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Objectives Changes of routine disease management associated with COVID-19 lockdown might have potentially affected the clinical course of juvenile idiopathic arthritis (JIA). Aim of our study was to assess the rate of disease flare before and during COVID-19 lockdown to investigate its impact on disease course in JIA children. Methods A single-center retrospective study was conducted, including patients presenting inactive JIA between September 1st , 2018 and March 9th , 2019 (group A) and between September 1st , 2019 and March 9th , 2020 (group B). For each patient, demographic and clinical data were collected. The rate of JIA flare from March 10th , 2019 to June 30th , 2019 for group A and from March 10th , 2020 to June 30th , 2020 for group B was compared. Results Group A included 126 patients and group B 124 patients. Statistical analysis did not show significant differences among the two cohorts with respect to age, sex, age of JIA onset, JIA subtype, co-occurrence of uveitis, ANA positivity and past or ongoing medications. The rate of disease flare during lockdown at time of first COVID-19 pandemic wave, was significantly higher in comparison to the previous year (16.9% vs 6.3%, p=0.009). Conclusion Our study showed that COVID-19 lockdown was associated with a higher rate of joint inflammation in JIA children. This finding has a considerable clinical implication, since restrictive measures may be necessary in order to contain pandemics. Our data highlight the need for rearrangement in the home and healthcare management of JIA children during lockdowns.

Background and Aims COVID-19 is associated with liver injury and elevated interleukin-6 (IL-6). We hypothesized that IL-6 trans-signaling in liver sinusoidal endothelial cells (LSECs) leads to endotheliopathy (a proinflammatory and procoagulant state) and liver injury in COVID-19. Methods Coagulopathy, endotheliopathy, and alanine aminotransferase (ALT) were retrospectively analyzed in a subset (n = 68), followed by a larger cohort (n = 3,780) of patients with COVID-19. Liver histology from 43 patients with COVID-19 was analyzed for endotheliopathy and its relationship to liver injury. Primary human LSECs were used to establish the IL-6 trans-signaling mechanism. Results Factor VIII, fibrinogen, D-dimer, von Willebrand factor (vWF) activity/antigen (biomarkers of coagulopathy/endotheliopathy) were significantly elevated in patients with COVID-19 and liver injury (elevated ALT). IL-6 positively correlated with vWF antigen (p = 0.02), factor VIII activity (p = 0.02), and D-dimer (p, Graphical abstract

Aim Coronavirus disease (COVID‐19) is characterized by pneumonia with secondary damage to multiple organs including the liver. Liver injury (elevated alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) often correlates with disease severity in COVID‐19 patients. The aim of this study is to identify pathological microthrombi in COVID‐19 patient livers by correlating their morphology with liver injury, and examine hyperfibrinogenemia and von Willebrand factor (vWF) as mechanisms of their formation. Methods Forty‐three post‐mortem liver biopsy samples from COVID‐19 patients were obtained from Papa Giovanni XXIII Hospital in Bergamo, Italy. Three morphological features of microthrombosis (sinusoidal erythrocyte aggregation [SEA], platelet microthrombi [PMT], and fibrous thrombi) were evaluated. Results We found liver sinusoidal microthrombosis in 23 COVID‐19 patients (53%) was associated with a higher serum ALT and AST level compared to those without (ALT: 10‐fold, p = 0.04; AST: 11‐fold, p = 0.08). Of 43 livers, PMT and SEA were observed in 14 (33%) and 19 (44%) cases, respectively. Fibrous thrombi were not observed. Platelet microthrombi were associated with increased ALT (p

Scurvy is a condition due to chronic ascorbic acid deficiency responsible for vascular fragility and impaired bone formation. The result is gingival bleeding, petechial lesions and articular and bone pain or limb swelling. Children may also present with irritability, limping or refusal to walk. Because of these symptoms it can be misdiagnosed with osteomyelitis, septic arthritis, bone and soft tissue tumour, leukaemia, bleeding disorders and other rheumatologic conditions. In highly developed countries it is rare, but should be suspected in children with underlying chronic condition characterized by selective eating as in developmental delay or autism spectrum disorders. The paper presents an emblematic case.

SARS2‐CoV‐2 breakout in Italy caused a huge number of severely ill patients with a serious increase in mortality. Although lungs seem to be the main target of the infection, very few information are available about liver involvement, possibly evocating a systemic disease. Post‐mortem wedge liver biopsies from 48 patients died from severe pulmonary COVID‐19 disease with respiratory failure were collected from two main hospitals in northern Italy. No patient had clinical symptoms of liver disease or signs of liver failure before and during hospitalization; for each of them liver function tests were available. All liver samples showed minimal inflammation features. Histological pictures compatible with vascular alterations were observed, characterized by increase in number of portal vein branches associated with lumen massive dilatation, partial or complete luminal thrombosis of portal and sinusoidal vessels, fibrosis of portal tract, focally markedly enlarged and fibrotic. SARS‐CoV‐2 was found in 15 of 22 samples tested by in situ hybridization method. Our preliminary results confirm the clinical impression that liver failure is not a main concern and this organ is not the target of significant inflammatory damage. Histopathological findings are highly suggestive for marked derangement of intrahepatic blood vessel network secondary to systemic changes induced by virus that could target not only lung parenchyma but also cardiovascular system, coagulation cascade and endothelial layer of blood vessels. It still remains unclear if the mentioned changes are directly related to virus infection or if SARS‐CoV‐2 triggers a series of reactions leading to striking vascular alterations.

Background Anti-mitochondrial autoantibodies (AMA) detected by indirect immunofluorescence (IIF) on rodent tissues are the diagnostic marker of primary biliary cholangitis (PBC). However, up to 15% of patients with PBC are AMA-negative by IIF. In the effort to close the serological gap and improve the diagnostic sensitivity of PBC testing, recently, novel autoantibodies specific for PBC, such as kelch-like 12 (KLHL12, KLp epitope) and hexokinase 1 (HK1) have been described. In this study, we evaluated the autoantibody profile in a large cohort of PBC patients and in patients with other liver disease, including anti-HK1 and anti-KLp autoantibodies. Methods Sera of 194 PBC patients (126 AMA-IIF-positive and 68 AMA-IIF-negative) and 138 disease controls were tested for a panel of PBC-specific antibodies (MIT3, sp100, gp210, HK1, KLp) using a new automated particle-based multi-analyte technology (PMAT) assay on the Aptiva instrument (Inova). Results Selecting a cutoff yielding a specificity of >95% for all the markers, the sensitivity for anti-MIT3, anti-sp100, anti-gp210, anti-HK1 and anti-KLp in the PBC AMA-IIF-negative cohort was 20.6%, 16.2%, 23.5%, 22.0%, 17.6 and 13.2%, respectively. Six out of the 68 (8.8%) AMA-IIF negative sera were positive for anti-HK1 or anti-KLp alone. Using these new markers in addition to anti-MIT3, anti-sp100 and anti-gp210, the overall sensitivity in this cohort of AMA-IIF-negative patients increased from 53% to 61.8%, reducing the serological gap in AMA-negative PBC patients. Conclusions PBC antibody profiling, made possible by the new Aptiva-PMAT technology, allows recognition of a higher number of AMA-negative PBC patients than conventional immunoassays and may represent a useful tool to evaluate the prognostic significance of autoantibody association in PBC patients.

