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AimTo examine the trajectory of forced expiratory volume in 1 s (FEV1) using data from the European Cystic Fibrosis (CF) Society Patient Registry collected from 2008 to 2016, hence the era before highly effective modulator therapy (HEMT). We evaluated risk factors for FEV1 decline.MethodsThe study population included patients with a confirmed diagnosis of CF recorded in the ECFPR (2008–2016). The evolution of FEV1% predicted with age (%FEV1), and the yearly change in %FEV1 were evaluated. Risk factors considered wereCFTRmutation class, gender, age at diagnosis, neonatal screening, meconium ileus, sweat chloride concentration at diagnosis, and country's income level.ResultsWe used 199,604 FEV1 recordings from 38,734 patients. The fastest decline was seen during puberty and in patients diagnosed before ten years. Males had a higher %FEV1 but a higher yearly %FEV1 loss between ages 15 and 25. We showed stabilization and even improvement in %FEV1 over age in adults with a class III mutation but a steady decline in patients homozygous for F508del or with both mutations of classes I/II. A faster decline in %FEV1 was found in patients from 'low-income' countries compared to a similar %FEV1 evolution in patients from middle- and high-income countries.ConclusionsThese longitudinal FEV1 data reflect the reality of CF across Europe in the era pre-HEMT and can serve as baseline for comparison with the post-HEMT era. The similar evolution in middle- and high-income countries underlines opportunities for low-income countries.

Long-term treatment with inhaled antibiotics is recommended for people with cystic fibrosis (pwCF) chronically infected with Pseudomonas aeruginosa (PA). However, pwCF without chronic PA infection are also commonly treated with inhaled antibiotics. Using data from the European Cystic Fibrosis Patient Registry (ECFSPR) we aimed to determine the prevalence and factors associated with inhaled antibiotic treatment in pwCF without chronic PA infection, and long-term outcomes with inhaled antibiotics use.The ECFSPR was searched for pwCF 6 years of age and older who were not chronically infected with PA at baseline. Factors associated with inhaled antibiotic use were first assessed through a logistic regression. From this model a propensity score was computed for each individual, providing the likelihood of being treated with inhaled antibiotics. Long-term outcomes with and without inhaled antibiotics were assessed separately for propensity scores tertiles.7210 pwCF without chronic PA infection at baseline were included, with 2722 (37.75%) receiving long-term treatment with inhaled antibiotics. Treatment with inhaled antibiotics was more prevalent with severe genotype, diabetes, pancreatic insufficiency, and past infection with chronic PA (OR 3.8, 95% CI, 2.88-5.04). Treatment with inhaled antibiotics was not associated with a reduced risk for acquisition of PA or other resistant pathogens, or with improved lung function decline, mortality, or transplantation.Many pwCF without chronic PA infection are receiving long-term treatment with inhaled antibiotics despite lack of support from clinical trials or practice guidelines. We did not observe improve outcomes with inhaled antibiotics. Our findings suggest controlled studies evaluating specific inhaled antibiotic regimens targeting specific pathogens or indications be performed to determine their effect.

Simone Gambazza,1,2,* Annalisa Orenti,2,* Giovanna Pizzamiglio,3 Anna Zolin,2 Carla Colombo,4,5 Dario Laquintana,1 Federico Ambrogi2,6 On behalf of ECFSPR1Healthcare Professions Department, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; 2Department of Clinical Sciences and Community Health, Laboratory of Medical Statistics, Biometry and Epidemiology “G. A. Maccacaro”, Università degli Studi di Milano, Milan, Italy; 3Cystic Fibrosis Center – Adult Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; 4Cystic Fibrosis Center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; 5Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy; 6Scientific Directorate, IRCCS Policlinico San Donato, San Donato Milanese, MI, Italy*These authors contributed equally to this workCorrespondence: Simone Gambazza, Healthcare Professions Department, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, Milan, 20122, Italy, Email simone.gambazza@policlinico.mi.itBackground: Association between dependence on oxygen therapy (OT) and natural disease progression in people with cystic fibrosis (pwCF) has not been estimated yet. The aim of this study is to understand the prognosis for pwCF on OT, evaluating how the transition probabilities from being alive without lung transplantation (LTx) to LTx and to death, and from being alive after LTx to death change in pwCF with and without OT.Methods: We used 2008– 2017 data from the 35-country European CF Society Patient Registry. A multi-state model was fitted to assess the effects of individual risk factors on transition probabilities.Results: We considered 48,343 pwCF aged from 6 to 50 years. OT (HR 5.78, 95% CI: 5.32– 6.29) and abnormal FEV1 (HR 6.41, 95% CI: 5.28– 7.79) were strongly associated with the probability of having LTx; chronic infection with Burkholderia cepacia complex (HR 3.19, 95% CI: 2.78– 3.67), abnormal FEV1 (HR 5.00, 95% CI: 4.11– 6.08) and the need for OT (HR 4.32, 95% CI: 3.93– 4.76) showed the greatest association with the probability of dying without LTx. Once pwCF received LTx, OT (HR 1.75, 95% CI: 1.41– 2.16) and abnormal FEV1 (HR 1.63, 95% CI: 1.18– 2.25) were the main factors associated with the probability of dying. An association of gross national income with the probability of receiving LTx and with the probability of dying without LTx was also found.Conclusion: Oxygen therapy is associated with poor survival in pwCF with and without LTx; harmonization of CF care throughout European countries and minimization of the onset of pulmonary gas exchange abnormalities using all available means remains of paramount importance.Keywords: cystic fibrosis, oxygen therapy, epidemiology, mortality, lung transplantation

During follow-up patients may experience non-fatal events related to disease progression and death. This is a “semi-competing risks” setting, as the occurrence of death before non-fatal events prevents the observation of the latter, but not vice versa. We developed a regression model for non-fatal event free survival in the presence of semi-competing risks based on pseudo-values. It is estimated in three steps: estimate non-parametrically non-fatal event free survival under a defined copula representing the joint distribution of time to fatal and non-fatal events; compute non-fatal event free survival pseudo-values for every individual at predefined time points; fit a GEE model using pseudo-values as a response variable. A simulation study is performed and two clinical examples are analysed. The proposed method provides covariate coefficient estimates almost unbiased, with standard errors slightly higher than those obtained with methods based on maximum likelihood estimation. However, pseudo-values regression, being based on estimation functions, has the advantage of enabling adjusted covariate effects estimation without convergence problems and allowing a direct smoothed estimate of the hazard function. Moreover, standard routines computing pseudo-values and GEE are available in statistical software.

