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Abstract This is a summary of the original article ‘Ten-year safety and clinical benefit from open label etanercept treatment in children and young adults with juvenile idiopathic arthritis’. Juvenile idiopathic arthritis (JIA) usually appears before the age of 16. JIA causes pain, swelling, and stiffness in the joints. People with JIA receive treatment for several years until the disease goes into prolonged remission. Therefore, the long-term safety of these treatments is an important topic. Etanercept is a treatment for JIA, which acts on the body’s immune system to reduce arthritis. This summary of research article describes safety and how well etanercept works in children with JIA taking it for up to 10 years.

Background and objective: The shift toward targeted biopsy (TBx) aims at enhancing prostate cancer (PCa) detection while reducing overdiagnosis of clinically insignificant disease. Despite the improved ability of TBx in identifying clinically significant PCa (csPCa), the optimal number and location of targeted cores remain unclear. This review aims to assess the optimal number of prostate biopsy magnetic resonance imaging (MRI)-targeted cores to detect csPCa. Methods: A narrative literature search was conducted using PubMed, focusing on studies published between January 2014 and January 2024, addressing factors influencing targeted core numbers during prostate biopsy. The search included both retrospective and prospective studies, prioritizing those with substantial sample sizes and employing terms such as “prostate biopsy”, “mpMRI”, “core number”, and “cancer detection”. Key findings and limitations: Two biopsy cores identified csPCa in 55–65% of cases. This detection rate improved to approximately 90% when the number of cores was ≥5. The inclusion of perilesional and systematic biopsies could maximize the detection of csPCa (from 10% to 45%), especially in patients under active surveillance or with prior negative biopsy results, although there is an increase in the overdiagnosis of indolent tumors (from 4% to 20%). Transperineal software-assisted target prostate biopsy may enhance cancer detection, particularly for tumors located at the apex/anterior part of the prostate. Increasing the number of TBx cores may incrementally raise the risk of complications (by 2–14% with each added core) and result in severe pain and significant discomfort for up to 17% and 25% of TBx patients, respectively. However, the overall rate and severity of these complications remain within acceptable limits. Conclusions and clinical implications: The optimal number of cores for targeted prostate biopsies should balance minimizing sampling errors with effective cancer detection and should be tailored to each patient’s unique prostate characteristics. Up to five cores per MRI target may be considered to enhance the detection of csPCa, with adjustments based on factors such as prostate and lesion volume, Prostate Imaging Reporting and Data System, biopsy techniques, complications, patient discomfort, and anxiety. Patient summary: In this report, we found that increasing the number of biopsy cores up to ≥5 improves the detection rates of significant prostate cancer significantly to around 90%. Although inclusion of nearby and systematic biopsies enhances detection, increasing the biopsy count may lead to higher risks of complications and indolent tumors. A customized biopsy approach based on multiple variables could be helpful in determining the appropriate number of targeted biopsies on a case-by-case basis.

Abstract Background Juvenile idiopathic arthritis (JIA) comprises a heterogeneous group of conditions that can cause marked disability and diminished quality of life. Data on predictors of clinical response are insufficient to guide selection of the appropriate biologic agent for individual patients. This study aimed to investigate the propensity of S100A8/9 and S100A12 as predictive biomarkers of abatacept response in polyarticular-course juvenile idiopathic arthritis (pJIA). Methods Data from a phase 3 trial (NCT01844518) of subcutaneous abatacept in patients with active pJIA (n = 219) were used in this exploratory analysis. Association between biomarker levels at baseline and improvements in JIA-American College of Rheumatology (ACR) criteria responses or baseline disease activity (measured by Juvenile Arthritis Disease Activity Score in 27 joints using C-reactive protein [JADAS27-CRP]) were assessed. Biomarker level changes from baseline to month 4 were assessed for disease outcome prediction up to 21 months. Results At baseline, 158 patients had available biomarker samples. Lower baseline S100A8/9 levels (≤ 3295 ng/mL) were associated with greater odds of achieving JIA-ACR90 (odds ratio [OR]: 2.54 [95% confidence interval (CI): 1.25–5.18]), JIA-ACR100 (OR: 3.72 [95% CI: 1.48–9.37]), JIA-ACR inactive disease (ID; OR: 4.25 [95% CI: 2.03–8.92]), JADAS27-CRP ID (OR: 2.34 [95% CI: 1.02–5.39]) at month 4, and JIA-ACR ID (OR: 3.01 [95% CI: 1.57–5.78]) at month 16. Lower baseline S100A12 levels (≤ 176 ng/mL) were associated with greater odds of achieving JIA-ACR90 (OR: 2.52 [95% CI: 1.23–5.13]), JIA-ACR100 (OR: 3.68 [95% CI: 1.46–9.28]), JIA-ACR ID (OR: 3.66 [95% CI: 1.76–7.61]), JIA-ACR90 (OR: 2.03 [95% CI: 1.07–3.87]), JIA-ACR100 (OR: 2.14 [95% CI: 1.10–4.17]), and JIA-ACR ID (OR: 4.22 [95% CI: 2.15–8.29]) at month 16. From baseline to month 4, decreases in S100A8/9 and S100A12 generally exceeded 50% among JIA-ACR90/100/ID responders. Conclusion Lower baseline levels of S100A8/9 and S100A12 proteins predicted better response to abatacept treatment than higher levels and may serve as early predictive biomarkers in pJIA. Decreases in these biomarker levels may also predict longer-term response to abatacept in pJIA.

