SerpinE1 drives a cell-autonomous pathogenic signaling in Hutchinson-Gilford progeria syndrome

Hutchinson-Gilford progeria syndrome (HGPS) is a rare, fatal disease caused by Lamin A mutation, leading to altered nuclear architecture, loss of peripheral heterochromatin and deregulated gene expression. HGPS patients eventually die by coronary artery disease and cardiovascular alterations. Yet, how deregulated transcriptional networks at the cellular level impact on the systemic disease phenotype is currently unclear. A genome-wide analysis of gene expression in cultures of primary HGPS fibroblasts identified SerpinE1, also known as Plasminogen Activator Inhibitor (PAI-1), as central gene that propels a cell-autonomous pathogenic signaling from the altered nuclear lamina. Indeed, siRNA-mediated downregulation and pharmacological inhibition of SerpinE1 by TM5441 could revert key pathological features of HGPS in patient-derived fibroblasts, including re-activation of cell cycle progression, reduced DNA damage signaling, decreased expression of pro-fibrotic genes and recovery of mitochondrial defects. These effects were accompanied by the correction of nuclear abnormalities. These data point to SerpinE1 as a novel potential effector and target for therapeutic interventions in HGPS pathogenesis

Globalization effects on the reports of non-endemic parasitosis in Italy

Protozoa and helminths are responsible for several intestinal parasite infections (IPIs). Generally, helminth infections are very unsafe but scarcely reported in high-income countries, while protozoa and helminth co-infections are usually reported in children living in inadequate hygienic-sanitary conditions and in rural areas. However, the impact of growing globalization, intense travelling, international adoptions and high levels of immigrants and refugees has significantly incremented the incidence of orofecal parasitosis in non-endemic areas. Although most IPs clear without treatment when population, even children, emigrate from endemic to different geographical areas, some IPIs such as strongyloidiasis may persist for decades as subclinical infections or as low-grade disease with nonspecific clinical manifestations, unless to reappear under impairment conditions. Herein we report an unusual case of Giardia lamblia and Trichuris spp. chronic asymptomatic co-infection in a healthy adopted Romanian child, living in a Central Italy rural area, and a hidden case of Strongyloides stercoralis in an adopted Burundian child, resident in South Italy, long misdiagnosed as a recurrent undefined dermatitis. Our report suggests the need to review primary care practitioner guidelines and children’s hospital procedures for appropriate IPIs screening and follow-up, hence providing new screening and prevention strategies, in agreement with international guidelines

Clinical Features, Cardiovascular Risk Profile, and Therapeutic Trajectories of Patients with Type 2 Diabetes Candidate for Oral Semaglutide Therapy in the Italian Specialist Care

Introduction: This study aimed to address therapeutic inertia in the management of type 2 diabetes (T2D) by investigating the potential of early treatment with oral semaglutide. Methods: A cross-sectional survey was conducted between October 2021 and April 2022 among specialists treating individuals with T2D. A scientific committee designed a data collection form covering demographics, cardiovascular risk, glucose control metrics, ongoing therapies, and physician judgments on treatment appropriateness. Participants completed anonymous patient questionnaires reflecting routine clinical encounters. The preferred therapeutic regimen for each patient was also identified. Results: The analysis was conducted on 4449 patients initiating oral semaglutide. The population had a relatively short disease duration (42%  60% of patients, and more often than sitagliptin or empagliflozin. Conclusion: The study supports the potential of early implementation of oral semaglutide as a strategy to overcome therapeutic inertia and enhance T2D management

Defining Kawasaki disease and pediatric inflammatory multisystem syndrome-temporally associated to SARS-CoV-2 infection during SARS-CoV-2 epidemic in Italy: results from a national, multicenter survey

Background: There is mounting evidence on the existence of a Pediatric Inflammatory Multisystem Syndrome-temporally associated to SARS-CoV-2 infection (PIMS-TS), sharing similarities with Kawasaki Disease (KD). The main outcome of the study were to better characterize the clinical features and the treatment response of PIMS-TS and to explore its relationship with KD determining whether KD and PIMS are two distinct entities. Methods: The Rheumatology Study Group of the Italian Pediatric Society launched a survey to enroll patients diagnosed with KD (Kawasaki Disease Group - KDG) or KD-like (Kawacovid Group - KCG) disease between February 1st 2020, and May 31st 2020. Demographic, clinical, laboratory data, treatment information, and patients' outcome were collected in an online anonymized database (RedCAP®). Relationship between clinical presentation and SARS-CoV-2 infection was also taken into account. Moreover, clinical characteristics of KDG during SARS-CoV-2 epidemic (KDG-CoV2) were compared to Kawasaki Disease patients (KDG-Historical) seen in three different Italian tertiary pediatric hospitals (Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste; AOU Meyer, Florence; IRCCS Istituto Giannina Gaslini, Genoa) from January 1st 2000 to December 31st 2019. Chi square test or exact Fisher test and non-parametric Wilcoxon Mann-Whitney test were used to study differences between two groups. Results: One-hundred-forty-nine cases were enrolled, (96 KDG and 53 KCG). KCG children were significantly older and presented more frequently from gastrointestinal and respiratory involvement. Cardiac involvement was more common in KCG, with 60,4% of patients with myocarditis. 37,8% of patients among KCG presented hypotension/non-cardiogenic shock. Coronary artery abnormalities (CAA) were more common in the KDG. The risk of ICU admission were higher in KCG. Lymphopenia, higher CRP levels, elevated ferritin and troponin-T characterized KCG. KDG received more frequently immunoglobulins (IVIG) and acetylsalicylic acid (ASA) (81,3% vs 66%; p = 0.04 and 71,9% vs 43,4%; p = 0.001 respectively) as KCG more often received glucocorticoids (56,6% vs 14,6%; p < 0.0001). SARS-CoV-2 assay more often resulted positive in KCG than in KDG (75,5% vs 20%; p < 0.0001). Short-term follow data showed minor complications. Comparing KDG with a KD-Historical Italian cohort (598 patients), no statistical difference was found in terms of clinical manifestations and laboratory data. Conclusion: Our study suggests that SARS-CoV-2 infection might determine two distinct inflammatory diseases in children: KD and PIMS-TS. Older age at onset and clinical peculiarities like the occurrence of myocarditis characterize this multi-inflammatory syndrome. Our patients had an optimal response to treatments and a good outcome, with few complications and no deaths