This paper presents a robust two-stage procedure for identification of outlying observations in regression analysis. The exploratory stage identifies leverage points and vertical outliers through a robust distance estimator based on Minimum Covariance Determinant (MCD). After deletion of these points, the confirmatory stage carries out an Ordinary Least Squares (OLS) analysis on the remaining subset of data and investigates the effect of adding back in the previously deleted observations. Cut-off points pertinent to different diagnostics are generated by bootstrapping and the cases are definitely labelled as good-leverage, bad-leverage, vertical outliers and typical cases. The procedure is applied to four examples.

Introduction: Most patients evaluated for suspected pulmonary embolism(PE) conclude the Emergency Department(ED) work-up with a diagnosis of PE not confirmed(PE excluded;PE-E). We aimed to investigate the clinical features, short and long-term mortality, and prognostic factors for death in elderly with PE-E, and to compare these figures with those of patients with PE confirmed(PE-C). Methods: Consecutive patients ≥65 years old evaluated in the ED for clinically suspected hemodynamically stable acute PE were included in this retrospective cohort study. Results: Study population: 657 patients with suspected PE, PE-C:162(24.65%). When compared with PE-C, patients with PE-E presented a higher prevalence of chronic cardiopulmonary disease (17.37% vs 8.02%, p = 0.003), a lower prevalence of pulse rate >110 (13.13% vs 25.93%; p0 was associated with higher short and long-term mortality (30-day:HR:5.31,p = 0.029; 5 year:HR:2.18, p < 0.001), meanwhile comorbidity (Charlson Comorbidity Index>0) only with higher long-term mortality (30-day: HR:1.60, p = 0.342; 5 year: HR:1.41, p = 0.038). Conclusion: In real world haemodinamically stable elderly patients evaluated in the ED for suspected PE, short and long-term mortality was markedly high regardless whether PE was confirmed or excluded. At the time to set management and follow up strategies, elderly patients with PE excluded should not be considered a low-risk population.

RATIONAL: People with cystic fibrosis carrying residual function (RF) mutations are considered to have a mild disease course. This may influence caregivers and patients on how intensive the treatments should be.OBJECTIVES: Characterize disease severity of patients carrying RF mutations, using the European CF Society Patient Registry (ECFSPR) data.METHODS: Demographic, clinical characteristics, lung function and death probability of patients carrying at least one RF mutation were analyzed and compared to patients homozygous to minimal function mutations (MF).MAIN RESULTS: Of the 44,594 eligible patients (median age 19.5 years, IQR 10-29.8), 6,636 (14.6%) carried RF mutations, and 37,958 (85.1%) MF mutations. Patients carrying RF mutations were older, diagnosed at a later age, had lower sweat chloride at diagnosis and better FEV1pp at each age group. However, their FEV1pp declined with age and rates of chronic Pseudomonas aeruginosa increased with age. A significant number of patients with RF had FEV1pp similar to patients with MF at each age group. 4.5% of RF patients were treated with oxygen and 2.61% had a lung transplant. With increasing age, 26.6% of RF patients were treated with pancreatic enzymes associated with a more severe lung disease. RF patients had shortened life spans, with mortality starting around the age of 20 years.CONCLUSIONS: Patients carrying an RF mutations experience a decline of pulmonary function with age, leading to life-shortening. Standard of care therapies and augmenting CFTR function may improve their survival and quality of life.

Objectives To analyze the impact of different patterns of healthcare delivery on remission of rheumatoid arthritis (RA) patients treated with targeted therapies during the first wave (2020) and second/third waves (2021) of the pandemic compared to the pre-pandemic period (2019). Methods In this observational real-life study, data from RA patients treated with biologic or targeted synthetic drugs were extracted from a longitudinal registry. Clinical Disease Activity Index (CDAI) was analyzed in the same period from the 22nd of February to the 18th of May for three consecutive years. These three periods were characterized by different patterns of healthcare delivery: (1) before the pandemic (2019) only in-person visits, (2) during the first wave (2020) both in-person visits and telehealth, and (3) during the second/third waves (2021) only in-person visits. A generalized linear model with the binomial error was fitted to evaluate the difference in the proportion of patients in CDAI remission. Quantile regression was used to compare the median of CDAI in difficult-to-treat (D2T) patients. Results In the three periods, we included 407, 450, and 540 RA patients respectively. The percentages of patients in CDAI remission were similar in the three periods (prevalence ratio 1.07, p value 0.423 between 2020 and 2019, and 1.01, p-value 0.934 between 2021 and 2019). The CDAI remission rate was 40.55% ( N = 163), 43.18% ( N = 155) and 40.82% ( N = 220) in 2019, 2020 and 2021, respectively. Among our cohort of D2T patients, CDAI remission was similar across the three periods ( N = 30, 22.22%; N = 27, 23.68%; and N = 34, 21.52% respectively). Conclusion Although the pandemic has imposed changes in our healthcare delivery, these different strategies seem to be effective in ensuring satisfactory management of RA treated with targeted therapies. The approaches modulated in the context of the different periods have been a feasible compensation for ensuring disease control even in D2T patients.