IntroductionNadofaragene firadenovec (Ad-IFNα/Syn3) is now approved for BCG-unresponsive bladder cancer (BLCA). IFNα is a pleiotropic cytokine that causes direct tumor cell killing via TRAIL-mediated apoptosis, angiogenesis inhibition, and activation of the innate and adaptive immune system. We established an immunocompetent murine BLCA model to study the effects of murine adenoviral IFNα (muAd-Ifnα) gene therapy on cancer cells and the tumor microenvironment using a novel murine equivalent of Nadofaragene firadenovec (muAd-Ifnα).MethodsTumors were induced by instilling MB49 cells into the bladders of mice; luciferase imaging confirmed tumor development. Mice were treated with adenovirus control (Ad-Ctrl; empty vector), or muAd-Ifnα (3x1011 VP/mL), and survival analysis was performed. For single-cell sequencing (scRNAseq) analysis (72h), bladders were harvested and treated with collagenase/hyaluronidase and TrypLE for cell dissociation. Single cells were suspended in PBS/1% FBS buffer; viability was assessed with Vicell cell counter. scRNAseq analysis was performed using 10X genomics 3’ sequencing. Raw RNAseq data were pre-processed using Cell Ranger single-cell software. Seurat (R package) was used to normalize and cluster the scRNA data. Pooled differential gene expression analysis in specific cell clusters was performed with DESeq2.ResultsWe identified 16 cell clusters based on marker expression which were grouped into epithelial (tumor), uroplakin-enriched, endothelial, T-cells, neutrophils, and macrophage clusters. Top differentially expressed genes between muAd-Ifnα and Ad-Ctrl were identified. Within the specific cell clusters, IPA analysis revealed significant differences between muAd-Ifnα and control. IFNα signaling and hypercytokinemia/chemokinemia were upregulated in all clusters. Cell death pathways were upregulated in tumor and endothelial clusters. T-cells demonstrated upregulation of the immunogenic cell death signaling pathway and a decrease in the Th2 pathway genes. Macrophages showed upregulation of PD1/PD-L1 pathways along with downregulation of macrophage activation pathways (alternate and classical). Multiplex immunofluorescence confirmed increased infiltration with macrophages in muAd-Ifnα treated tumors compared to controls. PD1/PD-L1 expression was reduced at 72h.DiscussionThis single-cell analysis builds upon our understanding of the impact of Ad-IFNα on tumor cells and other compartments of the microenvironment. These data will help identify mechanisms to improve patient selection and therapeutic efficacy of Nadofaragene firadenovec.

The PROpel trial assessed the combination of olaparib + abiraterone acetate (AA) plus prednisone and androgen deprivation therapy (ADT) versus AA plus prednisone and ADT alone as first-line treatment for metastatic castration-resistant prostate cancer (mCPRP). To contextualize the progression free survival (PFS) benefit in PROpel, we performed a systematic review and quasi-individual patient data network meta-analysis on randomized controlled trials of first-line hormonal treatments for mCPRC. Meta-analysis was performed for the PROpel control arm and PREVAIL (enzalutamide) and COU-AA-302 (AA) treatment arms. Kaplan-Meier PFS curves were digitally reconstructed and differences in restricted mean survival time (ΔRMST) were computed. Combination therapy yielded longer PFS (24-mo ΔRMST 1.5 mo, 95% confidence interval 0.6–2.4) in comparison to novel hormonal treatments alone. However, the lack of mature overall survival data, higher complication rates, and higher health care costs are limitations of combination therapy. Ultimately, combining treatments, rather than molecularly targeted sequencing in cases of failure, might not be justified in unselected patients with mCRPC. Patient summary: A recent trial showed that for metastatic prostate cancer that does not respond to hormone treatment, combined therapy with two drugs (olaparib and abiraterone) may prolong survival free from cancer progression. We included these data in an analysis of three trials that confirmed a small benefit. This combination approach has higher complication rates and is more expensive, and longer-term results for overall survival are needed.

