Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis

Altres ajuts: Fondo Europeo de Desarrollo Regional (FEDER), "A way of making Europe".Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including immune-mediated diseases. We investigated the association of C4 CN with systemic sclerosis (SSc) risk. Imputed total C4, C4A, C4B, and HERV-K CN were analyzed in 26,633 individuals and validated in an independent cohort. Our results showed that higher C4 CN confers protection to SSc, and deviations from CN parity of C4A and C4B augmented risk. The protection contributed per copy of C4A and C4B differed by sex. Stronger protection was afforded by C4A in men and by C4B in women. C4 CN correlated well with its gene expression and serum protein levels, and less C4 was detected for both in SSc patients. Conditioned analysis suggests that C4 genetics strongly contributes to the SSc association within the major histocompatibility complex locus and highlights classical alleles and amino acid variants of HLA-DRB1 and HLA-DPB1 as C4-independent signals

Oltre il soffitto di cristallo. Il difficile cammino delle donne.

Il libro rappresenta l’occasione per riflettere sul difficile percorso delle donne verso una effettiva parità di opportunità rispetto agli uomini, nel riconoscimento della differenza. Si divide in due parti. Nella prima la testimonianza di tre donne che sono andate oltre il soffitto di cristallo: Susanna Camusso, prima donna ad occupare la carica di segretario generale della CGIL; Silvana Arbia, unica donna dei tre principals della Corte penale internazionale all’Aja con ruolo di registral; Rosa Oliva, per merito di un suo ricorso il 13 maggio 1960 la Corte Costituzionale concede alle donne l’accesso alle carriere prefettizie e diplomatiche con una sentenza che aprirà la strada, tre anni dopo, anche della magistratura . Queste ultime due presentate rispettivamente da due giuriste: Carola Ricci e Silvia Illari. Nella seconda parte una riflessione più generale sulle ragioni che costringono ancora le donne in una situazione di subalternità e discriminazione. In tal senso Maria Antonietta Confalonieri traccia la storia degli organismi di parità e Agnese Canevari affronta il tema della democrazia paritaria, entrambe nel contesto del quadro italiano, europeo ed internazione. Barbarà Airò sposta lo sguardo alle donne protagoniste della primavera araba, sottolineando come l’apertura democratica conseguente a tali avvenimenti ha legittimato quei partiti di ispirazione islamici che stanno mettendo seriamente in discussione le conquiste ottenute dalle donne nel corso di questi ultimi decenni, se pure nel contesto di regimi autoritari. Infine Anna Rita Calabrò si chiede se e in che misura le donne siano in grado di produrre processi di cambiamento nel momento in cui cominciano ad occupare in numero significativo territori della vita pubblica fino a questo momento loro preclusi

[18F]FDG PET/CT: Lung Nodule Evaluation in Patients Affected by Renal Cell Carcinoma

Renal Cell Carcinoma (RCC) is generally characterized by low-FDG avidity, and [18F]FDG-PET/CT is not recommended to stage the primary tumor. However, its role to assess metastases is still unclear. The aim of this study was to evaluate the diagnostic accuracy of [18F]FDG-PET/CT in correctly identifying RCC lung metastases using histology as the standard of truth. The records of 350 patients affected by RCC were retrospectively analyzed. The inclusion criteria were: (a) biopsy- or histologically proven RCC; (b) Computed Tomography (CT) evidence of at least one lung nodule; (c) [18F]FDG-PET/CT performed prior to lung surgery; (d) lung surgery with histological analysis of surgical specimens; (e) complete follow-up available. A per-lesion analysis was performed, and diagnostic accuracy was reported as sensitivity and specificity, using histology as the standard of truth. [18F]FDG-PET/CT semiquantitative parameters (Standardized Uptake Value [SUVmax], Metabolic Tumor Volume [MTV] and Total Lesion Glycolysis [TLG]) were collected for each lesion. Sixty-seven patients with a total of 107 lesions were included: lung metastases from RCC were detected in 57 cases (53.3%), while 50 lesions (46.7%) were related to other lung malignancies. Applying a cut-off of SUVmax ≥ 2, the sensitivity and the specificity of [18F]FDG-PET/CT in detecting RCC lung metastases were 33.3% (95% CI: 21.4–47.1%) and 26% (95%CI: 14.6–40.3%), respectively. Although the analysis demonstrated a suboptimal diagnostic accuracy of [18F]FDG-PET/CT in discriminating between lung metastases from RCC and other malignancies, a semiquantitative analysis that also includes volumetric parameters (MTV and TLG) could support the correct interpretation of [18F]FDG-PET/CT images