BACKGROUND The aim of this study is to compare the performance of antitissue transglutaminase (atTG) chemiluminescence immunoassay (CLIA) with the standard enzyme-linked immunosorbent assay (ELISA) methods in monitoring celiac children after the start of gluten-free diet (GFD). METHODS Celiac children diagnosed between 2005 and 2016 at our centre were classified into 2 groups based on serum assay (ELISA vs CLIA) used for atTG monitoring, and were compared on percentage of decrease and time to normalization of atTG on GFD. RESULTS Among 260 included children, the rate of normalization of atTG levels at 30 months' follow-up was 86% and 70% in ELISA and CLIA group, respectively (P

Mutations in the gene encoding tRNA nucleotidyltransferase 1 (TRNT1) are associated with heterogeneous phenotypes and multisystem involvement of variable severity and progression. Immunodeficiency and inflammation are recurrent-associated features. The use of cytokine inhibitors in suppressing the inflammatory phenotype has been recently reported, with a 3-year follow-up for patients treated with Etanercept. We report on two unrelated patients sharing the same clinical condition, who had been referred to our Pediatric Rheumatology Unit because of recurrent fever associated with cutaneous lesions and increased levels of inflammatory markers since their first months of life. Whole exome sequencing allowed to identify compound heterozygosity for functionally relevant variants in TRNT1 as the only molecular event shared by the two patients. Both patients have been treated with Etanercept during 11 years, documenting normalization of inflammatory indexes and resolution of recurrent fever and associated symptoms. This is the longest follow-up assessment of Etanercept treatment in patients with TRNT1 mutations. Our findings confirm efficacy and safety of the treatment. Key Points • Mutations in TRNT1 have been associated with phenotypic heterogeneity. • We report on two patients with early-onset autoinflammatory syndrome. • Whole exome sequencing led to reveal compound heterozygosity for two variants in TRNT1 in both patients. • The patients were successfully treated with Etanercept for more than 10 years, the longest follow-up described in literature.

BackgroundThe most severely COVID-19 patients need intensive care and show increased risk of thromboembolic events. Although some patients meet the diagnostic criteria for the Disseminated Intravascular Coagulation, the pathogenesis of the diffuse thrombotic status remains unclear.The aim of the present study is to evaluate the presence of antiphospholipid antibodies (aPL) in sera of deceased patients with autoptic proven thrombotic microangiopathy to evaluate if some patients may have developed Catastrophic Antiphospholipid Syndrome (CAPS).MethodsThirty-five patients were enrolled. The available medical history, comorbidities, therapies, laboratory and autopsy findings were collected post-mortem from clinical records.IgA, IgG and IgM anti cardiolipin (ACA) and anti β2 glycoprotein 1 (β2GP1) antibodies, IgG and IgM anti phosphatidylserine/prothrombin (PS/PT) antibodies were tested for all the patients.Results3/35 (8.6%) patients were slightly positive for aPL: one for ACA IgG and two for ACA IgM but values were low (< 3X the cut off). No patients tested positive for ACA IgA neither for β2GP1 isotypes. 3/35 (8.6%) patients were positive for PS/PT, one for IgG and two for IgM, but values were less than 2X the cut off. No patients showed simultaneous positivity for ACA and PS/ PT.ConclusionsIt is difficult to categorize the vascular events into a conventional disease: we did not find significant association with anti-phospholipid antibodies. It is most likely that several factors contribute to trigger the hypercoagulability status and the thromboembolism but, on the basis our results, CAPS is probably not involved into the pathogenesis of these phenomena.

Background The serological screening for celiac disease (CD) is currently based on the detection of anti-transglutaminase (tTG) IgA antibodies, subsequently confirmed by positive endomysial antibodies (EMA). When an anti-tTG IgA positive/EMA IgA negative result occurs, it can be due either to the lower sensitivity of the EMA test or to the lower specificity of the anti-tTG test. This study aimed at verifying how variation in analytical specificity among different anti-tTG methods could account for this discrepancy. Methods A total of 130 consecutive anti-tTG IgA positive/EMA negative samples were collected from the local screening routine and tested using five anti-tTG IgA commercial assays: two chemiluminescence methods, one fluoroimmunoenzymatic method, one immunoenzymatic method and one multiplex flow immunoassay method. Results Twenty three/130 (17.7%) patients were diagnosed with CD. In the other 107 cases a diagnosis of CD was not confirmed. The overall agreement among the five anti-tTG methods ranged from 28.5% to 77.7%. CD condition was more likely linked to the positivity of more than one anti-tTG IgA assay (monopositive = 2.5%, positive with ≥ three methods = 29.5%; p = 0.0004), but it was not related to anti-tTG IgA antibody levels (either positive or borderline; p = 0.5). Conclusions Patients with positive anti-tTG/negative EMA have a low probability of being affected by CD. Given the high variability among methods to measure anti-tTG IgA antibodies, anti-tTG-positive/EMA-negative result must be considered with extreme caution. It is advisable that the laboratory report comments on any discordant results, suggesting to consider the data in the proper clinical context and to refer the patient to a CD reference center for prolonged follow up.

The commercial tests currently available as second-level tests to detect ANA sub-specificities are generally used independently from the ANA immunofluorescence (IIF) pattern. The aim of this study was to evaluate the efficacy of the use of a customizable pattern-oriented antigenic panel by immunoblot (IB) using the International Consensus on ANA Patterns (ICAP) classification scheme, in order to introduce a novel and updated autoimmune diagnostic flowchart. 710 sera referred for routine ANA testing were selected on the basis of the ANA pattern according to the ICAP nomenclature (nuclear speckled AC-2,4,5; nucleolar AC-8,9,10,29; cytoplasmic speckled AC-18,19,20) and on an IIF titer ≥1:320. They were then assayed by three experimental IB assays using a panel of selected antigens. ICAP-oriented IB detected 515 antibody reactivities vs. 457 of traditional anti-ENA in the nuclear speckled pattern group, 108 vs. 28 in the nucleolar pattern group, and 43 vs. 34 in the cytoplasmic speckled pattern. This pilot study may lead the way for a new approach introducing an ICAP pattern-oriented follow up testing as a valid alternative to the existing standard panels, thus enabling more patients with autoimmune rheumatic disease to be accurately diagnosed.