In the past few decades, braking systems with carbon discs have become the dominant technology for many racing applications, such as in the MotoGP class. Indeed, they provide higher friction coefficients. Moreover, thanks to their lightweight materials (with respect to conventional steel brakes), the unsprung masses and the gyroscopic effects can be reduced. Therefore, the motorcycle dynamic performance can be significantly improved. The usage of carbon brakes requires a very accurate assessment of their thermal behavior. In fact, although their operating temperature in real racing conditions may cover a wide range, their optimal braking performance can be achieved only within a relatively narrow temperature range. This work focuses on the development of the Unscented Kalman Filter (UKF) algorithm as a suitable mathematical tool for assessing the temperature gradient of the carbon disc mounted on the motorcycles competing in the MotoGP™ world championship. A one-dimensional (1D) finite element (FE) model of the disc is developed to provide the a priori state estimate that the filter will combine with the information measured by the temperature sensor available on board to compute the optimal posterior temperature estimation. Besides estimating temperature, the UKF is also exploited to identify the convection heat transfer coefficient (h) of the disc, which is a fundamental parameter for a proper model calibration.

Bladder cancer is a prevalent malignancy with limited therapeutic options, particularly for patients who are unresponsive to Bacillus Calmette-Guérin (BCG). The approval of interferon-α (IFNα) gene therapy with nadofaragene firadenovec (Adstiladrin®), the first gene therapy for genitourinary malignancies, has provided a promising alternative. This article reviews the research and milestones that led to the development and approval of nadofaragene firadenovec. Bladder cancer is well-suited for gene therapy due to direct access to the bladder and the availability of urine and tissue samples for monitoring. Early challenges included effective gene transfer across the urothelium, which was overcome initially by modulating the expression of coxsackie/adenovirus receptor (CAR) and, ultimately, by disrupting the urothelial barrier with Syn3. Nadofaragene firadenovec is a modified adenoviral vector carrying the IFNα gene. Clinical trials have shown promising results, with high response rates and manageable adverse events. Ongoing research focuses on improving patient selection, identifying biomarkers for response prediction, exploring alternative vectors for enhanced transfection efficiency, and developing combination strategies targeting resistance mechanisms. The approval of nadofaragene firadenovec marks a significant milestone in the field of gene therapy for bladder cancer, and future developments hold promise for further enhancing its efficacy and impact.

The treatment of early-stage penile carcinoma is usually represented by wide excision or partial penectomy with or without inguinal lymph node dissection. However, laser ablation of the tumor may have a prominent role as an organ-sparing approach. In this regard, the combination of UltraPulse CO2 laser and photodynamic therapy (PDT) may be a valid option, especially when surgery is not feasible or refused. UltraPulse CO2 laser allows for the formation of gentle cutaneous abrasion that destroys the malignant tissue and, at the same time, improving the uptake of methyl aminolevulinate and amplifying the photochemical reaction of PDT in the tumor and surrounding tissue.