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in people with cystic fibrosis (pwCF) can lead to severe outcomes.MethodsIn this observational study, the European Cystic Fibrosis Society Patient Registry collected data on pwCF and SARS-CoV-2 infection to estimate incidence, describe clinical presentation and investigate factors associated with severe outcomes using multivariable analysis.ResultsUp to December 31, 2020, 26 countries reported information on 828 pwCF and SARS-CoV-2 infection. Incidence was 17.2 per 1000 pwCF (95% CI: 16.0–18.4). Median age was 24 years, 48.4% were male and 9.4% had lung transplants. SARS-CoV-2 incidence was higher in lung-transplanted (28.6; 95% CI: 22.7–35.5) versus non-lung-transplanted pwCF (16.6; 95% CI: 15.4–17.8) (p≤0.001).SARS-CoV-2 infection caused symptomatic illness in 75.7%. Factors associated with symptomatic SARS-CoV-2 infection were age >40 years, at least one F508del mutation and pancreatic insufficiency.Overall, 23.7% of pwCF were admitted to hospital, 2.5% of those to intensive care, and regretfully 11 (1.4%) died. Hospitalisation, oxygen therapy, intensive care, respiratory support and death were 2- to 6-fold more frequent in lung-transplanted versus non-lung-transplanted pwCF.Factors associated with hospitalisation and oxygen therapy were lung transplantation, cystic fibrosis-related diabetes (CFRD), moderate or severe lung disease and azithromycin use (often considered a surrogate marker for Pseudomonas aeruginosa infection and poorer lung function).ConclusionSARS-CoV-2 infection yielded high morbidity and hospitalisation in pwCF. PwCF with forced expiratory volume in 1 s

COVID-19 pandemic in its early months has deeply influenced rheumatic patients’ follow-up in terms of treatment adherence, disease control achieved with treat-to-target and tight-control strategies. Nationwide mitigation strategies such as confinement, travel restrictions and inadequate access to routine visits catalysed the rapid switch to remote rheumatologic consultations as an attempt to partially compensate for the decline of in-person outpatient visits. This observational retrospective study was conducted to establish if the hybrid of in-person and telephone tight-control approach activated by our rheumatology unit in Milan (Italy) during the first lockdown (LD) period has been effective in maintaining remission in patients with rheumatoid arthritis (RA) treated with targeted therapies and to identify potential factors associated with its maintenance. Data were extracted from a longitudinal observational registry (Eethics Committee 138_1999) including consecutive adult patients with RA treated with biologic or targeted synthetic drugs. During the first pandemic wave, before the visit, rheumatologists provided virtual care handled by telephone to assess the clinical status and to guarantee the absence of current contraindications to therapy. After tele counselling, based on the care required, patients …

Background: Viral infections can cause significant morbidity in cystic fibrosis (CF). The current Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic could therefore have a serious impact on the health of people with CF (pwCF). Methods: We used the 38-country European Cystic Fibrosis Society Patient Registry (ECFSPR) to collect case data about pwCF and SARS-CoV-2 infection. Results: Up to 30 June 2020, 16 countries reported 130 SARS-CoV-2 cases in people with CF, yielding an incidence of 2.70/10 0 0 pwCF. Incidence was higher in lung-transplanted patients (n = 23) versus non transplanted patients (n = 107) (8.43 versus 2.36 cases/10 0 0). Incidence was higher in pwCF versus the age-matched general population in the age groups < 15, 15-24, and 25-49 years (p < 0.001), with similar trends for pwCF with and without lung transplant. Compared to the general population, pwCF (regardless of transplantation status) had significantly higher rates of admission to hospital for all age groups with available data, and higher rates of intensive care, although not statistically significant. Most pwCF recovered (96.2%), however 5 died, of whom 3 were lung transplant recipients. The case fatality rate for pwCF (3.85%, 95% CI: 1.26-8.75) was non-significantly lower than that of the general population (7.46%; p = 0.133). Conclusions: SARS-CoV-2 infection can result in severe illness and death for pwCF, even for younger patients and especially for lung transplant recipients. PwCF should continue to shield from infection and should be prioritized for vaccination. (c) 2021 The Authors. Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )

Introduction The prognostic accuracy of D-dimer for risk assessment in acute Pulmonary Embolism (APE) patients may be hampered by comorbidities. We investigated the impact of comorbidity burden (CB) by using the Charlson Comorbidity Index (CCI), on the prognostic ability of D-dimer to predict 30 and 90-day mortality in hemodynamically stable elderly patients with APE. Methods All patients aged >65 years with normotensive APE, consecutively evaluated in the Emergency Department since 2010 through 2014 were included in this retrospective cohort study. Area under the curve (AUC) and ½ Net Reclassification Improvement (NRI) were calculated. Results Study population: 162 patients, median age: 79.2 years. The optimal cut-off value of CCI score for predicting mortality was ≤1 (Low CB) and >1 (High CB), AUC = 0.786. Higher levels of D-dimer were associated with an increased risk death at 30 (HR = 1.039, 95%CI:1.000–1.080, p = 0.049) and 90 days (HR = 1.039, 95%CI:1.009–1.070, p = 0.012). When added to simplified Pulmonary Embolism Severity Index (sPESI) score, D-dimer increased significantly the AUC for predicting 30-day mortality in Low CB (AUC = 0.778, 95%CI:0.620–0.937, ½NRI = 0.535, p = 0.015), but not in High CB patients (AUC = 0.634, 95%CI:0.460–0.807, ½ NRI = 0.248, p = 0.294). Similarly, for 90-day mortality D-dimer increased significantly the AUC in Low CB (AUC = 0.786, 95%CI:0.643–0.929, ½NRI = 0.424, p-value = 0.025), but not in High CB patients (AUC = 0.659, 95%CI:0.541–0.778, ½NRI = 0.354, p-value = 0.165). Conclusion In elderly patients with normotensive APE, comorbidities condition the prognostic performance of D-dimer, which was found to be a better predictor of death in subjects with low CB. These results support multimarker strategies for risk assessment in this population.

Objective We aimed to study in SSc patients macrovascular involvement by using power Doppler ultrasound (PDUS) and microvascular one by PDUS and nailfold video-capillaroscopy (NVC) and to examine the association between history of digital ulcers (HDU) and imaging (PDUS and NVC) parameters. Methods NVC and PDUS were systematically performed in 106 consecutive SSc patients at the 3rd and 4th finger of the dominant hand after exclusion of ulnar artery occlusion (UAO). 22 MHz PDUS measurements included nailbed and fingertip qualitatively graded, and resistivity index (RI) of ulnar and radial proper digital arteries. Capillary number/mm was calculated by NVC on the same digits examined by PDUS. Results Vascularization at fingertip and nailbed showed a good correlation between them and to capillary number. RI, representative of macrovascular involvement, did not correlate to microvascular involvement as assessed by PDUS and NVC. RI and capillary number at NVC showed significant correlation to HDU while fingertip and nailbed vascularization as assessed by PDUS did not. As such, PDUS and NVC provide different and potentially complementary information on SSc-related peripheral macro- and micro-vascular involvement. Conclusion Macro- and micro-vascular involvement in SSc patients are different processes and are not present at the same time in every patient. Thus, both these aspects should be carefully evaluated in SSc patients.

