoinmunitarias sistemicas (ERAS), aunque no se conocen las implicaciones clinicas de esta asociacion. El objetivo del estudio es determinar la prevalencia de ERAS y de marcadores de autoinmunidad en una cohorte de pacientes con exposicion a inhalacion de polvo de silice y evaluar su impacto clinico. Metodo Estudio observacional prospectivo, en pacientes atendidos en una consulta monografica de silicosis, desde 2009 hasta diciembre 2017. El diagnostico de ERAS se confirmo por un especialista en Reumatologia segun criterios de la Sociedad Espanola de Reumatologia. Se analizaron marcadores de autoinmunidad, pruebas de funcion respiratoria, progresion radiologica e impacto clinico medido por visitas a Atencion Primaria, a Servicio de Urgencias, ingresos hospitalarios por causa respiratoria y mortalidad. Resultados Se estudiaron 489 casos de silicosis y 95 de exposicion a inhalacion de polvo de silice sin silicosis. De los pacientes con silicosis 54 (11,0%) tenian ERAS: 12 (2,4%) artritis reumatoide, 10 (2,0%) lupus eritematoso sistemico, 10 (2,0%) esclerosis sistemica, seis (1,2%) artritis psoriasica, tres (0,6%) sindrome de Sjogren, dos (0,4%) vasculitis asociada con anticuerpos anticitoplasma de neutrofilos, tres (0,6%) espondiloartritis y ocho (1,6%) enfermedad autoinmunitaria sin caracteristicas especificas. Los pacientes con ERAS realizaron mas visitas a urgencias (63,0 vs. 42,5%; p = 0,004), y experimentaron mayor progresion (22,2 vs. 11,7%; p = 0,030). Conclusiones Los pacientes con silicosis presentan una prevalencia de ERAS elevada y su presencia se asocia con una mayor progresion radiologica y un mayor impacto clinico.

Information on the association between diet and cardiovascular disease (CVD) in type 1 diabetes (T1D) is scarce. We assessed the association between biomarkers of fatty acid (FA) intake and the presence of carotid plaques (a surrogate marker of future CVD events) in this high-risk population. Cross-sectional study in 167 consecutive T1D patients without CVD and with at least one of the following: ≥ 40 years, diabetic nephropathy, or ≥ 10 years of T1D duration with another CVD risk factor. The FA profile of erythrocyte membranes was determined by gas chromatography, and the number of carotid plaques (intima-media thickness ≥ 1.5 mm) was assessed by ultrasonography. Regression models were constructed adjusting for classical (age, gender, blood pressure, smoking habit, LDL-cholesterol, body mass index and statins) and T1D-specific risk factors (diabetes duration, HbA1c and chronic complications). A total of 58.7% were men (mean age 48.3 ± 10.3 years, T1D duration 27.2 ± 10.1 years). Sixty-one patients (36.5%) showed carotid plaque. Linoleic acid decreased and all-C18:1trans increased with the number of carotid plaques (none, 1–2, ≥ 3 plaques; p for trend

Silicosis is a diffuse interstitial lung disease caused by sustained inhalation of silica and silicates. Several cytokines are activated by their inhalation and can mediate the process of pulmonary fibrosis. The identification of biomarkers could allow an early diagnosis before the development of radiological alterations and help monitor the evolution of patients. The objetive of this study was to determine the clinical significance of specific biomarkers, to estimate their association with the development, severity and/or progression of silicosis, and identify determinants of this evolution. We conducted a prospective observational study in patients attending the pulmonology clinic from 2009 to 2018. Serum levels of the following inflammatory mediators were assessed: interleukin-6 (IL-6), interleukin 2 receptor subunit alpha (IL2R) interleukin 1 beta (IL1B), interleukin-8 (IL-8), tumour necrosis factor-alpha (TNF-α), transforming growth factor-beta1 (TGF-β1), alpha-1 antitrypsin (AAT), C-reactive protein (CRP), lactate dehydrogenase (LDH) and ferritin in subjects exposed to silica, with and without silicosis. Association between those inflammatory mediators with lung function measurements and radiological severity of disease and their impact on prognosis were analysed. 337 exposed to silica (278 with silicosis) and 30 subjects in the control group were included. IL-8, α1AT, ferritin, CRP and LDH levels were higher in silicosis than in those exposed to silica without silicosis. IL-8, LDH and AAT levels were associated with progression of silicosis and IL-6, IL-8, LDH, AAT, ferritin, and CRP with vital status. The results of the ROC analysis indicated the potential of IL-8 as a biomarker in the presence of silicosis and for the prediction of mortality.

Background COVID-19 related in-hospital venous thromboembolism (VTE) incidence is high but data reported vary significantly. Some studies show that up to half of the events are diagnosed early after admission. Objectives To study symptomatic VTE incidence in acute COVID-19 hospitalized patients and to describe timing of VTE diagnosis. Methods Multicenter cohort of 5966 patients hospitalized with acute COVID-19. Multicenter Registry of 844 hospitalized patients with acute COVID-19 and associated acute VTE. Results By the time of cohort data collection, 68 patients (1.14%) were still hospitalized, 19.8% had died, and 5.4% required ICU. During a median follow-up of 6 days (IQR, 4–12), 183 patients (3.07%; 95% CI, 2.64–3.55) presented a symptomatic VTE event. The cumulative incidences of VTE at 7, 14 and 21 days in wards [2.3% (95% CI, 1.9–2.7), 3.6% (95% CI, 3.0–4.3), and 4.3% (95% CI, 3.5–5.1)] were similar to the ones reported in ICU [2.2% (95% CI, 1.0–4.4), 2.9% (95% CI, 1.5–5.3), and 4.1% (95% CI, 2.2–6.8)], but at 30 and 60 days were higher in ICU [6.9% (95% CI, 4.2–10.5), and 12.8% (95% CI, 8.1–18.5)] than in wards. Eighty-eight VTE events (48%) were diagnosed early, within 48 h of admission. VTE was not associated with death (HR, 0.79; 95% CI, 0.55–1.12). Conclusions Incidence of symptomatic VTE in our COVID-19 cohort is consistent with that of other real-life studies recently published. Early VTE events are, along with COVID-19, the reason for admission rather than an in-hospital complication.