Background: The European Association of Urology guidelines recommend the use of imaging, biomarkers, and risk calculators in men at risk of prostate cancer. Risk predictive calculators that combine multiparametric magnetic resonance imaging with prebiopsy variables aid as an individualized decision-making tool for patients at risk of prostate cancer, and advanced neural networking increases reliability of these tools. Objective: To develop a comprehensive risk predictive online web-based tool using magnetic resonance imaging (MRI) and clinical data, to predict the risk of any prostate cancer (PCa) and clinically significant PCa (csPCa) applicable to biopsy-naïve men, men with a prior negative biopsy, men with prior positive low-grade cancer, and men with negative MRI. Design, setting, and participants: Institutional review board–approved prospective data of 1902 men undergoing biopsy from October 2013 to September 2021 at Mount Sinai were collected. Outcome measurements and statistical analysis: Univariable and multivariable analyses were used to evaluate clinical variables such as age, race, digital rectal examination, family history, prostate-specific antigen (PSA), biopsy status, Prostate Imaging Reporting and Data System score, and prostate volume, which emerged as predictors for any PCa and csPCa. Binary logistic regression was performed to study the probability. Validation was performed with advanced neural networking (ANN), multi-institutional European cohort (Prostate MRI Outcome Database [PROMOD]), and European Randomized Study of Screening for Prostate Cancer Risk Calculator (ERSPC RC) 3/4. Results and limitations: Overall, 2363 biopsies had complete clinical information, with 57.98% any cancer and 31.40% csPCa. The prediction model was significantly associated with both any PCa and csPCa having an area under the curve (AUC) of 81.9% including clinical data. The AUC for external validation was calculated in PROMOD, ERSPC RC, and ANN for any PCa (0.82 vs 0.70 vs 0.90) and csPCa (0.82 vs 0.78 vs 0.92), respectively. This study is limited by its retrospective design and overestimation of csPCa in the PROMOD cohort. Conclusions: The Mount Sinai Prebiopsy Risk Calculator combines PSA, imaging and clinical data to predict the risk of any PCa and csPCa for all patient settings. With accurate validation results in a large European cohort, ERSPC RC, and ANN, it exhibits its efficiency and applicability in a more generalized population. This calculator is available online in the form of a free web-based tool that can aid clinicians in better patients counseling and treatment decision-making. Patient summary: We developed the Mount Sinai Prebiopsy Risk Calculator (MSP-RC) to assess the likelihood of any prostate cancer and clinically significant disease based on a combination of clinical and imaging characteristics. MSP-RC is applicable to all patient settings and accessible online.

BackgroundWith the advent of immuno-oncology compounds in randomized trials, we observe more and more survival curves crossing. From a statistical standpoint this corresponds to violation of the proportional hazard assumption. When this occurs, the hazard ratio from the Cox regression is not reliable as an estimate. Herein, we aimed to identify the most appropriate IO-based therapy for metastatic renal cell carcinoma applying an alternative method to overcome the issue of hazard assumption violation for meta-analyses.MethodsPubmed, EMBASE, Web of Science and Scopus databases were searched. Only phase III randomized clinical trials on IO-IO (nivo-ipi) or IO-TKI combinations were included. An algorithm to obtain survival data from published Kaplan-Meier curves was used to reconstruct data on overall survival (OS), progression-free survival (PFS) and duration of response (DoR). Differences in restricted mean survival time (RMST) were used for comparisons.Resultsindividual survival data from 4,206 patients from five trials were reconciled. Patients who received nivo-ipi or IO-TKI had better OS, PFS and DoR relative to sunitinib (all p

To find an association between genomic features of connective tissue and pejorative clinical outcomes on radical prostatectomy specimens. We performed a retrospective analysis of patients who underwent radical prostatectomy and underwent a Decipher transcriptomic test for localized prostate cancer in our institution (n = 695). The expression results of selected connective tissue genes were analyzed after multiple t tests, revealing significant differences in the transcriptomic expression (over- or under-expression). We investigated the association between transcript results and clinical features such as extra-capsular extension (ECE), clinically significant cancer, lymph node (LN) invasion and early biochemical recurrence (eBCR), defined as earlier than 3 years after surgery). The Cancer Genome Atlas (TCGA) was used to evaluate the prognostic role of genes on progression-free survival (PFS) and overall survival (OS). Out of 528 patients, we found that 189 had ECE and 27 had LN invasion. The Decipher score was higher in patients with ECE, LN invasion, and eBCR. Our gene selection microarray analysis showed an overexpression in both ECE and LN invasion, and in clinically significant cancer for COL1A1, COL1A2, COL3A1, LUM, VCAN, FN1, AEBP1, ASPN, TIMP1, TIMP3, BGN, and underexpression in FMOD and FLNA. In the TCGA population, overexpression of these genes was correlated with worse PFS. Significant co-occurrence of these genes was observed. When presenting overexpression of our gene selection, the 5-year PFS rate was 53% vs. 68% (p = 0.0315). Transcriptomic overexpression of connective tissue genes correlated to worse clinical features, such as ECE, clinically significant cancer and BCR, identifying the potential prognostic value of the gene signature of the connective tissue in prostate cancer. TCGAp cohort analysis showed a worse PFS in case of overexpression of the connective tissue genes.