Warfarin-related nephropathy is an unexplained acute kidney injury, and may occur in patients with supratherapeutic INR, in the absence of overt bleeding. Similar findings have been observed in rats treated with dabigatran etexilate. We conducted a prospective study in dabigatran etexilate-treated patients to assess the incidence of dabigatran-related nephropathy and to investigate the possible correlation between dabigatran plasma concentration (DPC) and worsening renal function. One hundred and seven patients treated long term with dabigatran etexilate for non-valvular atrial fibrillation (NVAF) were followed up for 90 days. DPC, serum creatinine (SCr) and serum cystatin C were prospectively measured. Ninety five patients had complete follow-up data and were evaluable for primary endpoint. Eleven patients had supratherapeutic DPC, defined as DPC higher than 200 ng/ml at study enrolment, but at the end of follow-up no patient showed a persistent increase in SCr. No patients experienced acute kidney injury. Our study shows that no persistent renal detrimental effect is associated with dabigatran treatment. An increase in SCr during dabigatran treatment is reversible and it seems to be unrelated to dabigatran itself.

We propose a two stage robust regression procedure to be applied when outliers and leverage points are present. It takes advantage of a high breakdown point MCD estimator and an efficient redescend...

BACKGROUND Emerging evidence suggests an association between COVID‐19 and acute pulmonary embolism (APE). AIMS To assess the prevalence of APE in patients hospitalized for non‐critical COVID‐19 who presented clinical deterioration, and to investigate the association of clinical and biochemical variables with a confirmed diagnosis of APE in these subjects. METHODS All consecutive patients admitted to the internal medicine department of a general hospital with a diagnosis of non‐critical COVID‐19, who performed a Computer Tomography Pulmonary Angiography (CTPA) for respiratory deterioration in April 2020, were included in this retrospective cohort study. RESULTS Study populations: 41 subjects, median(IRQ)age:71.7(63‐76)years, CPTA confirmed APE=8(19.51%,CI95%:8.82%‐34.87%). Among patients with and without APE, no significant differences were found with regards symptoms, comorbidities, treatment, Wells score and outcomes. The optimal cut‐off value of D‐dimer for predicting APE was 2454 ng/mL, sensitivity(CI95%):63(24‐91), specificity:73(54‐87), Positive Predictive Value:36(13‐65), Negative Predictive Value: 89(71‐98) and AUC:0.62(0.38‐0.85). The standard and age‐adjusted D‐dimer cut‐offs, and the Wells score >2 did not associate with confirmed APE, albeit a cut‐off value of D‐dimer=2454 ng/mL showed an RR:3.21;CI95%:0.92‐13.97;p=0.073. Heparin at anticoagulant doses was used in 70.73% of patients before performing CTPA. CONCLUSION Among patients presenting pulmonary deterioration after hospitalization for non‐critical COVID‐19, the prevalence of APE is high. Traditional diagnostic tools to identify high APE pre‐test probability patients do not seem to be clinically useful. These results support the use of a high index of suspicion for performing CTPA to exclude or confirm APE as the most appropriate diagnostic approach in this clinical setting. This article is protected by copyright. All rights reserved.

INTRODUCTION. Emerging evidence associates COVID-19 to an increased risk of acute pulmonary embolism (APE). The present study aimed to assess the prevalence of APE in patients admitted to internal medicine department wards for non-critical COVID-19 who presented clinical deterioration, and to investigate the association of clinical and biochemical variables with a confirmed diagnosis of APE in these subjects. METHODS. All consecutive patients admitted to the internal medicine department of a general hospital with a diagnosis of non-critical COVID-19, who performed a Computer Tomography Pulmonary Angiography(CTPA) for respiratory deterioration in April 2020, were included in this retrospective cohort study. RESULTS. Study populations: 41 subjects, median(IRQ) age: 71.7(63-76) years, CPTA confirmed APE=8(19.51%,CI95%:8.82%-34.87%). Among patients with and without APE, no significant differences were found with regards symptoms, comorbidities, treatment, Wells score and outcomes. The optimal cut-off value of D-dimer for predicting APE was 2454 ng/mL, sensitivity(CI95%):63(24-91), specificity:73(54-87), Positive Predictive Value:36(13-65), Negative Predictive Value: 89(71-98) and AUC:0.62(0.38-0.85). The standard and age-adjusted D-dimer cut-offs, and the Wells score > 2 did not associate with confirmed APE, albeit a cut-off value of D-dimer=2454 ng/mL showed an RR:3.21;CI95%:0.92-13.97;p=0.073.CONCLUSION. Among patients presenting pulmonary deterioration after admission to internal medicine wards for non-critical COVID-19, the prevalence of APE was high. The traditional diagnostic tools to identify high APE pre-test probability patients does not seem to be clinically useful. These results support the use of a low threshold of suspicion for performing CTPA to exclude or confirm APE as the most appropriate diagnostic approach in this clinical setting.

Inhaled therapies are relatively simple and easy to be managed however ineffective use of aerosols when self-administered may occur. We described variation of the number of clinic visits, lung function and number of antibiotic courses performed over 12 months in participants with cystic fibrosis (CF), when supervised or not by physiotherapists (PTs) at home. Participants in 8 Italian CF centers with a prescription of dry-powder antibiotic choose whether to be supervised at home (PT-FU) or not (non-PT-FU), in adjunct to routine clinic visits. PTs assisted participants with their inhaled therapies regimen and reviewed the airway clearance program in use. Mixed-effect regression models were fitted to evaluate the variation of selected endpoints over time. A total of 163 participants were included. Lung function declined over time in both groups, at higher extent in the non-PT-FU group at 6 months (-1.8, 95%CI: -4.4 to 0.7 % predicted), without reaching statistical significance, whereas in the PT-FU group only, nearly one visit less was recorded (p=0.027). Regardless the type of supervision adopted, the number of antibiotic courses did not change compared to the previous year. We counted 19/90 (21.1%) drop-out in the PT-FU, double compared to the group followed up at the clinics (p=0.065). Participants under a course of an inhaled antibiotic therapy showed a 1-year decline in lung function, whereas only the group receiving home supervision counted nearly one visit less at the CF center, whose clinical relevance should be further discussed.