Background: COVID-19 breakout in Italy caused a huge number of severely ill patients with a serious increase in mortality. Although lungs seem to be the main target of the infection very few information are available about liver involvement, possibly evocating a systemic disease. Methods: Post-mortem wedge liver biopsies from 48 patients died for COVID-19 infection were collected from two main hospitals in the north of Italy: all samples were obtained during autopsies. No patient had clinical symptoms of liver disease or signs of liver failure before and during hospitalization; for each of them liver function tests were available. Findings: All liver samples showed minimal inflammation features. Histological pictures compatible with vascular alterations were observed, characterized by increase of number of portal vein branches associated with lumen massive dilatation, partial or complete luminal thrombosis of portal and sinusoidal vessels, fibrosis of portal tract, focally markedly enlarged and fibrotic. Interpretation: Our preliminary results confirm the clinical impression that liver failure is not a main concern and this organ is not the target of significant inflammatory damage. Histopathological findings are highly suggestive for marked derangement of intrahepatic blood vessel network secondary to systemic changes induced by virus that could target not only lung parenchyma but also cardiovascular system, coagulation cascade and endothelial layer of blood vessels. Funding Statement: This work has no financial support. Declaration of Interests: None of the authors declare a conflict of interest Ethics Approval Statement: This work is based exclusively on routine file autoptic material and is ethical approval exempt to use anonymous data. The study followed the Italian general rules used for research related to scientific purposes (official regulations n.72-26 /03/2012).

BackgroundCurrent guidelines recommend assessing and relieving pain in all children and in all instances; yet, in clinical practice, management is frequently suboptimal. We investigated the attitude of Italian family pediatricians towards the evaluation and treatment of different types of acute pain in children aged 7–12 years.MethodsThis is a cross-sectional study based on a 17-question survey accessible online from October 2017 to October 2018. Responders had to describe cases of children suffering from any type of acute pain among headache, sore throat, musculoskeletal/post-traumatic pain, and earache. Children’s characteristics, pain assessment modalities and therapeutic approaches were queried. The following tests were used: Z-proportion to evaluate the distribution of categorical data; chi-squared and Kruskall-Wallis to explore data heterogeneity across groups; Mann-Whitney for head-to-head comparisons.ResultsOverall, 929 pediatricians presented 6335 cases uniformly distributed across the types examined. Pain was more frequently of moderate intensity (42.2%,P P N = 4438), the most commonly used first-line non-opioids were ibuprofen (53.3%) and acetaminophen (44.4%). Importantly, a non-recommended dosage was prescribed in only 5.3% of acetaminophen-treated cases (overdosing). Among the misconceptions emerged, there were the following: i) ibuprofen and acetaminophen have different efficacy and safety profiles (when choosing the non-opioid, effectiveness weighted more for ibuprofen [79.7% vs 74.3%,P P ConclusionsSeveral gaps exist between the current practice of pain assessment and treatment and recommendations. Further efforts are needed to raise awareness and improve education on the possible exposure of the child to short- and long-term consequences in case of suboptimal pain management.

Introduction: The advent of biologic agents has revolutionized therapeutic approaches in systemic juvenile idiopatic arthritis (sJIA) as their introduction has been shown to modify disease course and improve overall outcomes, particularly when initiated early. Few studies have reported the drug retention rate (DRR) of biologic drugs in JIA, and none of them has specifically investigated the DRR of interleukin (IL)-1 inhibitors on sJIA. Objectives: The primary aim of the study was to examine the overall DRR of IL-1 blockers in sJIA patients. Secondary aims of our study were to: (i) explore the influence of biologic line of treatment, adverse events (AEs), type of anti-IL-1 agent and the concomitant use of conventional disease modifying anti-rheumatic drugs (cDMARDs) on DRR; (ii) find eventual predictive factors associated with events leading to drug discontinuation. The corticosteroid sparing effect and the impact of disease duration and treatment delay on survival constituted ancillary aims. Methods: sJIA patients – diagnosed according to the revised International League of Association for Rheumatology (ILAR) criteria – treated with anakinra (ANA) and canakinumab (CAN) were enrolled in 15 Italian tertiary referral centers. Demographic, clinical and therapeutic data collected from medical records were retrospectively collected and statistically analyzed. Results: Seventy seven patients were enrolled for a total of 86 treatment courses. The cumulative retention rate of the IL-1 inhibitors at 12-, 24-, 48-, and 60-months of follow-up was 79.9, 59.5, 53.5, and 53.5%, respectively, without any statistically significant differences between ANA and CAN (p = 0.056), and between patients treated in monotherapy compared to the subgroup co-administered with conventional immunosuppressors (p = 0.058). On the contrary, significant differences were found between biologic-naive patients and those previously treated with biologic drugs (p = 0.038) and when distinguishing according to AEs occurrence (p = 0.04). In regression analysis, patients pre-treated with other biologics (HR = 3.357 [CI: 1.341–8.406], p = 0.01) and those experiencing AEs (HR = 2.970 [CI: 1.186–7.435], p = 0.020) were associated with a higher hazard ratio of IL-1 inhibitors withdrawal. The mean treatment delay was significantly higher among patients discontinuing IL-1 inhibitors (p = 0.0002). Conclusion: Our findings suggest an excellent overall DRR for both ANA and CAN that might be further augmented by paying attention to AEs and employing these agents as first-line biologics in an early disease phase.

Key Points Question Are chilblain-like lesions of the toes associated with SARS-CoV-2 infection or is the association merely temporal? Findings This case series of 17 adolescents found that chilblain-like lesions of the toes emerged during the COVID-19 pandemic in otherwise healthy adolescents without signs of SARS-CoV-2 infection or other inflammatory, autoimmune, or thrombophilic phenomena. Meaning These results suggest that chilblain-like lesions are not associated with systemic or localized SARS-CoV-2 infection., Importance Chilblain-like lesions have been one of the most frequently described cutaneous manifestations during the COVID-19 pandemic. Their etiopathogenesis, including the role of SARS-CoV-2, remains elusive. Objective To examine the association of chilblain-like lesions with SARS-CoV-2 infection. Design, Setting, and Participants This prospective case series enrolled 17 adolescents who presented with chilblain-like lesions from April 1 to June 30, 2020, at a tertiary referral academic hospital in Italy. Main Outcomes and Measures Macroscopic (clinical and dermoscopic) and microscopic (histopathologic) analysis contributed to a thorough understanding of the lesions. Nasopharyngeal swab, serologic testing, and in situ hybridization of the skin biopsy specimens were performed to test for SARS-CoV-2 infection. Laboratory tests explored signs of systemic inflammation or thrombophilia. Structural changes in peripheral microcirculation were investigated by capillaroscopy. Results Of the 17 adolescents (9 [52.9%] male; median [interquartile range] age, 13.2 [12.5-14.3] years) enrolled during the first wave of the COVID-19 pandemic, 16 (94.1%) had bilaterally localized distal erythematous or cyanotic lesions. A triad of red dots (16 [100%]), white rosettes (11 [68.8%]), and white streaks (10 [62.5%]) characterized the dermoscopic picture. Histologic analysis revealed a remodeling of the dermal blood vessels with a lobular arrangement, wall thickening, and a mild perivascular lymphocytic infiltrate. SARS-CoV-2 infection was excluded by molecular and serologic testing. In situ hybridization did not highlight the viral genome in the lesions. Conclusions and Relevance This study delineated the clinical, histologic, and laboratory features of chilblain-like lesions that emerged during the COVID-19 pandemic, and its findings do not support their association with SARS-CoV-2 infection. The lesions occurred in otherwise healthy adolescents, had a long but benign course to self-resolution, and were characterized by a microvascular remodeling with perivascular lymphocytic infiltrate but no other signs of vasculitis. These results suggest that chilblain-like lesions do not imply a concomitant SARS-CoV-2 infection. Ongoing studies will help clarify the etiopathogenic mechanisms., This case series examines the association of chilblain-like lesions with SARS-CoV-2 infection.