Abstract Background To derive a list of opportunistic infections (OI) through the analysis of the juvenile idiopathic arthritis (JIA) patients in the Pharmachild registry by an independent Safety Adjudication Committee (SAC). Methods The SAC (3 pediatric rheumatologists and 2 pediatric infectious disease specialists) elaborated and approved by consensus a provisional list of OI for use in JIA. Through a 5 step-procedure, all the severe and serious infections, classified as per MedDRA dictionary and retrieved in the Pharmachild registry, were evaluated by the SAC by answering six questions and adjudicated with the agreement of 3/5 specialists. A final evidence-based list of OI resulted by matching the adjudicated infections with the provisional list of OI. Results A total of 772 infectious events in 572 eligible patients, of which 335 serious/severe/very severe non-OI and 437 OI (any intensity/severity), according to the provisional list, were retrieved. Six hundred eighty-two of 772 (88.3%) were adjudicated as infections, of them 603/682 (88.4%) as common and 119/682 (17.4%) as OI by the SAC. Matching these 119 opportunistic events with the provisional list, 106 were confirmed by the SAC as OI, and among them infections by herpes viruses were the most frequent (68%), followed by tuberculosis (27.4%). The remaining events were divided in the groups of non-OI and possible/patient and/or pathogen-related OI. Conclusions We found a significant number of OI in JIA patients on immunosuppressive therapy. The proposed list of OI, created by consensus and validated in the Pharmachild cohort, could facilitate comparison among future pharmacovigilance studies. Trial registration Clinicaltrials.gov NCT 01399281; ENCePP seal: awarded on 25 November 2011.

Abstract Background Patients with polyarticular-course juvenile idiopathic arthritis (pJIA), receiving disease-modifying anti-rheumatic drugs with immunosuppressive effects, may be at increased risk of vaccine-preventable infections. This substudy assessed protective antibody responses to diphtheria and tetanus vaccination given prior to study enrolment in patients with pJIA. Findings This was a substudy of a 24-month, single-arm, open-label, multicenter, Phase III trial (NCT01844518) of subcutaneous abatacept in children with active pJIA (N = 219). Patients aged 2–5 years, with ≥2 continuous months of weekly weight-tiered (10– 0.1 IU/mL), and safety, were assessed. Overall, 29 patients were analyzed: 19 (65.5%), 1 (3.4%) and 9 (31.0%) patients had > 12, 6–12 and 2–

Abstract Background Prednisone (PDN) in juvenile dermatomyositis (JDM), alone or in association with other immunosuppressive drugs, namely methotrexate (MTX) and cyclosporine (CSA), represents the first-line treatment option for new onset JDM patients. No clear evidence based guidelines are actually available to standardize the tapering and discontinuation of glucocorticoids (GC) in JDM. Aim of our study was to provide an evidence-based proposal for GC tapering/discontinuation in new onset juvenile dermatomyositis (JDM), and to identify predictors of clinical remission and GC discontinuation. Methods New onset JDM children were randomized to receive either PDN alone or in combination with methotrexate (MTX) or cyclosporine (CSA). In order to derive steroid tapering indications, PRINTO/ACR/EULAR JDM core set measures (CSM) and their median absolute and relative percent changes over time were compared in 3 groups. Group 1 included those in clinical remission who discontinued PDN, with no major therapeutic changes (MTC) (reference group) and was compared with those who did not achieve clinical remission, without or with MTC (Group 2 and 3, respectively). A logistic regression model identified predictors of clinical remission with PDN discontinuation. Results Based on the median change in the CSM of 30/139 children in Group 1, after 3 pulses of methyl-prednisolone, GC could be tapered from 2 to 1 mg/kg/day in the first two months from onset if any of the CSM decreased by 50–94%, and from 1 to 0.2 mg/kg/day in the following 4 months if any CSM further decreased by 8–68%, followed by discontinuation in the ensuing 18 months. The achievement of PRINTO JDM 50–70-90 response after 2 months of treatment (ORs range 4.5–6.9), an age at onset > 9 years (OR 4.6) and the combination therapy PDN + MTX (OR 3.6) increase the probability of achieving clinical remission (p