The risk factors associated with the probability of central venous access device (CVAD)-associated deep vein thrombosis (DVT) resolution have been hardly evaluated in children. Current guidelines suggest anticoagulation for a maximum of 3 months in patients with provoked DVT if the provoking factor is resolved. To know if the thrombus will resolve after anticoagulant therapy will help to choose whether to initiate and/or continue this treatment or not. We did a retrospective study of 85 pediatric patients (45 girls, 40 boys) with CVAD-associated DVT to examine the risk factors associated with lack of thrombus resolution in the first 6 months after diagnosis. Sixty-two children had their thrombosis resolved after a median of 50 days (p25-p75 25-97) since diagnosis. In multivariate analysis, variables significantly associated with no resolution were total occlusion (OR 12.50, 95% CI 2.99-52.14, p=.001), location in upper extremity, head, and neck veins (OR 17.70, 95% CI 1.64-191.43, p=.018); collateral circulation in the first 45 days after diagnosis (OR 33.55, 95% CI 2.42-464.71, p=.009); and having between 0 and 3 prothrombotic risk factors at diagnosis (OR 6.20, 95% CI 1.21-31.75, p=.029).Conclusion: CVAD-associated DVT resolution in children in the first 6 months since diagnosis was significantly lower if the thrombosis was occlusive, if it was located in the upper extremity, head, and neck veins; if collateral circulation was seen on ultrasound in the first 45 days; and/or when the patient showed less prothrombotic risk factors at diagnosis. What is Known: • The risk factors associated with central venous access device-associated deep vein thrombosis resolution have been hardly evaluated in children. • Current guidelines suggest anticoagulation for a maximum of 3 months in provoked vein thrombosis if the provoking factor is resolved. What is New: • Thrombus resolution was lower if it was occlusive, located in the upper extremity veins, if collateral circulation was seen, and with less prothrombotic risk factors at diagnosis. • To know if the thrombus will resolve after anticoagulation will help to choose whether to initiate and/or continue it or not.

INTRODUCTION: We present the first registry of patients with congenital bleeding disorders and COVID-19. The study has been carried out in the Community of Madrid, which has the highest number of cases in Spain. The objective is to understand the incidence of COVID-19, the course of the disease if it occurs and the psychosocial and occupational impact on this population. METHODS: We included 345 patients (246 of haemophilia, 69 of von Willebrand Disease, two rare bleeding disorders and 28 carriers of haemophilia). A telephone survey was used to collect the data. RESULTS: Forty-two patients presented symptoms suggestive of infection by COVID-19, and in six cases, the disease was confirmed by RT-PCR. The cumulative incidence of our series was 1.73%. It is worth noting the complexity of the management of COVID-19 in two patients on prophylaxis with non-factor replacement therapy. Adherence to the prescribed treatment was maintained by 95.5% of patients. Although 94% were independent for daily living activities, 42.4% had a recognized disability and 58% required assistance, provided by the Madrid Haemophilia Association (Ashemadrid) in 75% of cases. Only 4.4% of consultations were held in person. CONCLUSIONS: Patients with congenital bleeding disorders infected with SARS-CoV-2 presented a mild course of the disease that did not require admission. Their identification and treatment by a specialist team from a Haemophilia Treatment Center are essential to make a correct assessment of the risk of haemorrhage/thrombosis. COVID-19 had a major impact on the psychosocial aspects of these patients which must be remedied with recovery plans.

Background: Although cardiovascular disease (CVD) remains the leading cause of mortality in type 1 diabetes (T1D), the use of cardioprotective drugs is scarce. We aimed to evaluate the impact of carotid ultrasonography (US) on the improvement in cardiovascular risk factors (CVRFs) in T1D.Methods: T1D patients without CVD meeting criteria for lipid treatment according to guidelines (age ≥40 years, nephropathy and/or ≥10 years of diabetes duration with ≥1 additional CVRFs) were included. The carotid-US group (US-G) underwent a standardized US protocol and CVRF assessment; recommendations were made according to subclinical atherosclerosis status. The control group (CG) followed usual clinical practice. Changes in CVRFs, specially statin use and LDL-cholesterol levels, at one year were analysed.Results: A total of 318 patients were included (51.3% female, mean age of 49.1 years and 25.5 years of diabetes duration): 211 in the US-G and 107 in the CG. Participants in the US-G had a higher baseline LDL-cholesterol than controls (114 vs. 102 mg/dL; pConclusions: Carotid-US is independently associated with an intensification of lipid-lowering therapy in a high-risk T1D population.

To evaluate exercise capacity using the 6-minute walk test (6MWT) in patients with complicated silicosis, and to determine how results shape the prognostic value of 6MWT for hospitalization and mortality.Prospective observational study in 143 patients with complicated silicosis who performed the 6MWT in our outpatient pulmonology clinic between 2009 and the end of 2016. Lung function tests, computed tomography findings and 6MWT parameters (distance walked and oxygen desaturation) were evaluated.Patients with complicated silicosis walked 387±92m. Results deteriorated as silicosis severity increased; category A: 407±97m, B: 370±88m, and C: 357±68m (P=.022). The 6MWT correlated positively with lung function and inversely with dyspnea determined by mMRC (P.001). Patients with moderate/severe emphysema and greater CT90 presented a worse result on 6MWT. Patients who walked350m had more hospitalizations (3.7±4.0) than those who walked350m (1.1±2.9). There was an impact on survival: non-survivors walked 327.9±73.0m, while survivors walked 404.5±89.7m (P.001).Spirometry values and category of complicated silicosis correlated with 6MWT and distance walked was a prognostic factor for hospitalization and mortality. The 6MWT is a useful tool in occupational health for monitoring patients with silicosis.

Background: A high neutrophil to lymphocyte ratio (NLR) has been associated with adverse outcomes in non-small cell lung cancer (NSCLC). However, information on epidermal growth factor receptor (EGFR)-mutant advanced NSCLC is scarce, and most of the studies published have been conducted in Asian populations. We aimed to assess the influence of pretreatment NLR on progression-free survival (PFS) and overall survival (OS) in Western European patients treated with EGFR tyrosine kinase inhibitors (TKIs). Methods: A retrospective evaluation of 41 patients with EGFR-mutant advanced NSCLC treated with EGFR TKIs between June 2010 and May 2016 was carried out. The association between several prognostic factors including pretreatment NLR and survival was analyzed. Results: Median PFS and OS were 10.58 and 20.84 months, respectively. OS for patients with a high NLR was 7.4 months, compared to 24.6 months for patients with a low NLR (p = 0.0122). In multivariate analysis, poor performance status (ECOG PS ≥ 2) and presence of ≥ 3 metastatic locations were identified as significant independent prognostic factors for worse PFS. For OS, unfavorable prognostic factors were a high NLR and central nervous system metastasis at diagnosis. Conclusion: Pretreatment NLR is an independent prognostic factor for OS in Western European patients with EGFR-mutant NSCLC treated with EGFR TKIs.