Childhood multisystem inflammatory syndrome associated with COVID-19 (MIS-C): a diagnostic and treatment guidance from the Rheumatology Study Group of the Italian Society of Pediatrics

Italy was the first Western country to be hit by the SARS-CoV-2 epidemic. There is now mounting evidence that a minority of children infected with SARS-CoV2 may experience a severe multisystem inflammatory syndrome, called Multisystem inflammatory Syndrome associated with Coronavirus Disease 2019 (MIS-C). To date no universally agreed approach is available for this disease. MAIN BODY: as Italy is now facing a second hity of COVID-19 cases, we fear a recrudescence of MIS-C cases. We have, therefore, decided to prepare a report that will help clinicians to face this novel and challenging disease. We propose a diagnostic algorithm, to help case definition and guide work-up, and a therapeutic approach. MIS-C should be promptly recognized, based on the presence of systemic inflammation and specific organ involvement. Early treatment is crucial, and it will be based on the combined use of corticosteroids, high-dose immunoglobulins and anti-cytokine treatments, depending on the severity of the disease. Ancillary treatments (such as. aspirin and thrombo-profilaxis) will be also discussed

Evaluation of the physician quality improvement initiative: the expected and unexpected opportunities

Abstract Background The Physician Quality Improvement Initiative (PQII) uses a well-established multi-source feedback program, and incorporates an additional facilitated feedback review with their department chief. The purpose of this mixed methods study was to examine the value of the PQII by eliciting feedback from various stakeholders. Methods All participants and department chiefs (n = 45) were invited to provide feedback on the project implementation and outcomes via survey and/or an interview. The survey consisted of 12 questions focused on the value of the PQII, it’s influence on practice and the promotion of quality improvement and accountability. Results A total of 5 chiefs and 12 physician participants completed semi structured interviews. Participants found the PQII process, report and review session helpful, self-affirming or an opportunity for self-reflection, and an opportunity to engage their leaders about their practice. Chiefs indicated the sessions strengthened their understanding, ability to communicate and engage physicians about their practice, best practices, quality improvement and accountability. Thirty participants (66.7 %) completed the survey; of the responders 75.9, 89.7, 86.7 % found patient, co-worker, and physician colleague feedback valuable, respectively. A total of 67.9 % valued their facilitated review with their chief and 55.2 % indicated they were contemplating change due to their feedback. Participants believed the PQII promoted quality improvement (27/30, 90.0 %), and accountability (28/30, 93.3 %). Conclusions The PQII provides an opportunity for physician development, affirmation and reflection, but also a structure to further departmental quality improvement, best practices, and finally, an opportunity to enhance communication, accountability and relationships between the organization, department chiefs and their staff

Predictors of Relapse after Discontinuing Systemic Treatment in Childhood Autoimmune Chronic Uveitis

OBJECTIVE: To identify clinical predictors of relapse in childhood autoimmune chronic uveitis after stopping systemic treatment. METHODS: A retrospective, multicenter, cohort study. RESULTS: Ninety-four children in remission, receiving no treatments and with at least a 6-month followup, were enrolled. A higher probability of maintaining remission after discontinuing treatment was shown in idiopathic compared with juvenile idiopathic arthritis uveitis (Mantel-Cox chi-square = 23.21) if inactivity had been obtained within 6 months from starting systemic treatment (Mantel- Cox chi-square = 24.17) and by antitumor necrosis factor-α treatment (Mantel-Cox chi-square = 6.43). CONCLUSION: Type of disease, time, and type of systemic therapy to achieve inactivity predict different duration of uveitis remission after treatment withdrawa

Predictors of relapse after discontinuing systemic treatment in childhood autoimmune chronic uveitis

9noOBJECTIVE: To identify clinical predictors of relapse in childhood autoimmune chronic uveitis after stopping systemic treatment. METHODS: A retrospective, multicenter, cohort study. RESULTS: Ninety-four children in remission, receiving no treatments and with at least a 6-month followup, were enrolled. A higher probability of maintaining remission after discontinuing treatment was shown in idiopathic compared with juvenile idiopathic arthritis uveitis (Mantel-Cox chi-square = 23.21) if inactivity had been obtained within 6 months from starting systemic treatment (Mantel-Cox chi-square = 24.17) and by antitumor necrosis factor-α treatment (Mantel-Cox chi-square = 6.43). CONCLUSION: Type of disease, time, and type of systemic therapy to achieve inactivity predict different duration of uveitis remission after treatment withdrawal.reservedmixedSimonini, Gabriele; Bracaglia, Claudia; Cattalini, Marco; Taddio, Andrea; Brambilla, Alice; De Libero, Cinzia; Marafon, Denise Pires; Caputo, Roberto; Cimaz, RolandoSimonini, Gabriele; Bracaglia, Claudia; Cattalini, Marco; Taddio, Andrea; Brambilla, Alice; De Libero, Cinzia; Marafon, Denise Pires; Caputo, Roberto; Cimaz, Roland