BackgroundMedian survival for cystic fibrosis (CF) patients in Europe is unknown and is likely to be influenced by socioeconomic factors. Using the European CF Society Patient Registry (ECFSPR), median survival estimates were obtained for CF patients across Europe and the impact of socioeconomic status on survival was examined.MethodsCF subjects known to be alive and in the ECFSPR between 2010 and 2014 were included. Survival curves were estimated using the Kaplan–Meier method. Differences in the survival curves were assessed using the log-rank test. Cox regression was used to estimate the association between socioeconomic factors and the age-specific hazard of death, with adjustment for sex, age at diagnosis, CF transmembrane conductance regulator (CFTR) genotype and transplant status.ResultsThe final analysis included 13 countries with 31 987 subjects (135 833 person-years of follow-up) and 1435 deaths. Median survival age for these patients in the ECFSPR was 51.7 (95% CI 50.0–53.4) years. After adjusting for potential confounders age at diagnosis, sex, CFTR genotype and transplant status, there remained strong evidence of an association between socioeconomic factors and mortality (pConclusionsMedian survival for patients with CF in Europe is comparable to that reported in other jurisdictions and differs by socioeconomic factors.

Background Monitoring changes in the epidemiology of cystic fibrosis (CF) pathogens is essential for clinical research, quality improvement, and clinical management. Methods We analyzed data reported to the European Cystic Fibrosis Society Patient Registry (ECFSPR) from 2011 to 2016 to determine the overall and the age-specific annual prevalence and incidence of selected CF pathogens and their trends during these years. The ECFSPR collects data on three chronic infections: Pseudomonas aeruginosa (PsA), Burkholderia cepacia complex Species (BCC) and Staphylococcus aureus (SA), as well as on the occurrence of non-tuberculous mycobacteria (NTM) and Stenotrophomonas maltophilia (SM). The same analyses were performed for different country groups, according to their gross national income (GNI). Results The pathogens with the highest prevalence were SA and PsA, with prevalence, in 2016, equal to 38.3% and 29.8% respectively, followed by SM (8.1%). The pathogens with the lowest prevalence were NTM (3.3%) and BCC (3.1%). The overall prevalence and incidence significantly decreased for PsA; they also decreased for BCC, while they increased significantly for SA. The overall prevalence of NTM and SM increased significantly. The most considerable prevalence changes were observed for PsA, which decreased across all income country groups and all age strata (with the exception of 0–1 years) The prevalence and incidence of pathogens differed significantly according to GNI. Conclusions The epidemiology of CF pathogens in Europe has changed; epidemiologic data differ significantly among countries with different socio-economic status. The causes of these observations are multifactorial and include improvements in clinical care and infection control.

Introduction Data on medium- and long-term prognostic factors for death in elderly patients with acute Pulmonary Embolism (APE) are lacking. The present study aimed to assess sPESI score and the Charlson Comorbidity Index (CCI) as medium- and long-term predictors of mortality in elderly patients with haemodinamically stable APE. Methods All consecutive patients aged≥65 years old, evaluated at the emergency department (ED) of our hospital from 2010 through 2014, with a final diagnosis of APE, were included in this retrospective cohort study. Results Study population:162 patients, female:36.5%, median age:79 years old, 74% presented a sPESI score>0, and 61% a CCI≥ 1. All causes mortality: 19.8%, 23.5%, 26.5%, 32.1% and 48.2% at 3, 6 months, 1, 2 and 5 years after APE. Univariate regression analysis: CCI≥1 was associated with a higher mortality at 3, 6 months, 1, 2 and 5 years. Multivariate Cox analysis: CCI≥1 associated with increased mortality at 3 months (HR:4.29; IC95%:1.46–12.59), 6 months (HR:5.33; IC95%:1.84–15.44), 1 year (HR:4.87; IC95%:1.87–12.70), 2 years (HR:3.78; IC95%:1.74–8.25), and 5 years (HR:2.30; IC95%:1.33–3.99). sPESI score≥1 was not found to be related to an increased medium-or long-term mortality. Negative predictive values (IC95%) of CCI≥1 were 93.65% (87.61–99.69), 93.65% (87.61–99.69), 92.06% (85.37–98.76), 87.3% (79.05–95.55) and 71.61% (60.13–83.1) for mortality at 3, 6 months, 1, 2 and 5 years. Conclusion In elderly patients with a confirmed normotensive APE, unlike sPESI score, CCI showed to be an independent prognostic factor for medium- and long-term mortality. In these patients, after the acute phase following a PE event, the assessment of the comorbidities burden represents the most appropriate approach for predicting medium- and long-term mortality., Public health; Cardiology; Cardiovascular system; Circulatory system; Hematological system; Respiratory system; Pulmonary embolism; Mortality; Prognosis; Aged

BACKGROUND: A1006E is a Cystic Fibrosis (CF) mutation that is still not widely known. We report phenotypic features and geographic distribution of the largest cohort of people with CF (pwCF) carrying A1006E to date. METHODS: Study of European pwCF carrying A1006E mutation, included in the European CF Society Patient Registry (ECFSPR). Genotype, ancestries and all variables recorded were compared to a cohort of F508del/F508del patients. Rate of decline in percentage-of-predicted FEV(1) (ppFEV(1)) was also analyzed using the 2010-2017 ECFSPR. RESULTS: 44 pwCF carrying A1006E were reported (59% males), median age 33 years old (3-58), 54.5% Spanish and 40.9% Italian, most with ancestry in Murcia (Spain) and Lazio (Italy) regions. Compared to F508del homozygous, A1006E-pwCF were significantly older (75% vs. 52.5% = 18 years old) and diagnosed at later median age (6.98 vs. 0.29 years); showed lower rates of meconium ileus (2.33% vs. 17.7%), pancreatic insufficiency (27.91% vs. 99.26%), diabetes (2.33% vs. 21.98%), liver disease (6.98% vs. 36.72%) and Pseudomonas aeruginosa chronic colonization (30.95% vs. 42.51%); and presented better nutrition (BMI z-score 0.44 vs. -0.43) and ppFEV(1) (90.8% vs. 78.6%), with 18.9% (most >40 years old) having a ppFEV(1)