Introduction: Idarucizumab is a humanized monoclonal antibody fragment that binds to dabigatran and reverses its anticoagulant activity. It has been available in Spain since June 2016 and is indicated for imminent surgery or invasive procedures and life-threatening bleeding. The aim of the study was to describe the actual experience with idarucizumab in different centers in Madrid. Methods: Patients with electronic prescription of idarucizumab between June 2016 and July 2021 were included. Demographic information, comorbidities, laboratory parameters, dabigatran indication, anticoagulation resumption, adverse events related to idarucizumab and death within 30 days were collected from medical records. Qualitative data are presented as frequencies and percentages. Quantitative data are presented as mean ± standard deviation (SD) or median (interquartile range -IQR-). Cumulative survival was calculated by dividing the number of patients alive by the number of patients in each indication category for idarucizumab in a 30-day post-infusion period. Results: A total of 69 patients from 8 hospitals in Madrid were included. Ninety-six percent received dabigatran for prevention of stroke and embolism in nonvalvular atrial fibrillation and 4% received it for the treatment of thromboembolic disease. The mean age was 73.5 ± 13.9 years, and 55.6% were men. Median aPTT was 45.6 seconds and was prolonged in 72.1% (49). Patient characteristics, concomitant conditions and laboratory parameters are reviewed in Table 1. The main indication for idarucizumab was reversal of anticoagulation for persistent bleeding (46.4%), followed by surgery (44.9%). Fibrinolysis due to ischemic stroke was performed in 3 patients (4.3%), dabigatran intoxication occurred in 3 patients due to acute renal failure (4.3%). Gastrointestinal bleeding was the most common type of bleeding. Two of the patients intoxicated with dabigatran also had gastrointestinal bleeding. Cardiac surgery was the most common type of intervention, with heart transplant being a common indication (9/13). Minor surgical procedures included 2 lumbar punctures and 1 central venous catheterization. In one case, the type of surgery was not available. Figure 1 A and B summarize the bleeding location and type of surgery. The median time between infusion of idarucizumab and cessation of bleeding or onset of surgery was 3 hours, however this information was only available in 43 patients. No reports of excessive bleeding during surgery or after fibrinolysis were noted. One patient with dabigatran intoxication was reported to have an episode of persistent melena in which the trough plasma level was 1178.1 ng/mL. This patient died of an aggressive lymphoproliferative disorder that couldn´t be biopsied due to altered coagulation. A case of auricular thrombosis occurred in a patient with a heart transplant due to hyperthophic cardiomiopathy and end-stage heart failure requiring thrombectomy. The patient required a biventricular assistance and died of myocardial infarction. Full 30-day follow-up was available for 68 patients, during this period 11 died. Five patients in the bleeding group died, 3 from hypovolemic shock, 1 from intraparenchymal hemorrhage and data were missing for 1. Two patients who received a heart transplant died, one as described previously 10 days after the transplant and the other 2 days after the transplant from hemorrhagic shock. Three patients who underwent abdominal surgery died of septic shock. One patient with dabigatran intoxication died. Cumulative survival after a follow-up period of 30 days was 86% (Figure 2). Seventy-seven percent (53) resumed anticoagulation after a median of 3 days (0-180), and 62.3% (33) were bridged with low molecular weight heparin (LMWH) at prophylactic doses. Finally, 75% (40) maintained LMWH (7) or restarted dabigatran or another direct oral anticoagulant (33). A total of 13 patients didn´t resume any anticoagulation. Conclusions: Idarucizumab is an effective drug for reversal of dabigatran anticoagulation in bleeding or imminent surgery/invasive procedures. In this cohort it was used safely in patients awaiting a heart transplant. No cases of bleeding after infusion or during surgery were reported, except for a single case of auricular thrombosis. Most patients resumed anticoagulation at discharge. The experience described confirms the safety of idarucizumab in daily clinical practice. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Background: Pre-evaluation of endogenous immunoglobulin levels is a potential strategy to improve the results of intravenous immunoglobulins in sepsis, but more work has to be done to identify those patients who could benefit the most from this treatment. The objective of this study was to evaluate the impact of endogenous immunoglobulins on the mortality risk in sepsis depending on disease severity. Methods: This was a retrospective observational study including 278 patients admitted to the ICU with sepsis fulfilling the SEPSIS-3 criteria, coming from the Spanish GRECIA and ABISS-EDUSEPSIS cohorts. Patients were distributed into two groups depending on their Sequential Organ Failure Assessment score at ICU admission (SOFA < 8, n = 122 and SOFA >= 8, n = 156), and the association between immunoglobulin levels at ICU admission with mortality was studied in each group by Kaplan-Meier and multivariate logistic regression analysis. Results: ICU/hospital mortality in the SOFA < 8 group was 14.8/23.0%, compared to 30.1/35.3% in the SOFA >= 8 group. In the group with SOFA < 8, the simultaneous presence of total IgG < 407 mg/dl, IgM < 43 mg/dl and IgA < 219 mg/dl was associated with a reduction in the survival mean time of 6.6 days in the first 28 days and was a robust predictor of mortality risk either during the acute or during the post-acute phase of the disease (OR for ICU mortality: 13.79; OR for hospital mortality: 7.98). This predictive ability remained in the absence of prior immunosuppression (OR for ICU mortality: 17.53; OR for hospital mortality: 5.63). Total IgG < 407 mg/dl or IgG1 < 332 mg/dl was also an independent predictor of ICU mortality in this group. In contrast, in the SOFA >= 8 group, we found no immunoglobulin thresholds associated with neither ICU nor hospital mortality. Conclusions: Endogenous immunoglobulin levels may have a different impact on the mortality risk of sepsis patients based on their severity. In patients with moderate organ failure, the simultaneous presence of low levels of IgG, IgA and IgM was a consistent predictor of both acute and post-acute mortalities., The GRECIA study was supported by Proyectos de Investigacion en Biomedicina, Consejeria de Sanidad, JCYL (Grant Code BOCYL-D-26072010). The authors thank also Instituto de Salud Carlos III for their financial support (Grant Code EMER 07/050, ISCIII-FIS-PI12-01815). The funding agencies were not involved neither in the design of the study and collection, nor in the analysis, interpretation of data or manuscript writing.

Aim Although insulin resistance (IR) is a growing trait among type 1 diabetes (T1D) population, its relationship with atherosclerosis has been scarcely studied. We assessed the association between IR indexes and carotid atherosclerosis in T1D, a population at high cardiovascular disease (CVD) risk. Materials and methods We evaluated 191 participants with T1D and no prior CVD with at least one of the following criteria: ≥40 years old; diabetic nephropathy; or T1D duration ≥10 years harbouring ≥1 additional CVD risk factor. IR was assessed with the metabolic syndrome (MetS) harmonized definition proposed in 2009 and the estimated glucose disposal rate (eGDR), a T1D-specific IR surrogate marker (lower values indicating higher IR). Standardized carotid ultrasonography was performed, recording intima-media thickness (IMT), plaque presence and maximum height of plaque. Comparisons between patients according to their MetS status as well as concerning eGDR values were performed. Results The participants' median age was 47.4 (41.1-53.3) years and diabetes duration 25.7 (21.6-32.5) years. Plaque prevalence was higher in patients with greater IR (49.1%, 29.1% and 20%, P = .001, for any plaque according to decreasing eGDR tertiles). Conversely, no statistically significant higher plaque prevalence was found in participants with MetS. In multivariate analyses (adjusted for general- and T1D-specific risk factors, and statin treatment), MetS was associated with neither IMT nor plaque. On the contrary, eGDR was independently related to ≥2 plaques (P = .018) and maximum plaque height (P Conclusions In T1D, IR assessed through eGDR but not by MetS definition was independently associated with plaque burden, a predictor of CVD.