Abstract Background To describe the 6-year safety and efficacy of etanercept (ETN) in children with extended oligoarticular juvenile idiopathic arthritis (eoJIA), enthesitis-related arthritis (ERA), and psoriatic arthritis (PsA) Methods Patients who completed the 2-year, open-label, phase III CLinical Study In Pediatric Patients of Etanercept for Treatment of ERA, PsA, and Extended Oligoarthritis (CLIPPER) were allowed to enroll in its 8-year long-term extension (CLIPPER2). Children received ETN at a once-weekly dose of 0.8 mg/kg, up to a maximum dose of 50 mg/week. Efficacy assessments included the JIA core set of outcomes, the JIA American College of Rheumatology response criteria (JIA-ACR), and the Juvenile Arthritis Disease Activity Score (JADAS). Efficacy data are reported as responder analyses using a hybrid method for missing data imputation and as observed cases. Safety assessments included treatment-emergent adverse events (TEAEs). Results Out of 127 patients originally enrolled in CLIPPER, 109 (86%) entered CLIPPER2. After 6 years of trial participation (2 years in CLIPPER and 4 years in CLIPPER2), 41 (32%) patients were still taking ETN, 13 (11%) entered the treatment withdrawal phase after achieving low/inactive disease (of whom 7 had to restart ETN), 36 (28%) discontinued treatment for other reasons but are still being observed, and 37 (29%) discontinued treatment permanently. According to the hybrid imputation analysis, proportions of patients achieving JIA ACR90, JIA ACR100, and JADAS inactive disease after the initial 2 years of treatment were 58%, 48%, and 32%, respectively. After the additional 4 years, those proportions in patients who remained in the trial were 46%, 35%, and 24%. Most frequently reported TEAEs [n (%), events per 100 patient-years] were headache [28 (22%), 5.3], arthralgia [24 (19%), 4.6], and pyrexia [20 (16%), 3.8]. Number and frequency of TEAEs, excluding infections and injection site reactions, decreased over the 6-year period from 193 and 173.8, respectively, during year 1 to 37 and 61.3 during year 6. A single case of malignancy (Hodgkin’s lymphoma) and no cases of active tuberculosis, demyelinating disorders, or deaths were reported. Conclusions Open-label etanercept treatment for up to 6 years was safe, well tolerated, and effective in patients with eoJIA, ERA, and PsA. Trial registration ClinicalTrials.gov: CLIPPER, NCT00962741, registered 20 August, 2009, CLIPPER2, NCT01421069, registered 22 August, 2011.

Abstract The Paediatric Rheumatology European Society (PReS) has over many years, developed a portfolio of educational activities to address increasing educational needs of workforce and support young clinicians to acquire skills to develop new knowledge and deliver clinical care in the future. These educational activities aim to facilitate growth of paediatric rheumatology and ultimately improve the clinical care for children and families. This article describes the current portfolio of PReS educational activities and their relevance to the international paediatric rheumatology community.

Abstract Background The availability of methotrexate and the introduction of multiple biological agents have revolutionized the treatment of juvenile idiopathic arthritis (JIA). Several international and national drug registries have been implemented to accurately monitor the long-term safety/efficacy of these agents. This report aims to present the combined data coming from Pharmachild/PRINTO registry and the national registries from Germany (BiKeR) and Sweden. Methods Descriptive statistics was used for demographic, clinical data, drug exposure, adverse events (AEs) and events of special interest (ESIs). For the Swedish register, AE data were not available. Results Data from a total of 15,284 patients were reported: 8274 (54%) from the Pharmachild registry and 3990 (26%) and 3020 (20%) from the German and the Swedish registries, respectively. Pharmachild children showed a younger age (median of 5.4 versus 7.6 years) at JIA onset and shorter disease duration at last available visit (5.3 versus 6.1–6.8) when compared with the other registries. The most frequent JIA category was the rheumatoid factor–negative polyarthritis (range of 24.6–29.9%). Methotrexate (61–84%) and etanercept (24%–61.8%) were the most frequently used synthetic and biologic disease-modifying anti-rheumatic drugs (DMARDs), respectively. There was a wide variability in glucocorticoid use (16.7–42.1%). Serious AEs were present in 572 (6.9%) patients in Pharmachild versus 297 (7.4%) in BiKeR. Infection and infestations were the most frequent AEs (29.4–30.1%) followed by gastrointestinal disorders (11.5–19.6%). The most frequent ESIs were infections (75.3–89%). Conclusions This article is the first attempt to present a very large sample of data on JIA patients from different national and international registries and represents the first proposal for data merging as the most powerful tool for future analysis of safety and effectiveness of immunosuppressive therapies in JIA. Registry registration The Pharmachild registry is registered at ClinicalTrials.gov (NCT01399281) and at the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) (http://www.encepp.eu/encepp/viewResource.htm?id=19362). The BiKeR registry is registered at ENCePP (http://www.encepp.eu/encepp/viewResource.htm?id=20591).