The assessment of planned discharges: agreement between BRASS index and clinical judgement.The BRASS (Blaylock Risk Assessment Screening Score) index is a risk screening tool for identification of patients at risk of difficult discharge.To assess the agreement of discharge options between the BRASS classification and the nurses' clinical judgement.Consecutive patients admitted to surgical wards of a large Italian hospital from November 2016 to June 2017 were assessed with the BRASS index within 48 hours from admission and 24 hours before discharge. After discharge a group of expert nurses, blind to the BRASS score and patient effective destination, planned the patients' discharge reviewing the clinical records. Patients were classified as needing ordinary discharge, with support or to hospital.The 90% of the 428 included patients remained in the same BRASS risk class; the agreement between BRASS score (K Cohen) at admission and clinical judgement was 0.474 and 0.533 at discharge. Of the 96 subject at need of discharge with support or to hospital, 60 were classified in the same class by the BRASS Index. Factors that impacted on the different classification were patients' age, presence of devices and availability and appropriateness of social support.Most patients remained in the same BRASS class. There is moderate agreement between BRASS index and clinical judgement, specifically for patients at medium/high risk of difficult discharge. Our data confirm the need for including new items in the Brass scale.

Elderly patients presenting with acute pulmonary embolism (PE) frequently have significant underlying comorbidities which may condition the prognosis. The current study aimed to determine the ability of Charlson comorbidity index (CCI) score to predict short and long-term mortality in elderly patients with hemodynamically stable acute PE. All hemodynamically stable patients aged >65 years with acute PE, evaluated in the Emergency Department since 2010 through 2014, were included in this retrospective cohort study. CCI, simplified pulmonary embolism severity index (sPESI) scores and vital status were recorded. Were included 162 patients with confirmed PE, out of 657 suspected cases (24.7%). Median age: 79.2 years, 74.1% presented an sPESI > 1 and 61.1% a CCI > 1. The overall 30, 90-day and 2-year mortality was 11.7% (95%CI 6.6–16.6), 19.8% (95%CI 13.4–25.7) and 31.8% (95%CI 24.1–38.8). For 30-day mortality sPESI showed an AUC 0.642 (95%CI 0.511–0.772) and adding CCI as covariate did not increase its prognostic performance. For 90-day mortality, in an adjusted model including sPESI and CCI, CCI showed a HR 1.282 (95%CI 1.151–1.429, p-value < 0.001), and sPESI a HR = NS(p-value = 0.267). For 2-year mortality, in an adjusted model including sPESI and CCI, CCI showed a HR 1.295 (95%CI 1.180–1.421, p-value < 0.001) and sPESI a HR = NS(p-value = 0.353). In elderly patients with hemodynamically stable PE, the CCI score was found to be an independent predictor of mortality. CCI shows a significantly better ability to predict 90-day and 2-year mortality than sPESI. The assessment of comorbidity burden by using the CCI score may be proposed as an useful tool to predict mortality in these patients.

Background & aims In Caucasian patients with compensated cirrhosis caused by hepatitis B virus (HBV), the risk of hepatocellular carcinoma (HCC) developing persist despite long-term nucleos(t)ide analogs (NUC) treatment. In the surveillance of this population with persistently normal transaminases because of NUCs, the added value of serum alpha-foetoprotein (AFP) monitoring is poorly defined. Methods Two hundred and fifty-eight Caucasian HCC-free patients with HBV-compensated cirrhosis who started tenofovir or entecavir while having normal serum AFP levels (≤7 ng/mL) at baseline or within the first year of treatment underwent HCC surveillance by semiannual ultrasound evaluation and serum AFP determination. Results During 96 (18-120) months of antiviral therapy, 3947 AFP values were collected, median AFP level was 2 ng/mL. Thirty-five patients developed an HCC at an overall 8-year crude cumulative incidence of 14% (annual incidence of 2%). HCC incidence increased in parallel with increasing AFP thresholds: 24%, 36%, 64% and 92% for AFP levels after exceeding 2, 4, 6 and 7 ng/mL for the first-time. Of the 12 patients who experienced an AFP rise > 7 ng/mL, 11 developed an HCC and one had liver metastases of lung cancer. Overall, an AFP > 7 ng/mL had 99.6% specificity, 31.4% sensitivity, 91.7% PPV, 90.2% NPV, LR+ 70.1 and LR- 0.69 for HCC; this excellent specificity was maintained up to 18 months before HCC detection. Conclusions In Caucasian patients with HBV-compensated cirrhosis on long-term NUC, an increase in AFP over 7 ng/mL shows excellent specificity, heralding HCC development within 1 year.

Background: Monitoring changes in the epidemiology of cystic fibrosis (CF) pathogens further improves our understanding of the potential impact of interventions. Methods: We performed a retrospective analysis using data reported to the European Cystic Fibrosis Society Patient Registry (ECFSPR) from 2011 to 2016 to determine the overall and the age specific annual prevalence and incidence of selected CF pathogens and their trends during these years. The ECFSPR collects data on three chronic infections: Pseudomonas aeruginosa (PsA), Burkholderia cepacia complex Species (BCC) and Staphylococcus aureus (SA), as well as on the occurrence of non-tuberculous mycobacteria (NTM) and Stenotrophomonas maltophilia (SM). The same analyses were performed after stratifying for different country groups, according to their gross national income (GNI). Findings: The pathogens with highest prevalence were SA and PsA, with prevalence rates, in 2016, equal to 38.27% and 29.83% respectively, followed by SM (8.14%). The pathogens with lowest prevalence were NTM (3.33%) and BCC (3.13%). The overall prevalence and incidence significantly decreased for PsA; they also decreased non-significantly for BCC, while they increased significantly for SA. The overall prevalence of NTM and SM increased significantly. Among the CF pathogens studied, PsA showed the largest changes in prevalence: it significantly decreased in all age strata, (except 0-1 years) and in all income countries groups. The prevalence and incidence of pathogens differed significantly according to GNI. For PA, BCC and SA the prevalence was significantly higher in lower income groups, while the prevalence and incidence of NTM was higher in countries with the highest income. Interpretation: The epidemiology of CF pathogens in Europe has changed over the 6-year study period; epidemiologic data differ significantly among countries with different socioeconomic status. The causes of these observations are likely multifactorial and include improvements in clinical care and infection prevention and control. Funding: None. Declaration of Interest: We declare that we have no conflicts of interest. Ethical Approval: Scientific and Steering committees of the European Cystic Fibrosis Society Patient Registry.