Blau syndrome (BS) is a rare granulomatous auto-inflammatory disease, characterized by the classic clinical triad of joints, skin and ocular involvements. Ocular manifestation usually consists in a bilateral insidious chronic anterior uveitis with a potential evolution to panuveitis. We describe the case of two siblings, an 8-years old female and a 5-years old male, with a diagnosis of BS, evaluated by Anterior Segment-Optical Coherence Tomography (AS-OCT). In the female patient, slit-lamp examination revealed bilateral anterior granulomatous uveitis and inflammatory sequelae. AS-OCT revealed high intensity reflective layers in the anterior cornea, hyperreflective dots both in the aqueous humor and in the posterior corneal surface. In the male, no signs of inflammation were detected both on slit-lamp examination and AS-OCT scans. AS-OCT is a valuable, non-invasive tool that could improve the diagnosis of ocular involvement, better characterize and follow-up corneal alterations and anterior segment features in pediatric patients with BS.

Background UF-5000 is the new fully automated urine particle analyser. We validated its performance. Methods 736 urines were analysed and results were compared by two pathologists on uncentrifuged samples, using Fuchs-Rosenthal chamber. Results AUC of ROC curve ranged between 0.86 and 0.99. Sensitivity was > 0.90 for all the elements and similar for RBC and yeasts. Specificity ranged between 0.74 and 0.89 for total cast, epithelial/non-squamous/renal-tubular cells and RBC. For all the other parameters specificity was > 0.90. Comparison with Fuchs-Rosenthal chamber was very good for all the parameters; r ranged between 0.52 and 0.99 except for pathological cast because of the lack of the pathological samples in medium and higher ranges. Linearity performance (R2) was 1.00, 1.00 and 0.99 respectively for RBC, WBC and epithelial cells (EC). No carry-over was observed. The within-run imprecision was 25.42%,13.81%,1.36% for RBC; 37.50%,10.16%,1.41% for WBC and 35.25%, 17.85%,6.30% for EC at low, near the cut off level and high concentrations, respectively. The between-run imprecision was 6.90%,1.60% for RBC, 4.10%,1.90% for WBC and 7.60%,7.30% for EC, using low and high positive quality controls, respectively. Conclusion UF-5000 is an analyser of great interest to detect urine particle related to pathological process of kidney and urinary tract.

Background: Juvenile idiopathic arthritis (JIA) is an autoimmune, chronic, inflammatory joint disease, affecting children and adolescents. Patients with JIA may have pain and fatigue in muscles. There are not studies evaluating the pressure pain thresholds (PPTs) of both masticatory muscles and temporomandibular joint (TMJ) in patients with JIA. Objective: This study aimed to investigate PPTs of masticatory muscles and TMJ in subjects with JIA. Methods: Fifty-one JIA patients and fifty-two healthy subjects were recruited. JIA group was assessed for with a standardised clinical examination for temporomandibular disorders. In all subjects, the PPT was evaluated in the following sites: anterior temporalis (AT) and masseter (MM) muscles, TMJ and thenar (TH) eminence. Comparisons between groups were assessed with unpaired t test and ANOVA (P

Background In 2008 the Paediatric Rheumatology European Society (PReS) promoted an International Project for the study of Autoinflammatory Diseases (AIDs) named Eurofever, whose main purpose is to create a web-based registry for the collection of information in AIDs patients. Objectives To implement the Registry with the new recently described AIDs and to increase the collection of longitudinal data. Methods The data were extracted from the Eurofever registry, which is hosted in the PRINTO website (http://www. printo.it). From February 2015 we started the longitudinal collection of follow-up data with particular focus on treatment, modification of the clinical picture, onset of complication/adverse events. We have enrolled patients included in the registry up to 28 September 2018. Results Up to date 4175 patients have been enrolled (3843 of them with complete demographic information, 1903 M e 1940 F) from 62 countries. For 3356 (87%) patients also clinical data from onset to diagnosis, collected during the first visit performed at referred pediatric or adult center, are available. For each disease the number of enrolled patients is: FMF 1086 pts (951 with complete clinical data); TRAPS 273 pts (256 complete); CAPS 298 pts (279 complete); MKD 205 pts (190 complete); Blau’s disease 49 pts (26 complete); PAPA 42 pts (41 complete); NLRP12 mediated periodic fever 13 pts (11 complete); DADA2 14 pts (9 complete); DIRA 3 pts (all complete); SAVI 3 pts (all complete); CANDLE 1 pt (complete) and Majeed 4 pts (all complete). Among multifactorial autoinflammatory diseases: PFAPA 676 pts (551 complete); CNO 581 pts (540 complete); Behcet 214 pts (186 complete), undefined periodic fever 368 pts (292 complete) and Schnitzler 13 pts (all complete). The median onset age is 4 years (range 1 month – 75 years), the median diagnosis age is 8 years (range 1 month – 78 years). Most of patients (3509, 91%) presented disease onset during pediatric age ( Conclusion The enrollment in Eurofever Registry is still ongoing. The analysis of data will improve our knowledge both on the natural history of the single disease and on the efficacy/safety of treatment commonly used in the clinical practice. Disclosure of Interests: Ilaria Gueli: None declared, Martina Finetti: None declared, Fabrizio De Benedetti Grant/research support from: Abbvie, SOBI, Novimmune, Roche, Novartis, Sanofi, Pfizer, Jordi Anton Grant/research support from: JA has received grant/research support, consulting fees and/or honoraria from AbbVie, Alexion, BMS, ChemoCentryx, Gebro, GSK, Novartis, Novimmune, Pfizer, Roche, Sanofi and Sobi, Consultant for: JA has received grant/research support, consulting fees and/or honoraria from AbbVie, Alexion, BMS, ChemoCentryx, Gebro, GSK, Novartis, Novimmune, Pfizer, Roche, Sanofi and Sobi, Maria Alessio: None declared, Joost Frenkel: None declared, Luca Cantarini: None declared, Romina Gallizzi: None declared, Judith Sanchez Manubens: None declared, Marco Cattalini: None declared, Efimia Papadopoulou-Alataki: None declared, Rolando Cimaz: None declared, Donato Rigante: None declared, Alma Nunzia Olivieri: None declared, Pavla Dolezalova: None declared, Alberto Martini Consultant for: I do not have any conflict of interest to declare since starting from 1 March 2016 I became the Scientific Director of the G. Gaslini Hospital; therefore, my role does not allow me to render private consultancies resulting in personal income. I perform consultancy activities on behalf of the Gaslini Institute for the companies listed below: AbbVie, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, EMD Serono, Janssen, Novartis, Pfizer, R-Pharm. The money received for these activities are directly transferred to the Gaslini Institute’s bank account. Before March 2016, I was the head of the Pediatric Rheumatology Department at the G. Gaslini Hospital, where the PRINTO Coordinating Centre is located. For the coordination activity of the PRINTO network, the Gaslini Hospital received contributions from the industries listed in this section. This money has been reinvested for the research activities of the hospital in fully independent manners besides any commitment with third parties., Nicolino Ruperto Grant/research support from: The Gaslini Hospital, where NR works as full-time public employee, has received contributions (> 10.000 USD each) from the following industries in the last 3 years: BMS, Eli-Lilly, GlaxoSmithKline, F Hoffmann-La Roche, Janssen, Novartis, Pfizer, Sobi. This funding has been reinvested for the research activities of the hospital in a fully independent manner, without any commitment with third parties., Consultant for: Received honoraria for consultancies or speaker bureaus (

