The Investigational Clinical Center: a clinical-supportive and patient-centered trial unit model. Ten years of experience through normal and pandemic times of a large pediatric trial center in Italy.

Evidence-based medicine relies on appropriately designed, conducted and reported clinical trials (CTs) to provide the best proofs of efficacy and safety for pharmacological and non-pharmacological treatments. Modern clinical research features high complexity and requires a high workload for the management of trials-related activities, often hampering physicians' participation to clinical trials. Dealing with children in clinical research adds complexity: rare diseases, parents or legal guardian reluctance to engage and recruitment difficulties are major reasons of pediatric trials failure.However, because in pediatrics many treatments are prescribed off-label or are lacking, well-designed clinical trials are particularly needed. Clinical Trial Units (CTUs) are indeed an important asset in the implementation of clinical trials, but their support to investigators is limited to administrative and non-clinical tasks. In this paper we present the model of the Investigational Clinical Center (ICC) of the Bambino Gesù Children's Hospital in Rome. The ICC includes clinicians supporting the Principal Investigators for clinical management of enrolled patients in compliance of Good Clinical Practice, the legal framework of Clinical Trials. Furthermore, we present 10 years' experience in pediatric clinical trials and how it has been affected in 2020 by the COVID-19 pandemic. The activity of the ICC has been evaluated according to specific metrics of performance. The ICC model offers a complete support, helping investigators, patients and their families to overcome majority of barriers linked to clinical research, even in time of pandemic. We propose this organization as an innovative model for total-supportive and patient-centered clinical trial implementation.

Platelet miRNA-26b down-regulates multidrug resistance protein 4 in patients on chronic aspirin treatment.

BACKGROUND: Multidrug resistance protein-4 (MRP4) is an ATP binding cassette membrane transporter, actively involved in the efflux of important pharmacological and physiological molecules. Recently, its over-expression has been associated with reduced aspirin (ASA) efficacy after by-pass surgery. MicroRNAs (miRNAs) are small molecules of non-coding RNA involved in the regulation of many physiological and pathophysiological pathways, are abundant in platelets, and can be modulated by several drugs. In the present study, we assessed the role of platelet miRNAs in modulating MRP4 function in response to ASA. METHODS: MRP4 mRNA expression has been analyzed by RealTime PCR in platelets from patients on chronic ASA treatment versus a control group. A panel of miRNAs was run on the pool of each cohort. MiRNAs validation was performed by RealTime PCR. To verify whether MRP4 is the target of miR-26b also in platelets, miR-26b was transfected in platelet and DAMI cells with miRNA mimic technology. MRP4 expression was evaluated by flow cytometry and western blotting. RESULTS: We observed a higher MRP4 mRNA expression in platelets of patients under ASA treatment compared to the control group (p<0.005). MiR-26b was found significantly down-regulated in patients on ASA treatment as compared to control group (P < 0.005) and this was validated by RealTime PCR. MiR-26b transfection in platelets was associated to a significant down-regulation of MRP4 expression (p<0.005). MiR-26b transfection in DAMI cells was associated to a significant reduction of MRP4 mRNA and protein level (P < 0.05). CONCLUSION: We found that miR-26b is down-regulated in platelets in patients on chronic ASA treatment. Importantly, miR-26b can specifically downregulate MRP4. Thus, miR-26b seems to be involved in MRP4 modulation and may contribute to ASA resistance.

Perilipin 2 levels are increased in patients with in-stent neoatherosclerosis: A clue to mechanisms of accelerated plaque formation after drug-eluting stent implantation.

BACKGROUND: Perilipin 2 (PLIN2) is a protein that potentially facilitates atherogenesis in native coronary arteries or arteries with an implanted drug-eluting stent (DES). The aim of the study was to determine PLIN2 protein levels in peripheral monocytes of enrolled subjects and compare them between patients with native coronary artery disease (CAD) and those with an in-stent restenosis (ISR) due to neoatherosclerosis occurring >1 year after DES implantation. METHODS: Forty-two patients were prospectively enrolled in the study in 3:1 fashion and underwent coronary catheterization. Both groups were angiographically matched for CAD burden with respect to the number of diseased vessels. Neoatherosclerosis was determined by intracoronary optical coherence tomography (OCT) among patients with ISR. RESULTS: Patients with ISR due to neoatherosclerosis had significantly higher PLIN2 protein levels in peripheral blood monocytes compared to patients with native CAD (342.47 ±â€¯75.63[SE] versus 119.51 ±â€¯20.95, p < 0.001). PLIN2 protein levels did not significantly differ between unstable and stable disease phenotype (125.59 ±â€¯131.02 vs. 146.14 ±â€¯111.87, p = 0.109). CONCLUSIONS: In this explorative study, PLIN2 protein levels are significantly increased in patients with neoatherosclerosis, irrespective of clinical presentation, implicating that it might play a pathogenetic role in accelerated atherosclerosis after DES implantation. Further larger clinical studies are warranted to confirm these initial findings.