In a general population with acute Pulmonary Embolism (PE) elevated D-dimer concentrations associate with increased mortality. The aim of the study was to assess the ability of D-dimer to predict 30 and 90-days mortality in elderly patients with acute PE. Hemodynamically stable patients aged ≥65 years old with confirmed PE were included in this retrospective cohort study. A pulmonary computerized tomography angiography scan, D-dimer concentrations, simplified Pulmonary Embolism Severity Index (sPESI) variables and vital status were available for all patients. The study included 154 confirmed cases of PE (23.5 % of suspected), median age 79.1 years. D-dimer was higher in patients dead than in those alive at 30 (median 14,547 vs. 8340 ng/mL, p = 0.05) and 90 days (13,604 vs. 7973 ng/mL, p = 0.013). When adding D-dimer to sPESI, the discriminant capacity to predict mortality within 30 and 90 days was increased by 0.080 and 0.089, respectively. The contribution of D-dimer to the discriminating ability was NRI = 0.286 (95 % CI -0.198 to 0.770, p value: 0.247) at 30 days and NRI = 0.605 (95 % CI 0.223-0.988, p-value: 0.002) at 90 days.D-dimer concentration was associated with 30 and 90-days mortality and showed a higher discriminant capacity than sPESI alone to predict 90-days mortality. Adding D-dimer concentrations to sPESI score seems to improve its prognostic ability, supporting multivariable risk models as the best approach to estimate prognosis in elderly patients with PE.

To evaluate the associations between single nucleotide polymorphisms (SNPs) of factors involved in the development of invasive bacterial disease (IBD) in children, 47 SNPs of 18 candidate genes were analysed in 49 children with IBD and 100 controls. The G/T genotype of TLR2 rs2149356 and the C genotype of LTA rs2229094 were associated with significantly reduced risk of developing IBD ( P = 0.04 and P = 0.05, respectively), whereas the C/T genotype of RFP175 rs1585110 was associated with a significantly higher risk of developing IBD ( P = 0.02). These results support the evidence that some genetic variants of factors involved in innate immunity may influence IBD risk in children.

Despite the clear endocrine-metabolic relationship between androgenic activity and adiposity, the role of androgens in breast cancer prognosis according to patient's adiposity is scarcely explored. Here, we aimed at investigating the prognostic value of circulating testosterone in association with patient's body mass index (BMI).Circulating testosterone and BMI were evaluated at breast cancer diagnosis in 460 estrogen receptor (ER)-positive postmenopausal patients. Local relapse, distant metastasi(e)s and contralateral breast cancer were considered recurrence events. The Kruskal-Wallis test was performed to evaluate if testosterone levels differed within subgroups of categorical tumour characteristics. The Cox proportional hazard regression model was fitted to estimate the impact of standard prognostic factors on relapse-specific hazard ratio (HR). After backward selection, a model including continuous testosterone level, BMI categories ( 25, normal-weight; =25-30, overweight; ≥30 kg/mDuring a median follow up of 6.3 years, 45 patients relapsed. Testosterone levels significantly increased across BMI categories (p = 0.001). Both circulating testosterone and BMI were positively associated with disease free survival (p = 0.005 and p = 0.021, respectively). A significant interaction was found between testosterone and BMI (p = 0.006). For normal-weight women, testosterone concentration around median (0.403 ng/mL) or third quartile (0.532 ng/mL) showed a high significant HR of relapse (5.52; 95% CI:1.65-18.49 and 4.55; 95% CI:1.09-18.98, respectively). Overweight patients showed increased HR at increasing testosterone levels, reaching a significant high HR (4.68; 95% CI:1.39-15.70) for testosterone values of 0.782 ng/mL (95th percentile). For obese patients HR decreased (not significantly) at increased testosterone concentrations, explaining the interaction between testosterone levels and BMI categories.In ER-positive postmenopausal breast cancer patients, high testosterone levels are associated with worse prognosis in normal-weight and overweight women, whereas in obese seems to be associated with a better outcome. Although the results require further validation, they suggest that assessment of circulating testosterone and BMI could help to identify postmenopausal ER-positive patients at higher risk of relapse and potentially open new therapeutic strategies.

The objective of this study was to compare survival rate and clinical and radiological outcomes of a cementless mobile-bearing total ankle replacement (TAR) between two groups of patients, affected by end-stage ankle arthritis, with or without a pre-operative varus deformity.A total of 81 patients (81 ankles) were included in the study and divided in two groups. Group A, "varus" group, includes 11 patients with pre-operative varus deformity of more than 10 ° and group B, "neutral" group, includes 70 patients, with a varus/valgus deformity of less than 10 °. American Orthopedic Foot and Ankle Society (AOFAS) ankle-hindfoot score, visual analogue scale (VAS), and Short Form (SF)-12 score were used to compare clinical outcomes. Radiological parameters, complications, and survival rate at last follow-up were also recorded.In both groups, all clinical and radiological parameters improved after surgery (p 0.05) without statistically significant difference. Complications were similar between two groups. Overall in three cases, an implant revision was necessary: 1 in group A (9%) at 3.1 years follow-up and 2 (3%) in group B at 3.8 years, without statistically significant difference (p 0.001).Severe varus malalignment should not be considered a contraindication for a mobile-bearing TAR. Nevertheless, TAR in severe deformity should be performed only by experienced surgeons.