Summary Background Acute respiratory distress syndrome (ARDS) is a lung inflammatory process caused mainly by sepsis. Most previous studies that identified genetic risks for ARDS focused on candidates with biological relevance. We aimed to identify novel genetic variants associated with ARDS susceptibility and to provide complementary functional evidence of their effect in gene regulation. Methods We did a case-control genome-wide association study (GWAS) of 1935 European individuals, using patients with sepsis-associated ARDS as cases and patients with sepsis without ARDS as controls. The discovery stage included 672 patients admitted into a network of Spanish intensive care units between January, 2002, and January, 2017. The replication stage comprised 1345 individuals from two independent datasets from the MESSI cohort study (Sep 22, 2008–Nov 30, 2017; USA) and the VISEP (April 1, 2003–June 30, 2005) and MAXSEP (Oct 1, 2007–March 31, 2010) trials of the SepNet study (Germany). Results from discovery and replication stages were meta-analysed to identify association signals. We then used RNA sequencing data from lung biopsies, in-silico analyses, and luciferase reporter assays to assess the functionallity of associated variants. Findings We identified a novel genome-wide significant association with sepsis-associated ARDS susceptibility (rs9508032, odds ratio [OR] 0·61, 95% CI 0·41–0·91, p=5·18 × 10−8) located within the Fms-related tyrosine kinase 1 (FLT1) gene, which encodes vascular endothelial growth factor receptor 1 (VEGFR-1). The region containing the sentinel variant and its best proxies acted as a silencer for the FLT1 promoter, and alleles with protective effects in ARDS further reduced promoter activity (p=0·0047). A literature mining of all previously described ARDS genes validated the association of vascular endothelial growth factor A (VEGFA; OR 0·55, 95% CI 0·41–0·73; p=4·69 × 10−5). Interpretation A common variant within the FLT1 gene is associated with sepsis-associated ARDS. Our findings support a role for the vascular endothelial growth factor signalling pathway in ARDS pathogenesis and identify VEGFR-1 as a potential therapeutic target. Funding Instituto de Salud Carlos III, European Regional Development Funds, Instituto Tecnologico y de Energias Renovables.

The use of statins in non-selected type 1 diabetes (T1D) populations is low. We assessed the prevalence and factors associated with statin treatment in patients meeting criteria for this therapy for primary prevention of cardiovascular disease (CVD).From 2015 to 2018, T1D patients from a tertiary hospital were selected. Inclusion criteria were: ≥40 years-old, diabetic nephropathy, or T1D duration ≥10 years with ≥1 cardiovascular risk factor (CVRF). A standardized cardiovascular risk evaluation protocol was performed. Prevalence of statin treatment was evaluated according to presence of several CVRFs, and multivariable models were constructed to assess independent determinants of statin use.We included 241 patients (50% women, age 48.2±9.9 years, T1D duration 26.6±9.0 years). Diabetic retinopathy and nephropathy, active smoking, and hypertension were present in 38%, 12%, 28%, and 27%, respectively. Overall, 43% of patients were on statins and 27% had LDL-cholesterol100mg/dl. Statin users were older, and had higher body mass index (BMI), prevalence of kidney dysfunction, and hypertension (p0.05 for all). However, among both T1D-related and classical CVRFs, only hypertension (odds ratio [OR], 2.96; 95% confidence interval [CI] 1.48-5.91) and BMI (OR, 1.08; CI, 1.01-1.16) were independently associated with statin use in multiple regression analysis.Less than half of T1D patients from a tertiary hospital who met criteria for statin use were on treatment. Hypertension and BMI emerged as the only CVRFs independently associated with statin therapy. New strategies are needed to better address CVD prevention in this very high-risk population.

Introduction: The 6-minute walk test (6MWT) is a useful tool for pulmonary function evaluation in chronic respiratory diseases, but its value in silicosis is not well defined. Objective: The aim of this study is 1) to assess 6MWT in patients with silicosis and its relationship with pulmonary function test (PFT) and thoracic computed tomography (CT) findings; 2) to identify the clinical variables that reduce the 6MWT-distance. Method: Prospective observational study of patients with silicosis attended in our hospital from 2009 to 2017. PFT, thoracic CT and 6MWT (distance and O2 desaturation) were evaluated. Data were compared by different tests (Chi-square, Student-t, ANOVA, Pearson) as required. Results: 220 men with silicosis (77 simple, 143 complicated; mean age 52.3±10.5) were included. Mean 6MWT-distance was similar in both groups (simple 402±90m, complicated 387±92m; p=0.271). There were significant differences among complicated silicosis A: 407±97, B: 370±88, and C: 357±68 (p=0.022), respectively. The 6MWT correlated directly with PFT [FEV1 (r=0.47), FVC (r=0.37) and FEV1/FVC (r=0.54); p >0.001], and inversely with mMRC dyspnea scale (r=-0.60; p Conclusions: Reduced 6MWT-distance is found in complicated silicosis, and is associated with emphysema, more hospitalisations and higher mortality. These findings outlines the usefulness of 6MWT as a prognostic marker in silicosis.

Objective To describe the clinical, functional and radiographic differences of respiratory disease caused by environmental mycobacteria in patients with and without silicosis. Method Retrospective, observational study in patients with nontuberculous mycobacteria isolated in the Hospital Meixoeiro (University Hospital of Vigo) microbiology laboratory between January 2007 and December 2013. Patients were grouped according to the presence or absence of silicosis and mycobacterial lung disease, using American Thoracic Society criteria. Results In 156 cases, at least one species of environmental mycobacteria had been isolated from the respiratory culture. A total of 71% were identified in men, 40 (25.6%) of whom had silicosis. Sixty patients (38.5%) met American Thoracic Society microbiological criteria: 62.5% of the silicosis group and 30.2% of the non-silicosis group. The most common species were Mycobacterium avium complex, Mycobacterium genavense and Mycobacterium chelonae. American Thoracic Society criteria for environmental mycobacterial disease were met in 34 (22.7%) patients: 14 in the silicosis group and 20 in the non-silicosis group. Treatment was administered in 24 cases, with better bacteriological eradication levels in the non-silicosis group. Conclusions In our series, a history of silicosis was related with a higher incidence of environmental mycobacterial disease. The causative species in the majority of cases in our setting was Mycobacterium avium complex, followed by Mycobacterium genavense. Patients with silicosis showed lower cure rates after treatment.