Background In a generalist laboratory, the integration of the data obtained from hematology analyzers (HAs) with those from multiparametric flow cytometry (FMC) could increase the specificity and sensitivity of first level screening to identify the pathological samples. The aim of this study was to perform a preliminary evaluation of a new simple hybrid method (HM). The method was obtained by integration between HAs reagents into FCM, with a basic monoclonal antibodies panel for the leukocytes differential count. Methods Eighty-one peripheral blood samples, collected in K3EDTA tubes, were analyzed by XN-module, and CyFlow Space System, using both standard MoAbs and HM method analysis, and with the optical microscopy (OM). Within-run imprecision was carried out using normal samples, the carryover was evaluated, data comparison was performed with Passing-Bablok regression and Bland-Altman plots. Results The within-run imprecision of HM methods ranged between 1.4% for neutrophils (NE) and 10.1% for monocytes (MO) always equal or lower to the OM. The comparison between HM methods vs. OM shows Passing-Bablok regression slopes comprised between 0.83 for lymphocyte (LY) and 1.14 for MO, whilst the intercepts ranged between −0.18 for NE and 0.25 for LY. Bland-Altman relative bias was comprised between −12.43% for NE, and 19.77% for eosinophils. In all 11 pathological samples the agreement between the methods was 100%. Conclusions The new hybrid method generates a leukocytes differential count suitable for routine clinical use and it is also useful for identifying morphological abnormalities with a reduction in cost and improvement of screening for first level hematology workflow.

OBJECTIVES: Mevalonate kinase deficiency (MKD) is a rare metabolic disease characterized by recurrent inflammatory episodes. This study aimed to describe the genotype, phenotype and the response to treatment in an international cohort of MKD patients. METHODS: All MKD cases were extracted from the Eurofever registry (EAHC Project No. 2007332), an international, multicenter registry that retrospectively collects data on children and adults suffering from autoinflammatory diseases. RESULTS: One hundred and fourteen MKD patients were included in this study. The median age of onset was 0.5 years. Patients had on average 12 episodes per year. Most patients had gastrointestinal symptoms (n=112), mucocutaneous involvement (n=99), lymphadenopathy (n=102) or musculoskeletal symptoms (n=89). Neurological complaints included headache (n=43), but also cerebellar syndrome (n=2) and mental retardation (n=4). AA-amyloidosis was noted in five patients, almost twice as many as expected from previous cohorts. Macrophage activation syndrome occurred in one patient. Between attacks patients were generally well, but 10-20% patients suffered from constitutional symptoms, such as fatigue, between febrile attacks. Patients with p.V377I/p.I268T compound heterozygosity suffered significantly more often from AA-amyloidosis. Patients without a p.V377I mutation suffered more often from severe musculoskeletal involvement. Treatment with NSAIDs could relieve symptoms. Steroids given during attacks, anakinra and etanercept appeared to improve symptoms and could induce complete remission in MKD patients. CONCLUSION: This study described the clinical and genetic characteristics of 114 MKD patients, which is the largest cohort studied so far. The clinical manifestations confirm earlier reports. However, the prevalence of AA-amyloidosis was far higher than expected.

Objectives Anti-parietal cell antibodies (APCA) are a serologic marker of autoimmune gastritis. Their prevalence in healthy individuals is not well defined. Methods We evaluated APCA prevalence in 515 healthy blood-donors by rat/primate tissue indirect immunofluorescence (IIF), enzyme-linked immunosorbent assay (ELISA), and immunoblot. Results Fifty-three of 515 (10.3%) subjects were positive for APCA by at least one method: 18 only by ELISA, 10 by rodent tissue IIF, and one by primate tissue IIF; 18 were positive by ELISA and primate tissue IIF, and one by ELISA and rodent tissue IIF. Two were positive by both IIF methods, and three were triple positive. APCA positivity was confirmed by immunoblot in 100% of ELISA positive, in 95.8% of positive primate tissue IIF, and in 50% of positive rat tissue IIF. Conclusions A great discrepancy in APCA prevalence detected by different methods in this cohort was apparent. Thus, the results on APCA prevalence in healthy individuals are likely method-dependent.

Aim This study aimed to investigate whether it is useful both for diagnostic purposes and for cost savings to associate a solid-phase monotest called CTD screen to the immunofluorescence (IIF) test, to detect anti-nuclear and anti-cytoplasmic antibodies (ANA). Methods Fifteen Italian laboratories participated in the study enrolling at least 250-each consecutive unselected samples from patients routinely referred for ANA testing. They all used the conventional IIF method on HEp-2 cells associated to a solid phase CTD screen method. Seven centers used the EliA FEIA CTD screen method on the Phadia 250 instrument (ThermoFisher), five centers used the QUANTAFlash CTD Screen method (Inova Diagnostics) on the BioFlash CLIA instrument, while three centers used both methods, albeit in two different series of patients. Results A total of 5043 samples were tested. We focused attention to the 1674 discrepant results: 106 (2%) were ANA-IIF negative/CTD screen positive and 1568 (31%) were ANA-IIF positive/CTD screen negative. Specific antibodies were detected in 87/106 (82%) of the ANA-IIF negative/CTD screen positive samples, mainly Ro52, Ro60, dsDNA, PM/Scl and Jo1. Thirty four of these patients were diagnosed with an ANA-associated autoimmune rheumatic disease (AARD) (seven SLE, 15 Sjӧgren's syndrome, nine autoimmune inflammatory myositis, three systemic sclerosis). Among 1568 ANA-IIF positive/CTD screen negative discrepant patients, a specific antibody was found in 94 (6%) samples (28 patients with AARD, 13 with undifferentiated connective tissue disease, two with undifferentiated arthritis, and 51 without a rheumatic disease). Conclusions This study is the first that compares the IIF method vs. solid-phase assays in the detection of ANA, on a very large sample size from the routine work-up (real-life approach). Results show that the association of solid-phase CTD screen tests to the ANA-IIF test increases the sensitivity (from 89.2% to 97.4%) and the specificity (from 64.6% to 98.4%) of serological tests for ANA screening. Analysis of costs demonstrated that combination of the two tests is also cost-effective, reducing global costs for the immunoserological diagnosis of AARD by 22%.