Background: Despite the clear endocrine-metabolic relationship between androgenic activity and adiposity, the role of androgens in breast cancer prognosis according to patient's adiposity is scarcely explored. Here, we aimed at investigating the prognostic value of circulating testosterone in association with patient's body mass index (BMI). Methods: Circulating testosterone and BMI were evaluated at breast cancer diagnosis in 460 estrogen receptor (ER)-positive postmenopausal patients. Local relapse, distant metastasi(e)s and contralateral breast cancer were considered recurrence events. The Kruskal-Wallis test was performed to evaluate if testosterone levels differed within subgroups of categorical tumour characteristics. The Cox proportional hazard regression model was fitted to estimate the impact of standard prognostic factors on relapse-specific hazard ratio (HR). After backward selection, a model including continuous testosterone level, BMI categories (, SCOPUS: ar.j, info:eu-repo/semantics/published

Background In systemic sclerosis (SSc) vascular involvement plays a pivotal role in the pathogenesis and clinical manifestations.1 Intravenous (IV) iloprost (ILO), a prostacyclin analogue, is administered in SSc, according to EULAR recommendations, to improve Raynaud’s phenomenon (RP) and to achieve digital ulcers (DU) healing and prevention,2 even though no further indications about the regimen are specified. Objectives The aim of this study was to evaluate acute and chronic effects of IV ILO administered with two different regimens as assessed by power Doppler ultrasound (PDUS) and nailfold videocapillaroscopy (NVC) and in a group of patients not treated with ILO. Methods This was a single centre pragmatic non-randomised trial on 96 patients with SSc divided in 3 groups: no ILO (group A), ILO once monthly (group B) and ILO for 5 consecutive days every 3 month (group C). At each evaluation patients underwent PDUS and NVC. Group A patients were examined at baseline and after 3 months. Group B every month before and after IV ILO monthly therapy for 3 months. Group C before and after the 1 and 5 days of therapy at baseline and after 3 months. PDUS parameters included resistivity index (RI), finger pulp blood flow (FPBF) and periungual vascularisation. The sum of capillaries apex width in one millimetre was assessed through NVC. Results were analysed considering the average outdoor temperature at the place of residence. Results An acute IV ILO effect was observed for FPBF in group B and C (p Conclusions IV ILO therapy was able to cause an acute effect with respect to PDUS parameters, especially in group B. The acute effect was not any longer maintained until the following infusion. Future studies are needed to assess time for re-treating. References [1] Matucci-Cerinic M, et al. Review: evidence that systemic sclerosis is a vascular disease. Arthritis Rheum. 2013;65(8):1953–62. [2] Kowal-Bielecka, et al. Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis. 2017;76(8):1327–1339. Acknowledgements We thank Meteo Operations Italia (MOPI) SrL – Centro Epson Meteo for providing temperature data. Disclosure of Interest None declared

Objectives I.v. iloprost (ILO) may be used in the treatment of refractory RP and digital ulcers. We aim to evaluate the acute and chronic effects of two different ILO regimens by power Doppler US (PDUS) and nailfold videocapillaroscopy. Methods In this 3-month single-centre pragmatic non-randomized trial, 96 SSc patients were included and stratified according to ILO treatment as: no ILO (group A), ILO once monthly (group B) and ILO for five consecutive days (group C). Resistivity index (RI), finger pulp blood flow and periungual vascularization by PDUS, and sum of capillaries apex width in 1 mm by nailfold videocapillaroscopy were evaluated. Results were adjusted for the average outdoor temperature at the place of residence. Results An acute ILO effect was observed for only finger pulp blood flow in groups B and C (P < 0.001 and P < 0.005, respectively). An acute effect was observed for RI and periungual vascularization only in group B. A progressive increase was observed for other parameters without statistical difference. ILO effects were not observed any longer before the following infusion. Some parameters (finger pulp blood flow in group B and RI in group C) showed a statistically higher increase the lower the outdoor temperature was. Conclusion ILO had an acute effect as assessed by PDUS, especially in group B. By contrast, an ILO chronic effect was not detectable before the following infusion in both treatment groups. More studies are needed to define how often ILO should be administered.

The BCH procedure introduced by Billor, Chatterjee, and Hadi for fitting linear models was found to be inefficient for y-outliers in the presence of a high perturbation level. We propose to modify the first step of the BCH procedure, so that the robust distances are computed on the matrix Z = (y, X) of the basic subset. The performance of the present note procedure (PNP), as compared to the BCH procedure and the ordinary least-square (OLS) method, was studied by processing several datasets used in the literature for robust regression and by performing a Monte Carlo experiment. PNP performs better particularly with datasets having high perturbation.

Evaluation of a therapeutic strategy is complex when the course of a disease is characterized by the occurrence of different kinds of events. Competing risks arise when the occurrence of specific events prevents the observation of other events. A particular case is semi-competing risks when only fatal events can prevent the observation of the non fatal ones. Kaplan-Meier is the most popular method to estimate overall or event free survival. On the other hand when a subset of events is considered and net survival is of concern, different estimators have been proposed. Kaplan-Meier method can be used only under the independence assumptions otherwise estimators based on multivariate distribution of times are needed. If causes of death are unknown, relative survival can approximate net survival only under specific assumptions on the mortality pattern. Kaplan-Meier method cannot be used to estimate crude cumulative incidence of specific events. The aim of this work is to present the survival functions used in competing risks framework, their non parametric estimators and semi parametric estimators for net survival based on Archimedean Copulas. This would be a help for the reader who is not experienced in competing risks analysis. A simulation study is performed to evaluate performances of net survival estimators. To illustrate survival functions in presence of different causes of death and of different kind of events a numerical example is given, a literature dataset on prostate cancer and a case series of breast cancer patients have been analysed.

In patients with Raynaud’s phenomenon (RP), the role of medical history, capillaroscopy, and autoantibodies in order to provide an early diagnosis of connective tissue disease (CTD) were examined. 115 consecutive adults with uni-, bi-, or triphasic colour changes of the fingers were studied. RP was bilateral in 92.7% of patients. The middle finger was significantly more affected. A lack of association between fingers affected by RP and fingers with capillary abnormalities was observedOR=0.75(0.34–1.66). RP with the cyanotic phase had a higher risk at capillaroscopy to have hemorrhagesOR=4.46(1.50–13.30) and giant capillariesOR=24.85(1.48–417.44). The thumb and triphasic involvement have an OR of 1.477 and 1.845, respectively. RP secondary to systemic sclerosis (SSc) had greater value of VAS pain (p=0.011). The presence of anti-centromere antibodies was significantly associated with a higher risk of SSc (p<0.001). 44.3% of subjects had uniphasic blanching of the fingers, and among these, 27% was diagnosed as having an overt or suspected CTD. Markers of a potential development of CTDs include severe RP symptoms, positive autoantibodies, and capillary abnormalities. These data support the proposal to not discharge patients with uniphasic blanching of the fingers to avoid missing the opportunity of an early diagnosis.