The open lung approach is a mechanical ventilation strategy involving lung recruitment and a decremental positive end-expiratory pressure trial. We compared the Acute Respiratory Distress Syndrome network protocol using low levels of positive end-expiratory pressure with open lung approach resulting in moderate to high levels of positive end-expiratory pressure for the management of established moderate/severe acute respiratory distress syndrome.A prospective, multicenter, pilot, randomized controlled trial.A network of 20 multidisciplinary ICUs.Patients meeting the American-European Consensus Conference definition for acute respiratory distress syndrome were considered for the study.At 12-36 hours after acute respiratory distress syndrome onset, patients were assessed under standardized ventilator settings (FIO2≥0.5, positive end-expiratory pressure ≥10 cm H2O). If Pao2/FIO2 ratio remained less than or equal to 200 mm Hg, patients were randomized to open lung approach or Acute Respiratory Distress Syndrome network protocol. All patients were ventilated with a tidal volume of 4 to 8 ml/kg predicted body weight.From 1,874 screened patients with acute respiratory distress syndrome, 200 were randomized: 99 to open lung approach and 101 to Acute Respiratory Distress Syndrome network protocol. Main outcome measures were 60-day and ICU mortalities, and ventilator-free days. Mortality at day-60 (29% open lung approach vs. 33% Acute Respiratory Distress Syndrome Network protocol, p = 0.18, log rank test), ICU mortality (25% open lung approach vs. 30% Acute Respiratory Distress Syndrome network protocol, p = 0.53 Fisher's exact test), and ventilator-free days (8 [0-20] open lung approach vs. 7 [0-20] d Acute Respiratory Distress Syndrome network protocol, p = 0.53 Wilcoxon rank test) were not significantly different. Airway driving pressure (plateau pressure - positive end-expiratory pressure) and PaO2/FIO2 improved significantly at 24, 48 and 72 hours in patients in open lung approach compared with patients in Acute Respiratory Distress Syndrome network protocol. Barotrauma rate was similar in both groups.In patients with established acute respiratory distress syndrome, open lung approach improved oxygenation and driving pressure, without detrimental effects on mortality, ventilator-free days, or barotrauma. This pilot study supports the need for a large, multicenter trial using recruitment maneuvers and a decremental positive end-expiratory pressure trial in persistent acute respiratory distress syndrome.

Background Late-onset neutropenia (LON) is a known adverse effect to rituximab therapy. Information about its real incidence and clinical implications comes from case reports and few retrospective studies specifically designed to study LON. However, large prospective studies of LON are lacking in the literature. We aimed to determine the incidence of LON in a group of non-Hodgkin lymphoma patients treated with rituximab and to analyze the clinical course, complications, and risk factors associated with LON. Patients and Methods We retrospectively reviewed 183 patients with a diagnosis of non-Hodgkin lymphoma consecutively treated with rituximab alone or in combination with chemotherapy. Results We identified 11 patients with grade 3/4 LON (13 episodes) out of 183 patients (6%). The median time to onset of LON was 75 days, and the median time to recovery from neutropenia was 100 days. The median neutrophil count nadir was 0.55 × 10 9 /L (range, 0.06-0.9 × 10 9 /L). Two patients presented infectious complications, one with fatal outcome. Conclusion In our experience, the incidence of recognized LON is low (6%), although its real incidence may be greater because of the asymptomatic course and quick recovery in most cases. Infectious complications are unusual, but life-threatening complications can emerge. A careful evaluation of all cases of LON is warranted.

Objectives Overall mortality in patients with acute respiratory distress syndrome is a composite endpoint because it includes death from multiple causes. In most acute respiratory distress syndrome trials, it is unknown whether reported deaths are due to acute respiratory distress syndrome or the underlying disease, unrelated to the specific intervention tested. We investigated the causes of death after contracting acute respiratory distress syndrome in a large cohort. Design A secondary analysis from three prospective, multicenter, observational studies. Setting A network of multidisciplinary ICUs. Patients We studied 778 patients with moderate-to-severe acute respiratory distress syndrome treated with lung-protective ventilation. Interventions None. Measurements and main results We examined death in the ICU from individual causes. Overall ICU mortality was 38.8% (95% CI, 35.4-42.3). Causes of acute respiratory distress syndrome modified the risk of death. Twenty-three percent of deaths occurred from refractory hypoxemia due to nonresolving acute respiratory distress syndrome. Most patients died from causes unrelated to acute respiratory distress syndrome: 48.7% of nonsurvivors died from multisystem organ failure, and cancer or brain injury was involved in 37.1% of deaths. When quantifying the true burden of acute respiratory distress syndrome outcome, we identified 506 patients (65.0%) with one or more exclusion criteria for enrollment into current interventional trials. Overall ICU mortality of the "trial cohort" (21.3%) was markedly lower than the parent cohort (relative risk, 0.55; 95% CI, 0.43-0.70; p Conclusions Most deaths in acute respiratory distress syndrome patients are not directly related to lung damage but to extrapulmonary multisystem organ failure. It would be challenging to prove that specific lung-directed therapies have an effect on overall survival.

Background: Early appropriate antibiotic treatment is essential in sepsis. We aimed to evaluate the impact of a multifaceted educational intervention to improve antibiotic treatment. We hypotheyzed that the intervention would hasten and improve the appropriateness of empirical antibiotic administration, favor de-escalation, and decrease mortality. Methods: We prospectively studied all consecutive patients with sepsis/septic shock admitted to 72 intensive care units (ICUs) throughout Spain in two 4-month periods (before and immediately after the 3-month intervention). We compared process-of-care variables (resuscitation bundle and time-to-initiation, appropriateness, and de-escalation of empirical antibiotic treatment) and outcome variables between the two cohorts. The primary outcome was hospital mortality. We analyzed the intervention's long-term impact in a subset of 50 ICUs. Results: We included 2628 patients (age 64.1 +/- 15.2 years; men 64.0%; Acute Physiology and Chronic Health Evaluation (APACHE) II, 22.0 +/- 8.1): 1352 in the preintervention cohort and 1276 in the postintervention cohort. In the postintervention cohort, the mean (SD) time from sepsis onset to empirical antibiotic therapy was lower (2.0 (2.7) vs. 2.5 (3.6) h; p= 0.002), the proportion of inappropriate empirical treatments was lower (6.5% vs. 8.9%; p= 0.024), and the proportion of patients in whom antibiotic treatment was de-escalated was higher (20.1% vs. 16.3%; p= 0.004); the expected reduction in mortality did not reach statistical significance (29.4% in the postintervention cohort vs. 30.5% in the preintervention cohort; p= 0.544). Gains observed after the intervention were maintained in the long-term follow-up period. Conclusions: Despite advances in sepsis treatment, educational interventions can still improve the delivery of care; further improvements might also improve outcomes., Research grant Instituto de Salud Carlos III (FIS 10/01497), CM12/00066.