Forbush Decrease (FD) effects on cloud composition and structure are under study and the results are still controversial. Time-scales are of paramount importance for supporting either a ‘microphysical hypothesis’, which hypothesizes a relation between FD and cloud microphysical parameters variability, or a different one. A most controversial question is related to the time delay between FD and cloud structure modification. The timescales of a radiative–dynamical mechanism, investigated through a simple model, are compatible with the observed variability with respect to cloud structure. Thus the delayed modification on cloud structure has to be put in relation with solar radiation variability, being coherent with the observed statistically significant Total Solar Irradiance (TSI), temperature and baric field variations, while not supporting the ‘microphysical hypothesis’.

A high-resolution, well-dated foraminiferal δ18O record from a shallow-water core drilled from the Gallipoli Terrace in the Gulf of Taranto (Ionian Sea), previously measured over the last two millennia, has been extended to cover 707 BC–AD 1979. Spectral analysis of this series, performed using singular-spectrum analysis (SSA) and other classical and advanced methods, strengthens the results obtained analysing the shorter δ18O profile, detecting the same highly significant oscillations of about 600, 380, 170, 130 and 11 years, respectively explaining about 12, 7, 5, 2 and 2% of the time series total variance, plus a millennial trend (18% of the variance). The comparison with the results of multi-channel singular-spectrum analysis (MSSA) applied to a data set of 26 Northern Hemisphere (NH) temperature-proxy records shows that NH temperature anomalies share with our local record a~long-term trend and a bicentennial (170-year period) cycle. These two variability modes, previously identified as temperature-driven, are the most powerful modes in the NH temperature data set. Both the long-term trends and the bicentennial oscillations, when reconstructed locally and hemispherically, show coherent phases. Furthermore, the corresponding local and hemispheric amplitudes are comparable if changes in the precipitation–evaporation balance of the Ionian sea, presumably associated with temperature changes, are taken into account.

Objectives 2012 European Society of Pediatric Gastroenterology, Hepatology and Nutrition guidelines allow to establish a celiac disease diagnosis without duodenal biopsy in symptomatic pediatric patients with antitissue transglutaminase (anti-tTG) titers >10 times the upper limit of normal. For some years now, new chemiluminescence immunoassays have been made available: it is important to establish the clinical performance of anti-tTG and to determine the cut-off best suited to predict Marsh ≥2 to avoid gastrointestinal endoscopy not only in children, but also in the adult population. Methods A total of 2565 patients performed duodenal biopsy from July 2012 to September 2016; we selected all the patients who had undergone QUANTA Flash anti-tTG immunoglobulin A (IgA) within -3 months of duodenal biopsy and before the start of gluten-free diet. A total of 827 patients fulfilled the criteria for selection. Results Using a cut-off of 20 chemiluminescent unit (CU; area under the curve: 0.995), sensitivity, specificity, positive, and negative predictive value were 98.2%, 98.4%, 97.9%, and 98.6%, respectively. For the correlation with Marsh ≥2, in the pediatric population, positive predictive values (PPV) were 92.1%, 99%, and 100% at 200 CU (10×), 560 CU (28×), and 1000 CU (50×), respectively. In the adult population PPV was 94.2%, 98.2%, and 100% at 200 CU (10×), 350 CU (15×), and 400 CU (20×). Conclusions Sensitivity, specificity, positive, and negative predictive value of QUANTA Flash h-tTG IgA were excellent. The cut-off providing an optimized PPV for histological lesions compatible for celiac disease (Marsh ≥2) for the QUANTA Flash h-tTG IgA is 350 CU (15×) in adult and 560 CU (28×) in children.

Objective To describe the clinical, laboratory, and histopathologic features, current treatment, and outcome of patients with macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (JIA). Methods In this multinational, multicenter study, pediatric rheumatologists and hemato-oncologists entered patient data collected retrospectively into a web-based database. Results A total of 362 patients, 22% of whom had MAS at the onset of systemic JIA, were included in the study by 95 investigators from 33 countries. The most frequent clinical manifestations were fever (96%), hepatomegaly (70%), and splenomegaly (58%). Central nervous system dysfunction and hemorrhages were recorded in 35% and 20% of the patients, respectively. Platelet count and liver transaminase, ferritin, lactate dehydrogenase, triglyceride, and d-dimer levels were the sole laboratory biomarkers showing a percentage change of >50% between the pre-MAS visit and MAS onset. Evidence of macrophage hemophagocytosis was found in 60% of the patients who underwent bone marrow aspiration. MAS occurred most frequently in the setting of active underlying disease, in the absence of a specific trigger. Nearly all patients were given corticosteroids, and 61% received cyclosporine. Biologic medications and etoposide were given to 15% and 12% of the patients, respectively. Approximately one-third of the patients required admission to the intensive care unit (ICU), and the mortality rate was 8%. Conclusion This study provides information on the clinical spectrum and current management of systemic JIA–associated MAS through the analysis of a very large patient sample. MAS remains a serious condition, as a sizeable proportion of patients required admission to the ICU or died.

Background Autoimmune hepatitis (AIH) is a rare condition characterized by the presence of autoantibodies distinctive of type 1 AIH (AIH-1) and type 2 AIH (AIH-2). The aim of this study was to evaluate the autoantibody profile in a cohort of pediatric and adult AIH patients, using both indirect immunofluorescence (IIF) and a new multiplexed line-blot assay. Methods Sera from 63 pediatric and 53 adult AIH patients were tested for antinuclear (ANA), antismooth muscle (SMA), anti-liver kidney microsome 1 (anti-LKM1), anti-liver cytosol 1 (anti-LC1) autoantibodies using IIF methods; for anti-LKM1, anti-LC1, and soluble liver antigen/liver-pancreas (anti-SLA/LP) autoantibodies using the line-blot; for anti-F-actin autoantibodies using IIF both on VSM47 cell-line and on rat intestinal epithelial cells. Results AIH-1 was the most common type of AIH in the adult cohort (73.6%), while AIH-2 was the most common AIH in the pediatric cohort (61.9%). Both in adult and pediatric AIH-2 anti-LKM1 were the prevalent autoantibodies. In pediatric AIH-2 anti-LC1 autoantibodies were more frequent than in adult AIH-2 (59 vs. 28.6%), and in 35.9% of cases they were present alone. In 17 patients anti-LC1 autoantibodies were detected only with the line-blot assay. The levels of anti-LKM1 and of anti-LC1 were not different between adult and pediatric AIH, and the overall agreement between the results obtained with the two IIF methods for F-actin detection was 98.8% (CI 95%: 94.4-99.7%). Conclusions The line-blot assay showed a higher sensitivity than IIF for anti-LC1 detection. Anti-LKM1 and anti-LC1 autoantibody levels are not different in adults and children. An almost perfect agreement between the two IIF methods for anti-F-actin detection has been observed.

We evaluated whether perfusion brain abnormalities by single-photon emission computed tomography (SPECT) imaging improves diagnostic and prognostic assessment in Sydenham chorea. Twenty-three children with acute autoimmune chorea underwent technetium-99m hexamethylpropyleneamine oxime brain SPECT imaging. In 16 children, SPECT was repeated during the follow-up. A pattern of basal ganglia hyperperfusion was observed in 20 (87%) patients. In 4 of 10 patients with generalized chorea, perfusion was comparable in right and left striatum and right and left thalamus. In 13 patients with hemi-chorea and in 3 with generalized chorea, unilateral hyperperfusion was detected. Three patients with generalized chorea had normal perfusion. Tracer uptake of basal ganglia of the patients at the acute phase was higher than at the follow-up ( P < .001). SPECT seems a useful noninvasive tool in pediatric patients with Sydenham chorea to support the clinicians during the acute phase of disease and to monitor the course of autoimmune chorea.