Accuracy of serum procalcitonin for the diagnosis of sepsis in neonates and children with systemic inflammatory syndrome: a meta-analysis.

BACKGROUND: A number of biomarkers have been studied for the diagnosis of sepsis in paediatrics, but no gold standard has been identified. Procalcitonin (PCT) was demonstrated to be an accurate biomarker for the diagnosis of sepsis in adults and showed to be promising in paediatrics. Our study reviewed the diagnostic accuracy of PCT as an early biomarker of sepsis in neonates and children with suspected sepsis. METHODS: A comprehensive literature search was carried out in Medline/Pubmed, Embase, ISI Web of Science, CINAHL and Cochrane Library, for studies assessing PCT accuracy in the diagnosis of sepsis in children and neonates with suspected sepsis. Studies in which the presence of infection had been confirmed microbiologically or classified as "probable" by chart review were included. Studies comparing patients to healthy subjects were excluded. We analysed data on neonates and children separately. Our primary outcome was the diagnostic accuracy of PCT at the cut-off of 2-2.5 ng/ml, while as secondary outcomes we analysed PCT cut-offs <2 ng/ml and >2.5 ng/ml. Pooled sensitivities and specificities were calculated by a bivariate meta-analysis and heterogeneity was graphically evaluated. RESULTS: We included 17 studies, with a total of 1408 patients (1086 neonates and 322 children). Studies on neonates with early onset sepsis (EOS) and late onset sepsis (LOS) were grouped together. In the neonatal group, we calculated a sensitivity of 0.85, confidence interval (CI) (0.76; 0.90) and specificity of 0.54, CI (0.38; 0.70) at the PCT cut-off of 2.0-2.5 ng/ml. In the paediatric group it was not possible to undertake a pooled analysis at the PCT cut-off of 2.0-2.5 ng/ml, due to the paucity of the studies. CONCLUSIONS: PCT shows a moderate accuracy for the diagnosis of sepsis in neonates with suspected sepsis at the cut-off of 2.0-2.5 ng/ml. More studies with high methodological quality are warranted, particularly in neonates, studies considering EOS and LOS separately are needed to improve specificity. TRIAL REGISTRATION: PROSPERO Identifier: CRD42016033809 . Registered 30 Jan 2016.

Permanent polymer of drug eluting stents increases eosinophil cationic protein levels following percutaneous coronary intervention independently of C-reactive protein.

AIM: To assess eosinophil cationic protein (ECP) and C-reactive protein (CRP) serum levels at three time points according to different stent types. METHODS: 54 patients (age 64 ± 10 years, male 78%), undergoing Bare Metal Stent (BMS) (n = 11), mammalian Target Of Rapamycin (mTOR)-inhibitor DES (n = 27) and mTOR-inhibitor bioabsorbable DES (BES) (n = 16) implantation for stable angina (SA) or non-ST-elevation acute coronary syndromes (NSTE-ACS), were prospectively enrolled. ECP and CRP serum levels were assessed before revascularization, at 1-month and at 1-year after the procedure. Moreover, 21 patients found to have inducible ischemia or angina symptoms at 6 month-stress test underwent 1-year follow-up (FU) angiography. RESULTS: Baseline and 1-month ECP levels were similar among the 3 groups, whilst 1-year ECP was significantly higher in m-TOR-DES [8.61 (6.55-19.77) µg/ml] compared with m-TOR-BES [2.03 (1.78-5.53) µg/ml] and BMS-treated patients [2.23 (1.45-8.95) µg/ml] (p = 0.02), without significant difference between BES and BMS. CRP was similar among the 3 groups at all time points. 1-year ECP significantly correlated with late loss in patients undergoing FU angiography (r = 0.64, p = 0.002), while CRP did not (p = NS). CONCLUSIONS: Our finding suggests that mTOR-DES stent type is associated with an increase of ECP levels at 1-year, possibly reflecting a persistent eosinophil activation triggered by permanent polymer.