Purpose: To determine the epidemiology and outcome of severe sepsis and septic shock after 9 years of the implementation of the Surviving Sepsis Campaign (SSC) and to build a mortality prediction model. Methods: This is a prospective, multicenter, observational study performed during a 5-month period in 2011 in a network of 11 intensive care units (ICUs). We compared our findings with those obtained in the same ICUs in a study conducted in 2002. Results: The current cohort included 262 episodes of severe sepsis and/or septic shock, and the 2002 cohort included 324. The prevalence was 14% (95% confidence interval: 12.5-15.7) with no differences to 2002. The population-based incidence was 31 cases/100 000 inhabitants/year. Patients in 2011 had a significantly lower Acute Physiology and Chronic Health Evaluation II (APACHE II; 21.9 ± 6.6 vs 25.5 ± 7.07), Logistic Organ Dysfunction Score (5.6 ± 3.2 vs 6.3 ± 3.6), and Sequential Organ Failure Assessment (SOFA) scores on day 1 (8 ± 3.5 vs 9.6 ± 3.7; P < .01). The main source of infection was intraabdominal (32.5%) although microbiologic isolation was possible in 56.7% of cases. The 2011 cohort had a marked reduction in 48-hour (7% vs 14.8%), ICU (27.2% vs 48.2%), and in-hospital (36.7% vs 54.3%) mortalities. Most relevant factors associated with death were APACHE II score, age, previous immunosuppression and liver insufficiency, alcoholism, nosocomial infection, and Delta SOFA score. Conclusion: Although the incidence of sepsis/septic shock remained unchanged during a 10-year period, the implementation of the SSC guidelines resulted in a marked decrease in the overall mortality. The lower severity of patients on ICU admission and the reduced early mortality suggest an improvement in early diagnosis, better initial management, and earlier antibiotic treatment.

Aim: To evaluate the influence of two variants of P450 oxidoreductase (POR), rs2868177 and POR*28, on the stable dosage of acenocoumarol. Patients & methods: For this observational, cross-sectional study, patients were undergone stable anticoagulant treatment with acenocoumarol. Univariate and multiple regression analyses were performed to assess the influence of POR polymorphisms. Results: About 340 patients were enrolled. Multiple regression had a coefficient of determination (R2) of 51.5% and an Akaike information criterion of 234.22. The inclusion of POR*28 polymorphisms increased the R2 to 52.0% and reduced the Akaike information criteria to 230.58. The POR*28 heterozygote showed statistical significance in the algorithm. Conclusion: The POR*28 heterozygote appears to be associated with the stable dose of acenocoumarol, but its clinical contribution to the prediction of the dosing of this drug is minimal.

ABSTRACT The prognosis of follicular lymphoma (FL) has significantly improved over the last decade, particularly following the introduction of the anti-CD20 monoclonal antibody rituximab, which has challenged the old concept of FL as an incurable disease. However, the decision whether to start treatment in a patient with advanced FL or adopt a watch-and-wait policy remains a subject of controversy. Furthermore, the optimal first-line treatment for FL remains a clinical challenge owing to the numerous different therapeutic options available. In this review, the authors focus on the initial management of patients with newly diagnosed FL, consider the different treatment options for every stage, paying special consideration to the therapeutic approaches for each clinical scenario, and discuss future directions.

Objective The impact of endogenous immunoglobulin isotypes on the prognosis of patients with severe sepsis has not been sufficiently explored. The aim of this study was to evaluate the association between immunoglobulin levels in plasma and survival in patients with this condition. Design and patients A prospective multicentre cohort study was conducted. A total of 172 adult patients admitted to the intensive care unit (ICU) with severe sepsis or septic shock were recruited. Patients were classified based on deciles of immunoglobulin concentrations at diagnosis of sepsis. Categorical variables were created and tested for their association with survival during hospitalization in the ICU. Results Overall, 42 patients died in the ICU during the study. Kaplan–Meier analysis showed that immunoglobulin concentrations below 300 mg dL−1 for IgG1, 35 mg dL−1 for IgM and 150 mg dL−1 for IgA were associated with shorter survival times. Multivariate regression analysis showed that IgG1 < 300 mg dL−1 was a risk factor for mortality [odds ratio (OR) 2.50, 95% confidence interval (CI) 1.04–6.03; P = 0.042]. The combined presence of IgG1, IgM and IgA levels below the described thresholds had a synergistic impact on mortality risk (OR 5.27, 95% CI 1.41–19.69; P = 0.013). A similar effect was observed for combined low levels of IgG1 and IgA (OR 4.10, 95% CI 1.28–13.12; P = 0.018) and also of IgG1 and IgM (OR 3.10. 95% CI 1.13–8.49; P = 0.028). Conclusions The combined presence of low levels of the endogenous immunoglobulins IgG1, IgM and IgA in plasma is associated with reduced survival in patients with severe sepsis or septic shock. Assessment of the concentrations of these immunoglobulins could improve the results of treatment with exogenous immunoglobulins in patients with sepsis.

There is no standard treatment for patients with gastric marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT lymphoma) who are resistant to, or ineligible for, anti-Helicobacter pylori (anti-HP) therapy. In this study, we investigated the activity of the rituximab, cyclophosphamide, vincristine and prednisone (R-CVP) regimen in patients with gastric MALT lymphoma. Patients were included provided they had untreated gastric MALT lymphoma (except for anti-HP therapy) and were resistant to, or ineligible for, anti-HP therapy. Treatment plan consisted of six to eight 21-daycycles of the R-CVP chemotherapy regimen. Toxicity, response, relapse and survival were evaluated. Twenty patients (12 women and 8 men) were included in the analyses with median age of 59years. Thirteen patients (65%) had stage I tumours, and seven patients (35%) had stages II–IV tumours. The overall response rate was 100%, with 19 (95%) complete responses and one (5%) partial response. Regimen toxicity was mild and mainly hematological, and no cases of gastric bleeding or perforation occurred. After a median followup of 56.3months, three patients had relapsed, and 19 patients remained alive (specific lymphoma survival 100%), of whom 17 had no evidence of disease. In our experience, the R-CVP regimen is a well-tolerated and effective treatment for patients with gastric MALT lymphoma who are resistant to, or ineligible for, anti-HP therapy. Copyright © 2013 John Wiley & Sons, Ltd.