To compare primary versus secondary intraocular lens (IOL) implantation after cataract removal in patients with juvenile idiopathic arthritis (JIA).Retrospective interventional study. Data were obtained for 40 children (40 eyes) with JIA-associated uveitis operated on for cataract before the age of 16 years between January 1998 and January 2005.Twenty-one patients underwent primary IOL implantation at a mean age of 13.1 ± 2.6 (9-16) years. Mean follow-up was 48.2 ± 5.4 (35-64) months. Nineteen patients underwent cataract removal at a mean age 12.3 ± 2.0 (9-16) years and secondary IOL implantation 13.6 ± 0.3 (11-16) months later. Mean follow-up was 47.2 ± 6.5 (32-64) months. BCVA difference between the two groups was significant at 24-month visit only (p = 0.001). Incidence of secondary glaucoma was significantly lower in the group that underwent secondary IOL implantation (p = 0.01).Secondary IOL implantation after cataract removal in children with JIA-related uveitis provided a significantly lower incidence of secondary glaucoma.

Summary Background: We evaluated the performance of Sysmex UF- 1000i for cell counting and differential cell count, as well as for assessment of bacteria load in cerebrospinal fluid (CSF), as a potential approach for the rapid screening of meningitis or bacterial encephalitis. Methods: We analyzed 77 consecutive CSF samples, 34 of which (44%) displayed leukocyte count >5 white blood cell (WBQ/^iL with optical microscopy. Results on the UF-1000i were compared with those obtained by microscopic analysis. Imprecision was evaluated by testing three CSF samples with leukocyte values between 3.5 and 28.8 WBC/nL in 10 repli- cates. Carry-over was evaluated with the Broughton formula on three CSF pools with leukocyte counts between 93.5 and 132.5 WBC/^L. Linearity was assessed according to CLSI document EP6-A. In the presence of bacteria, identification and antibiogram were performed with Vitex (Biomerieux), except for Neisserie meningitidis (ApiNH, Biomerieux). Sensitivity tests were performed with Vitex and disc diffusion. Results: Optimal correlation was found between UF-1000i and optical microscopy, displaying Pearson's correlation of 0.99 and mean bias of-3.5 WBC/^L (95% Cl, from -7.0 to 0.0 WBC/nL). Imprecision varied between 12 and 16%. Li- nearity was excellent, 4-278 WBC/nL. Carry-over was neg- ligible. ROC analysis yielded AUC of 0.99 for both WBC and bacterial counts. The agreement at threshold >4 WBC/nL was 0.91, with sensitivity and specificity of 1.00 and 0.84. At S19 bacteria^nL cut-off, accuracy was 0.98, sensitivity 1.00 and specificity 0.97. Conclusions: According to these results, CSF screening with UF-I000i seems a reliable approach in terms of instrument performance, turnaround time and overall laboratory effi- ciency.

Objective.Abatacept (ABA) has recently been proposed as second-line treatment in patients with juvenile idiopathic arthritis (JIA)–associated uveitis refractory to anti–tumor necrosis factor-α (anti-TNF) agents, but little is known about its efficacy as a first-line approach. The aim of the present study was to compare the safety and efficacy of ABA as a first-line biological agent (ABA-1) with that of ABA as a second-line treatment after 1 or more anti-TNF agents (ABA-2), in patients with severe JIA-related uveitis.Methods.In this multicenter study, we collected data on patients with severe JIA-related uveitis treated with ABA as a first-line or second-line biological agent. Changes in frequency of uveitis flares/year and ocular complications before and after ABA treatment, clinical remission, and side effects were recorded.Results.Thirty-five patients with a mean age of 10.8 years were treated with ABA for a mean period of 19.6 months. In 4 patients, ABA administration was discontinued, owing to inefficacy on arthritis in 3 cases and allergic reaction in 1. Thirty-one patients, 14 in the ABA-1 group and 17 in the ABA-2 group, completed the 12-month followup period; of these, 17 (54.8%) had clinical remission. The mean frequency of uveitis flares decreased from 4.1 to 1.2 in the ABA-1 group (p = 0.002) and from 3.7 to 1.2 in the ABA-2 group (p = 0.004). Preexisting ocular complications improved or remained stable in all but 5 patients, all in the ABA-2 group. No significant difference was found between the efficacy of the 2 treatment modalities. ABA confirmed its good safety profile.Conclusion.ABA, used as first-line biological treatment or after 1 or more anti-TNF agents, induces a comparable improvement in severe refractory JIA-related uveitis.

Thanks to the precise core dating and the high sedimentation rate of the drilling site (Gallipoli Terrace, Ionian Sea) we were able to measure a foraminiferal δ18O series covering the last 2,200 years with a time resolution shorter than 4 years. In order to support the quality of this data-set we link the δ18O values measured in the foraminifera shells to temperature and salinity measurements available for the last thirty years covered by the core. Moreover, we describe in detail the dating procedures based on the presence of volcanic markers along the core and on the measurement of 210Pb and 137Cs activity in the most recent sediment layers. The high time resolution allows for detecting a δ18O decennial-scale oscillation, together with centennial and multicentennial components. Due to the dependence of foraminiferal δ18O on environmental conditions, these oscillations can provide information about temperature and salinity variations in past millennia. The strategic location of the drilling area makes this record a unique tool for climate and oceanographic studies of the Central Mediterranean.

Discrete-time signals are, in general, infinite-length sequences of numerical values that may either arise from sampling of continuous-time signals, or be generated directly by inherently-discrete-time processes. Deterministic signals have a univocal mathematical description, so that future signal values are exactly predictable. Random signals do not allow for such a description: their treatment requires statistical tools since signal evolution cannot be exactly foreseen. This chapter introduces basic concepts related to discrete-time signals, as well as mathematical operators, called discrete-time systems, that are employed to process them. The main constraints imposed on discrete-time systems, namely linearity, time invariance, stability and causality, are introduced along with the quantities used to describe a system: the impulse response, the transfer function and the frequency response. Finite-impulse-response (FIR) and infinite-impulse-response (IIR) systems are defined. Linear convolution and the linear constant-coefficient-difference equation (LCCDE) are introduced to express the input-output relation of discrete-time systems.