Objectives Long-term safety and efficacy of adalimumab among patients with juvenile idiopathic arthritis (JIA) was evaluated through 6 years of treatment.Methods Children aged 4–17 years with polyarticular JIA were enrolled in a phase III, randomised-withdrawal, double-blind, placebo-controlled trial consisting of a 16-week open-label lead-in period, 32-week randomised double-blind period and 360-week long-term extension. Patients were stratified by baseline methotrexate use. Adverse events (AEs) were monitored, and efficacy assessments included JIA American College of Rheumatology (JIA ACR) 30%, 50%, 70% or 90% responses and the proportions of patients achieving 27-joint Juvenile Arthritis Disease Activity Score (JADAS27) low disease activity (LDA, ≤3.8) and inactive disease (ID, ≤1).Results Of 171 patients enrolled, 62 (36%) completed the long-term extension. Twelve serious infections in 11 patients were reported through 592.8 patient-years of exposure. No cases of congestive heart failure-related AEs, demyelinating disease, lupus-like syndrome, malignancies, tuberculosis or deaths were reported. JIA ACR 30/50/70/90 responses and JADAS27 LDA were achieved in 66% to 96% of patients at week 104, and 63 (37%) patients achieved clinical remission (JADAS27 ID sustained for ≥6 continuous months) during the study. Attainment of JIA ACR 50 or higher and JADAS27 LDA or ID in the initial weeks were the best predictors of clinical remission. Mean JADAS27 decreased from baseline, 22.5 (n=170), to 2.5 (n=30) at week 312 (observed analysis).Conclusions Through 6 years of exposure, adalimumab was well tolerated with significant clinical response (up to clinical remission) and a relatively low retention rate.

Strain Modal Testing (SMT), based on strain sensors signal processing, is an unconventional approach to perform Experimental Modal Analysis which is typically based on data measured by accelerometers. SMT is still mainly restricted to academia and requires additional investigation for a successful transition towards industry. This paper critically reviews why the automotive sector can benefit from this relatively new approach for a variety of reasons. Moreover, a case study representative of the automotive field is analyzed and discussed. Specifically, an SMT methodology is applied to evaluate the modal properties of a reinforced composite roof belonging to a racing solar powered vehicle. In the experimental activity, signals from Fiber Bragg Grating (FBG) sensors, strain gauges, and accelerometers were simultaneously acquired and further processed. The advantages of using optical fibers were discussed, together with their weaknesses and ongoing challenges. The FBG results were compared with the conventional analysis performed with the accelerometers, emphasizing the main similarities and discrepancies.

Abstract Background Diagnosis of Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) is currently based on a set of criteria proposed in 1999 modified from Marshall’s criteria. Nevertheless no validated evidence based set of classification criteria for PFAPA has been established so far. The aim of this study was to identify candidate classification criteria PFAPA syndrome using international consensus formation through a Delphi questionnaire survey. Methods A first open-ended questionnaire was sent to adult and pediatric clinicians/researchers, asking to identify the variables thought most likely to be helpful and relevant for the diagnosis of PFAPA. In a second survey, respondents were asked to select, from the list of variables coming from the first survey, the 10 features that they felt were most important, and to rank them in descending order from most important to least important. Results The response rate to the first and second Delphi was respectively 109/124 (88%) and 141/162 (87%). The number of participants that completed the first and second Delphi was 69/124 (56%) and 110/162 (68%). From the first Delphi we obtained a list of 92 variables, of which 62 were selected in the second Delphi. Variables reaching the top five position of the rank were regular periodicity, aphthous stomatitis, response to corticosteroids, cervical adenitis, and well-being between flares. Conclusion Our process led to identification of features that were felt to be the most important as candidate classification criteria for PFAPA by a large sample of international rheumatologists. The performance of these items will be tested further in the next phase of the study, through analysis of real patient data.

Abstract Background To assess the views of juvenile idiopathic arthritis (JIA) patients and their parents on the care and treatment they receive in referral pediatric rheumatology centers throughout Europe. Methods In a collaboration between physicians and patient associations, a questionnaire was developed, covering various domains of JIA care, including demographics, diagnosis, referrals to various health care professionals, access to pain and fatigue management and support groups, information they received about the disease and awareness of and participation in research. The questionnaire was translated and distributed by parent associations and pediatric rheumatologists in 25 countries, 22 of which were European. After completion the replies were entered on the PRINTO website. Replies could either be entered directly by parents on the website or on paper. In these cases, the replies were scanned and emailed by local hospital staff to Utrecht where they were entered by I.R. in the database. Results The survey was completed by 622 parents in 23 countries. The majority (66.7%) of patients were female, with median age 10–11 years at the completion of the questionnaire. Frequencies of self-reported JIA categories corresponded to literature. Some patients had never been referred to the ophthalmologist (22.8%) or physiotherapist (31.7%). Low rates of referral or access to fatigue (3.5%) or pain management teams (10.0%), age appropriate disease education (11.3%), special rehabilitation (13.7%) and support groups (20.1%) were observed. Many patients indicated they did not have contact details for urgent advice (35.9%) and did not receive information about immunizations (43.2%), research (55.6%) existence of transition of care clinics (89,2%) or financial support (89.7%). While on immunosuppressive drugs, about one half of patients did not receive information about immunizations, travelling, possible infections or how to deal with chickenpox or shingles. Conclusions Low rates of referral to health care professionals may be due to children whose illness is well managed and who do not need additional support or information. Improvements are needed, especially in the areas of supportive care and information patients receive. It is also important to improve doctor patient communication between visits. Physicians can be instrumental in the setting up of support groups and increasing patients’ awareness of existing support. Suggestions are given to convey crucial pieces of information structurally and repeatedly to ensure, among other things, compliance.