The driving pressure (plateau pressure minus positive end-expiratory pressure) has been suggested as the major determinant for the beneficial effects of lung-protective ventilation. We tested whether driving pressure was superior to the variables that define it in predicting outcome in patients with acute respiratory distress syndrome.A secondary analysis of existing data from previously reported observational studies.A network of ICUs.We studied 778 patients with moderate to severe acute respiratory distress syndrome.None.We assessed the risk of hospital death based on quantiles of tidal volume, positive end-expiratory pressure, plateau pressure, and driving pressure evaluated at 24 hours after acute respiratory distress syndrome diagnosis while ventilated with standardized lung-protective ventilation. We derived our model using individual data from 478 acute respiratory distress syndrome patients and assessed its replicability in a separate cohort of 300 acute respiratory distress syndrome patients. Tidal volume and positive end-expiratory pressure had no impact on mortality. We identified a plateau pressure cut-off value of 29 cm H2O, above which an ordinal increment was accompanied by an increment of risk of death. We identified a driving pressure cut-off value of 19 cm H2O where an ordinal increment was accompanied by an increment of risk of death. When we cross tabulated patients with plateau pressure less than 30 and plateau pressure greater than or equal to 30 with those with driving pressure less than 19 and driving pressure greater than or equal to 19, plateau pressure provided a slightly better prediction of outcome than driving pressure in both the derivation and validation cohorts (p0.0000001).Plateau pressure was slightly better than driving pressure in predicting hospital death in patients managed with lung-protective ventilation evaluated on standardized ventilator settings 24 hours after acute respiratory distress syndrome onset.

Background Although much has evolved in our understanding of the pathogenesis and factors affecting outcome of patients with acute respiratory distress syndrome (ARDS), still there is no specific pharmacologic treatment for ARDS. Several clinical trials have evaluated the utility of corticoids but none of them has demonstrated a definitive benefit due to small sample sizes, selection bias, patient heterogeneity, and time of initiation of treatment or duration of therapy. We postulated that adjunctive treatment of persistent ARDS with intravenous dexamethasone might change the pulmonary and systemic inflammatory response and thereby reduce morbidity, leading to a decrease in duration of mechanical ventilation and a decrease in mortality. Methods/design This is a prospective, multicenter, randomized, controlled trial in 314 patients with persistent moderate/severe ARDS. Persistent ARDS is defined as maintaining a PaO2/FiO2 ≤ 200 mmHg on PEEP ≥ 10 cmH2O and FiO2 ≥ 0.5 after 24 hours of routine intensive care. Eligible patients will be randomly allocated to two arms: (i) conventional treatment without dexamethasone, (ii) conventional treatment plus dexamethasone. Patients in the dexamethasone group will be treated with a daily dose of 20 mg iv from day 1 to day 5, and 10 mg iv from day 6 to day 10. Primary outcome is the number of ventilator-free days, defined as days alive and free from mechanical ventilation at day 28 after intubation. Secondary outcome is all-cause mortality at day 60 after enrollment. Discussion This study will be the largest randomized controlled clinical trial to assess the role of dexamethasone in patients with persistent ARDS. Trial registration Registered on 21 November 2012 as DEXA-ARDS at ClinicalTrials.gov website (NCT01731795). Electronic supplementary material The online version of this article (doi:10.1186/s13063-016-1456-4) contains supplementary material, which is available to authorized users.

While our understanding of the pathogenesis and management of acute respiratory distress syndrome (ARDS) has improved over the past decade, estimates of its incidence have been controversial. The goal of this study was to examine ARDS incidence and outcome under current lung protective ventilatory support practices before and after the diagnosis of ARDS.This was a 1-year prospective, multicenter, observational study in 13 geographical areas of Spain (serving a population of 3.55 million at least 18 years of age) between November 2008 and October 2009. Subjects comprised all consecutive patients meeting American-European Consensus Criteria for ARDS. Data on ventilatory management, gas exchange, hemodynamics, and organ dysfunction were collected.A total of 255 mechanically ventilated patients fulfilled the ARDS definition, representing an incidence of 7.2/100,000 population/year. Pneumonia and sepsis were the most common causes of ARDS. At the time of meeting ARDS criteria, mean PaO(2)/FiO(2) was 114 ± 40 mmHg, mean tidal volume was 7.2 ± 1.1 ml/kg predicted body weight, mean plateau pressure was 26 ± 5 cmH(2)O, and mean positive end-expiratory pressure (PEEP) was 9.3 ± 2.4 cmH(2)O. Overall ARDS intensive care unit (ICU) and hospital mortality was 42.7% (95%CI 37.7-47.8) and 47.8% (95%CI 42.8-53.0), respectively.This is the first study to prospectively estimate the ARDS incidence during the routine application of lung protective ventilation. Our findings support previous estimates in Europe and are an order of magnitude lower than those reported in the USA and Australia. Despite use of lung protective ventilation, overall ICU and hospital mortality of ARDS patients is still higher than 40%.

Resumen Introduccion y objetivo Analizar la frecuencia, las caracteristicas y la supervivencia de los pacientes con cancer de pulmon (CP) y enfermedad pulmonar obstructiva cronica (EPOC), comparandolas con las de pacientes sin EPOC. Material y metodos Se ha realizado un estudio retrospectivo de pacientes diagnosticados de CP mediante citohistologia. Se estimo la supervivencia por el metodo de Kaplan-Meier. El analisis estadistico se realizo con el programa SPSS 15.0. Resultados Se diagnostico de CP a 996 pacientes, el 39,8% con EPOC. La edad media (± desviacion estandar) de estos ultimos era de 70±9,19 anos. En cuanto a los estadios GOLD, el 18,2% se encontraba en estadio I, el 53,6% en estadio II, el 24% en estadio III y el 4,2% en estadio IV. Segun la citohistologia, el 48,2% de los CP eran escamosos, el 22% adenocarcinomas y el 22,5% microciticos. La supervivencia fue mayor en el grupo con EPOC. Conclusiones El CP y la EPOC se asocian en un 39,8% de los casos. La estirpe mas frecuente del CP es la escamosa y la supervivencia es mayor en el grupo con EPOC.

REACH is the largest international registry designed to identify the clinical characteristics of atherothrombosis in the real-life setting. The present study describes the baseline and 1-year follow-up characteristics of 67,888 patients with coronary, cerebrovascular or peripheral vascular disease (VD group) or with three or more risk factors for developing atherothrombosis (RFO group) followed-up by 5,473 physicians. At baseline the patients had a high prevalence of risk factors, especially obesity, insufficient treatment (69.4% statins and 78.6% platelet antiaggregants) and involvement of more than one vascular territory in 15.9%. At 1 year of follow-up, 4.24% had a combination of cardiovascular death, myocardial infarction or stroke (4.69% in the VD group and 2.15% in the ORF group). This finding was related to the number of diseased vascular territories (2.15% in the ORF group and 9.21% in patients with three diseased territories). The REACH registry shows that the patients studied had multiple vascular involvement, undertreatment and high morbidity.