Cohort enrichment strategies for progressive interstitial lung disease in systemic sclerosis from EUSTAR

BACKGROUND: Enrichment strategies from clinical trials for progressive systemic sclerosis-associated interstitial lung disease (SSc-ILD) have not been tested in a real-life cohort. RESEARCH QUESTION: Do enrichment strategies for progressive ILD impact efficacy, representativeness and feasibility in SSc-ILD patients from the European Scleroderma Trials and Research (EUSTAR) database? STUDY DESIGN AND METHODS: We applied the inclusion criteria of major recent SSc-ILD trials (focuSSced, SLS II and SENSCIS) and assessed progressive ILD, defined as absolute change in forced vital capacity (FVC) and as significant progression (FVC decline ≥10%). Data were compared to all patients and patients not fulfilling any inclusion criteria. RESULTS: In total, 2258 SSc-ILD patients were included, with 31.2% meeting SENSCIS, 5.8% SLS II, 1.6% focuSSced and 1529 (67.7%) not meeting any criteria. In the first 12+/-3 months, the absolute FVC decline in all and in patients fulfilling criteria from SENSCIS was -0.1%, from focuSSced -3.7%, and from SLS II 2.3%, with accompanying more progressors in focuSSced. The patient populations fulfilling the different study inclusion criteria significantly differed in various clinical parameters. In the second 12 months period, SENSCIS enriched patients had a further absolute FVC% decline as described for the total cohort. In contrast, patients fulfilling the focuSSced and SLS II criteria showed numerical improvement of lung function. There were no significant associations of enrichment criteria and ILD progression. INTERPRETATION: The application of enrichment criteria from previous clinical trials showed enrichment for progression with variable success, leading to selected patient populations reducing feasibility of recruitment. These findings are important for future clinical trial design and interpretation of the results of published trials

The role of TAPSE/sPAP ratio in predicting pulmonary hypertension and mortality in the systemic sclerosis EUSTAR cohort

OBJECTIVES The study aim was to evaluate the predictive role of the echocardiography-derived tricuspid annular plane systolic excursion/systolic pulmonary artery pressure (TAPSE/sPAP) ratio for pulmonary hypertension (PH) diagnosis and mortality in the European Scleroderma Trials and Research (EUSTAR) cohort. METHODS Eligible patients were systemic sclerosis (SSc) patients registered in the EUSTAR database with at least one visit recording TAPSE and sPAP data. Individual centres were required to provide TAPSE and sPAP data at 12 ± 3 months before right heart catheterization (RHC). Logistic regression analysis was applied to analyse the predictive ability of TAPSE/sPAP ratio for PH diagnosis. Cox regression analysis was performed to evaluate TAPSE/sPAP ratio as a predictive factor for all-cause mortality. RESULTS 2555 SSc patients met the inclusion criteria for this study with 355 SSc patients having available RHC data at baseline. PH was confirmed by RHC in 195 SSc patients (54.9%). TAPSE/sPAP ratio < 0.55 mm/mmHg [OR 0.251 (95% CI 0.084-0.753), p < 0.05] and FVC/DL$_{CO}$ [OR 2.568 (95% CI 1.227-5.375), p < 0.05] were significantly associated with PH diagnosis. In logistic regression analysis with echocardiographic parameters at 12 ± 3 months before RHC, TAPSE/sPAP ratio < 0.55 mm/mmHg [OR 0.265 (95% CI 0.102-0.685), p < 0.01] and FVC/DL$_{CO}$ [OR 2.529 (95% CI 1.358-4.711), p < 0.01] were associated with PH diagnosis. In multivariate Cox regression analysis, TAPSE/sPAP ratio ≤ 0.32 mm/mmHg [HR 0.310 (0.164-0.585), p < 0.001] was the most significant predictive factor for death. CONCLUSIONS TAPSE/sPAP ratio < 0.55 mm/mmHg is a predictive risk factor for PH. TAPSE/sPAP ratio ≤ 0.32 mm/mmHg is a predictive risk marker for all-cause mortality