Digital IIR filters have an infinitely long impulse response and therefore can be associated with analog filters that have the same characteristics. For this reason, the classical method for digital IIR filter design is based on the design of an analog filter, which is later transformed into an equivalent digital filter through a mapping in the complex plane. The advantage of such a technique lies in the fact that analog filter design and mapping methods for analog-to-digital (A/D) transformation are well known and have sound theoretical foundations. The process is based on a lowpass filter, and frequency transformation methods are later applied if a different type of frequency selectivity is desired. These frequency transformations are again well-known mapping procedures in the complex plane. In this chapter, we will first discuss the design of the main types of lowpass analog filters, namely Butterworth, Chebyshev and elliptic lowpass filters, all of which represent different ways of approximating the desired ideal frequency response. Then we will learn how to transform the analog lowpass filter into an equivalent IIR digital lowpass filter via bilinear transformation, and finally how to transform the IIR lowpass filter into a highpass, bandpass or bandstop filter, if needed. The appendix to this chapter provides deeper insight into the mathematical facets of elliptic design, discussing elliptic integrals of the first kind, Jacobi elliptic functions, and the elliptic rational function on which the transfer function of the analog elliptic filter is based. It must be explicitly noted that all classically-designed lowpass IIR filters are inadequate for specifications with cutoff frequency close to zero and narrow transition band. In such cases, it may be advisable to preliminarily downsample the signal and then design a filter with a less extreme cutoff frequency, allowing for a wider transition band.

The beginning of this chapter contains general considerations about the design of a digital filter. The form in which the filter specifications must be expressed by the designer are illustrated, and the reasons why an IIR or an FIR filter might be preferred are listed. Then the discussion focuses on the design of linear phase (LP) or generalized linear phase (GLP) FIR filters, which exist in four types. Issues related to the selection of the design method and to the quantitative approximation criteria that may be established to judge the resemblance of the designed filter with the desired one are discussed. The properties of LP/GLP FIR filters are examined in detail, and a factorization of the zero-phase response, useful to unify the symmetry condition for the coefficients of the four filter types, is presented: the zero-phase response is split into a fixed factor, depending on the filter type but not on specifications, and an adjustable factor, with coefficients to be determined according to specifications. The most flexible and optimum design method for LP/GLP FIR filters is then described: this is the minimax method, which ensures the filter meets specifications with the minimum possible order. The properties of optimum FIR filters are finally studied.

The wavelet transform can be seen as a wavelet-based expansion (decomposition) of a finite-energy signal. In the discrete wavelet transform (DWT), economy in the representation of the signal and possibility of perfect signal reconstruction (PR) are crucial. The simplest formulation of the DWT problem includes two types of basis functions for the expansion: the scaling and wavelet functions. We will see how an ideal, infinite-length but finite-energy signal can be decomposed from the point of view function spaces, and how this decomposition can be obtained using a two-channel digital filter bank. The description of a fast wavelet decomposition/reconstruction algorithm will lead us to the practical implementation of the DWT in the real-life case of a finite-length, sampled input signal, as well as to the properties of PR filters, which are strictly related to the scaling and wavelet functions. After allowing for the necessary conditions that the filters of the bank must satisfy, primarily biorthogonality or orthogonality, a number of degrees of freedom remain available to design different wavelet systems suited for different purposes. A real-world example of signal DWT decomposition will be provided. The chapter ends with an appendix in which the various wavelet systems used for the CWT and/or DWT are reviewed.

In this chapter, parametric methods of spectral estimation are presented. They rely on fitting a proper stochastic model to the data record. The model is supposed to represent the persistence, i.e., autocorrelation, present in the process generating the observed signal. The signal’s spectral characteristics are then derived from the estimated model. This approach requires selecting model type and order (number of parameters), and then estimating the parameters. This can be done in several different ways, and the method of parameter estimation gives its name to the parametric spectral method: we thus have the Yule-Walker method, the covariance and modified covariance methods, Burg’s method and the maximum entropy method. These methods provide better resolution than non-parametric ones, especially when the record is short.

In this chapter, the invertible transforms used to work on discrete-time signals are discussed. Given a complex variable z, the z-transform is defined as an infinite series in the z-plane that exists in the region(s) of the plane where the series exhibits absolute convergence to an analytic function. The corresponding infinite-length signal is required to be absolutely summable. Unit-amplitude z values identify the unit circle, on which the z-transform becomes a continuous function of frequency, called the discrete-time Fourier transform (DTFT). The DTFT representation can also be extended to sequences for which the z-transform does not exist, such as signals that are only square-summable, or periodic signals like sinusoids. If a sequence has finite length, it may be represented in the frequency domain by a finite number of values obtained by properly sampling the DTF, i.e., by the discrete Fourier transform (DFT). The properties of the DFT emerge clearly if this transform is introduced passing through the discrete Fourier series (DFS) of the signal’s periodic extension. The DFT can be efficiently computed via fast Fourier transform (FFT). Each inverse transform represents an expansion of the signal in an orthogonal basis. At the end of the chapter, an appendix provides an overview of the mathematical foundations of analog and discrete-time signal expansions.

The first part of this chapter examines the properties of frequency-selective filters that are LTI stable systems with a real and causal impulse response and a rational transfer function. Their frequency response is classified according to four prototypes: the lowpass, highpass, bandpass, and bandstop ideal filters. Ideal filters have real frequency response with jump discontinuities at band edges and are not computationally realizable: they must be approximated by continuous complex functions. The conditions for realizability are discussed in terms of magnitude and phase of the frequency response. The phase of a realizable filter presents jump discontinuities that are eliminated passing to a continuous-phase representation. Linear phase (LP) and generalized linear phase (GLP) filters are then studied, which do not cause phase distortion between input and output waveforms. Only FIR filters of four types can have exactly LP/GLP, and their impulse response must satisfy precise symmetry conditions. The second part of the chapter deals with implementing digital filtering, by arranging the difference equation into the most convenient structure. Finally, applications using downsampling before filtering are described.

This chapter deals with the minimum sampling interval \(T_s\) needed to correctly represent an analog signal by samples extracted periodically from it, so as to be able to reconstruct the continuous-time signal from its discrete-time version. The sampling theorem prescribes this lower limit and highlights the fact that a representative sampling is possible if, and only if, the analog signal does not contain frequencies higher than the Nyquist frequency \(1/(2 T_s)\): no finite-rate sampling can capture the variations of an analog signal which is not bandlimited. Other issues related to analog signals, such as the signal’s concentrations in the time and frequency domains and their mutual inverse dependence (uncertainty principle), as well as the definition of bounded support in both domains, are also discussed. An appendix provides a summary of the relations among the variables used to express the concept of frequency in the continuous-time and discrete-time cases.

A modern approach to spectral analysis of non-stationary signals is provided by the continuous wavelet transform (CWT), in which the signal in its entirety is not compared with infinitely-long sinusoids, but with waveforms called wavelets, which are concentrated in time and frequency. In this method, the concept of period (inverse of a frequency) is replaced by the concept of scale. Using the language of continuous time-signals that allows for avoiding some mathematical difficulties, we will describe what a wavelet is and how signals can be analyzed in time and scale; we will then establish a relation between scale and frequency and investigate CWT resolution in time and frequency, thus introducing the concept of multiresolution analysis (MRA). We will also define the conditions under which a signal can be reconstructed from its CWT coefficients. For practical applications, the CWT must be made discrete in time and scale; we will discuss the most popular discretization scheme. Next we will show how an average power spectrum estimate, the global power spectrum (GWS), can be derived from CWT by averaging over time, and how significance tests for the spectral features detected in CWT analysis can be devised. Real-world application examples will be provided.