Intravenous immunoglobulins (IVIGs) have not yet demonstrated robust evidence in the benefit for treatment of sepsis. In spite of multiple clinical trials performed with IVIG in sepsis, it remains an experimental therapy for this severe condition. Nonetheless, these trials do not address a number of potential confounding factors, concerning both the patient and the IVIG preparations, which could greatly affect the final result. To name a few, endogenous levels of immunoglobulin isotypes and subclasses are not assessed prior to treatment. The presence/absence of patient antibodies against the microorganism(s) causing sepsis is not evaluated. The accuracy of antibiotic prescription is not included as an adjusting variable. The degree of patient immunosuppression (previous or induced by sepsis) is not documented. In turn, the concentration and antimicrobial specificities of the antibodies contained in the batches of IVIG are not assessed. Neither the pharmacokinetics of IVIG nor its potential immunomodulatory effects are evaluated. In addition, the concept of 'window of opportunity' for IVIG administration following diagnosis of sepsis is not considered. In conclusion, addressing these factors could help to individualise treatment with IVIG for sepsis, which could enhance the opportunities of this drug to show benefits in terms of survival in this severe condition.

This work was funded by the Instituto de Salud Carlos III (CB06/06/1088, PI10/00393, PI14/00844, FI11/00074) and by the European Regional Development Funds “A way of making Europe.” MPY was supported by a post-doctoral fellowship from Fundación Ramón Areces, Madrid, Spain., Acosta-Herrera, M., Pino-Yanes, M., Blanco, J., Ballesteros, J.C., Ambrós, A., Corrales, A., Gandía, F., Subirá, C., Domínguez, D., Baluja, A., Añón, J.M., Adalia, R., Pérez-Méndez, L., Flores, C., Villar, J., Fernández, L.R., Espinosa, E., Campo, R.D., Fernández, R., Rodríguez, J.A., álvarez, J., González, E., Hernández, O., Solano, R., Pérez-Crespo, J., Arellano, P., Zavala, E., Martínez, J., Torres, A., Badia, J., Alba, F., Corpas, R., Muriel, A., Sagredo, V., Taboada, F., Albaiceta, G.M., Bobillo, F., Tamayo, L., Labattut, A.G., Carriedo, D., Collado, J., Diaz, F.J., Valledor, M., Antuña, M., de Frutos, M., López, M.J., Cortina, J.J., Saldaña, T., Caballero, A., álvarez, T., álvarez, B., Sandoval, J.

Tumour necrosis factor-alpha antagonist drugs represent a significant advance in the treatment of inflammatory diseases, such as rheumatoid arthritis, spondyloarthropathies, and intestinal inflammatory disease. The increase in tuberculosis with infliximab is known, but there is less data available that specifically associates tuberculosis with adalimumab. We present the cases of 2 patients with rheumatoid arthritis and one patient with ankylopoietic spondylitis on treatment with adalimumab, who developed pulmonary and disseminated tuberculosis despite following the screening and prophylaxis measures recommended in guidelines. We also review the association between treatment with tumour necrosis factor-alpha antagonists and tuberculosis.

a b s t r a c t Silicosis is one of the occupational respiratory diseases most commonly encountered in our setting. It is caused by inhalation of crystalline silica that triggers a fibrotic response in the lung parenchyma. It presents as diffuse interstitial disease and clinical expression ranges from asymptomatic forms to chronic respiratory failure. Diagnosis is based on clinical history and radiological findings. There is no effective treatment, and once diagnosed, the patient must avoid all sources of occupational exposure. In these guidelines, the clinical, radiological, and functional aspects of silicosis are reviewed, and strategies for diagnosis, monitoring, and classification of patients are proposed, along with recommendations regarding the occupational implications of this disease.

Producción Científica, Polynuclear neutrophils can play dual roles in sepsis: on the one hand they mediate major antimicrobial activities and on the other hand they can contribute to the development of multiple organ failure [1]. Nonetheless, in spite of the importance of these cells in sepsis, the influence of the circulating neutrophil count (CNC) on the prognosis of septic patients with this pathology has not been properly evaluated. We analyzed the association between CNC and outcome in two cohorts of patients with diagnostic criteria of septic shock (SS) [2]: the first was recruited in the context of a single center study (EXPRESS study, discovery cohort, n = 195; Table 1), and the second in the context of a multi-centric study (GRECIA study, validation cohort, n = 194; Table 2). Written informed consent was obtained from each patient or their legal representative. The two studies were approved by the Research Ethics Committee of the Hospital Clínico Universitario, Valladolid, Spain (for the EXPRESS study) and Hospital Universitario Río Hortega, Valladolid, Spain (coordinating center for the GRECIA study)., Instituto de Salud Carlos III (grant PI 10/01362), Junta de Castilla y León (grant BOCYL-D-26072010)

Residual beta-cell function and gastrointestinal hormones have been suggested as relevant determinants of improved glycemic control ensuing Roux-en-Y gastric bypass (RYGB). The objective of this study was to compare the glycemic control up to 24 months after RYGB in C-peptide negative morbidly obese (MO) type 1 diabetes mellitus (T1 DM) women (n = 7) and C-peptide positive (.6 ng/mL) MO women with type 2 diabetes mellitus (T2 DM, n = 7) on basal-bolus insulin therapy. The glucagon-like peptide 1 (GLP-1) and glucagon response to a mixed meal challenge were also compared between groups.Percent excess weight loss (%EWL), HbA1c, and daily insulin dose (DID) after RYGB were compared between groups. The GLP-1 and glucagon response (area under the curve 0-120 minutes) after a mixed meal at last follow-up visit were also compared.At 24-months, marked %EWL was observed in women with T1 DM and women with T2 DM (mean±standard error, 82.6% ± 11.3% and 87.4% ± 30.5%, respectively; P = .722]. In women with T1 DM, HbA1c (4 months, P.05) and DID improved transiently (P.05, up to 8 months) but were comparable to baseline thereafter (HbA1c: baseline, 8.3 ± 1.2 and 24 months, 8.2 ± .9, P = 1.00; DID: baseline, .61 ± .17 and 24 months .62 ± .12 IU/kg/d, P = 1.00]. In contrast, in MO women with T2 DM, HbA1c decreased significantly throughout follow-up, with 2 patients presenting diabetes remission and all but one an HbA1c7% at 24 months. The GLP-1 response was comparable between groups (P = .612), and was not accompanied by suppression of the glucagon response to meal intake.In the absence of residual beta-cell, RYGB results in no significant benefit on glycemic control, despite a marked response of GLP-1 to meal intake.