Chronic Apical and Nonapical Right Ventricular Pacing in Patients with High-Grade Atrioventricular Block: Results of the Right Pace Study

Objective. The aim of the study was to compare the two approaches to chronic right ventricular pacing currently adopted in clinical practice: right ventricular apical (RVA) and non-RVA pacing. Background. Chronic RVA pacing is associated with an increased risk of atrial fibrillation, morbidity, and even mortality. Non-RVA pacing may yield more physiologic ventricular activation and provide potential long-term benefits and has recently been adopted as standard procedure at many implanting centers. Methods. The Right Pace study was a multicenter, prospective, single-blind, nonrandomized trial involving 437 patients indicated for dual-chamber pacemaker implantation with a high percentage of RV pacing. Results. RV lead-tip target location was the apex or the interventricular septum. RVA (274) and non-RVA patients (163) did not differ in baseline characteristics. During a median follow-up of 19 months (25th–75th percentiles, 13–25), 17 patients died. The rates of the primary outcome of death due to any cause or hospitalization for heart failure were comparable between the groups (log-rank test, p=0.609), as were the rates of the composite of death due to any cause, hospitalization for heart failure, or an increase in left ventricular end-systolic volume ≥ 15% as compared with the baseline evaluation (secondary outcome, p=0.703). After central adjudication of X-rays, comparison between adjudicated RVA (239 patients) and non-RVA (170 patients) confirmed the absence of difference in the rates of primary (p=0.402) and secondary (p=0.941) outcome. Conclusions. In patients with indications for dual-chamber pacemaker who require a high percentage of ventricular stimulation, RVA or non-RVA pacing resulted in comparable outcomes. This study is registered with ClinicalTrials.gov (identifier: NCT01647490)

Representativeness of Systemic Sclerosis Patients in Interventional Randomized Trials: an analysis of the EUSTAR database

To estimate the extent of and the reasons for ineligibility in randomized controlled trials (RCTs) of systemic sclerosis (SSc) patients included in the EUSTAR database, and to determine the association between patient's features and generalizability of study results

Phenotype of limited cutaneous systemic sclerosis patients with positive anti-topoisomerase I antibodies: data from EUSTAR cohort

Objectives: To characterize patients with positive anti-topoisomerase I (ATA) in the limited cutaneous Systemic Sclerosis (lcSSc). Methods: SSc patients enrolled in the EUSTAR cohort with disease duration ≤3 yrs at database entry were considered. We assessed the risk of major organ involvement in the following groups: 1) ATA-lcSSc vs anticentromere (ACA)-lcSSc and vs antinuclear antibodies without specificity (ANA)-lcSSc; 2) ATA-lcSSc vs ATA-diffuse cutaneous (dc)SSc. Cox regression models with time-dependent covariates were performed with the following outcomes: new-onset interstitial lung disease (ILD), ILD progression (Forced Vital Capacity, FVC decline ≥10% and ≥5% vs values at ILD diagnosis); primary myocardial involvement (PMI); pulmonary hypertension (PH); any organ involvement and all-cause mortality. Results: We included 1252 patients (194 ATA-lcSSc, 15.5%), with 7.7 ± 3.5 yrs follow-up. ILD risk was higher in ATA-lcSSc vs ACA- and ANA-lcSSc, and similar to ATA-dcSSc, although with less frequent restrictive lung disease. Risk of FVC decline ≥ 10% (35% of ATA-lcSSc) was lower in ATA-lcSSc than in ATA-dcSSc, whereas FVC decline ≥5% occurs similarly between ATA-lcSSc (58% of patients) and other SSc subsets, including ATA-dcSSc. The risk of PMI was similar in ATA-lcSSc and ANA-lcSSc, lower than in ACA-lcSSc; no difference in PH and mortality risk was observed among lcSSc subsets. Risk of any organ involvement, PMI, PH was lower and the mortality tended to be lower in ATA-lcSSc vs ATA-dcSSc. Conclusion: ATA-lcSSc patients have a high risk of ILD, albeit with a lower risk of progression compared with ATA-dcSSc, supporting a careful screening for ILD in this subgroup