Abstract Background Juvenile idiopathic arthritis (JIA) is the most common pediatric rheumatic disease and a leading cause of childhood disability. The objective of this study was to characterize the PK, safety, and taste acceptability of tofacitinib in patients with JIA. Methods This Phase 1, open-label, multiple-dose (twice daily [BID] for 5 days) study of tofacitinib in patients with active (≥ 5 joints) polyarticular course JIA was conducted from March 2013–December 2015. Patients were allocated to one of three age-based cohorts: Cohort 1, 12 to

Abstract Background Hereditary recurrent fevers (HRF) are a group of rare monogenic diseases leading to recurrent inflammatory flares. A large number of variants has been described for the four genes associated with the best known HRF, namely MEFV, NLRP3, MVK, TNFRSF1A. The Infevers database ( http://fmf.igh.cnrs.fr/ISSAID/infevers ) is a large international registry collecting variants reported in these genes. However, no genotype-phenotype associations are provided, but only the clinical phenotype of the first patient(s) described for each mutation. The aim of this study is to develop a registry of genotype-phenotype associations observed in patients with HRF, enrolled and validated in the Eurofever registry. Results Genotype-phenotype associations observed in all the patients with HRF enrolled in the Eurofever registry were retrospectively analyzed. For autosomal dominant diseases (CAPS and TRAPS), all mutations were individually analyzed. For autosomal recessive diseases (FMF and MKD), homozygous and heterozygous combinations were described. Mean age of onset, disease course (recurrent or chronic), mean duration of fever episodes, clinical manifestations associated with fever episodes, atypical manifestations, complications and response to treatment were also studied. Data observed in 751 patients (346 FMF, 133 CAPS, 114 MKD, 158 TRAPS) included in the Eurofever registry and validated by experts were summarized in Tables. A total of 149 variants were described: 46 TNFRSF1A and 27 NLRP3 variants, as well as various combinations of 48 MVK and 28 MEFV variants were available. Conclusions We provide a potentially useful tool for physicians dealing with HRF, namely a registry of genotype-phenotype associations for patients enrolled in the Eurofever registry. This tool is complementary to the Infevers database and will be available at the Eurofever and Infevers websites.

Radical prostatectomy (RP) is the most frequent treatment with curative intent performed for prostate cancer to date. Different surgical approaches (perineal, transperitoneal, and extraperitoneal) and techniques (laparoscopic and robot assisted) have been described to increase the efficiency and potentially diminish the postoperative complications of this procedure. The aim of this narrative review is to investigate and define the factors that influence postprostatectomy urinary continence. We highlighted the anatomical landmarks and the modifications of surgical techniques aimed at improving the continence rates and thus, patient quality of life. After RP, the long-term continence rates range from 84% to 97%. In order to achieve good continence rates, a careful dissection along with meticulous anatomical reconstruction is required. To this end, a detailed knowledge of the periprostatic anatomy is mandatory.

Urologic prostate surgery has changed dramatically over the past decades. Following the introduction of the robot, the surgical approach has been modified and thanks to the magnification allowed by the robot a further level of precision can be achieved. Moreover, advances in the anatomical studies have provided new evidence regarding the periprostatic anatomy. The aim of this review is to describe our approach to robot-assisted radical prostatectomy. Our holistic perspective towards patient selection, pre- and postoperative care is provided. In our center, robot-assisted radical prostatectomy is performed by means of an anterograde approach. A nonbladder-sparing dissection with a graded approach towards nerve preservation is carried out. The procedure is concluded with what we call ‘total anatomical reconstruction’.

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children. Herein, we evaluated the relationship between the gut microbiome (GM) and disease phenotype by an integrated omics fused approach. In a multicenter, observational cohort study, stools from Italian JIA patients were collected at baseline, active, and inactive disease stages, and their GM compared to healthy controls (CTRLs). The microbiota metabolome was analyzed to detect volatile- and non-volatile organic compounds (VOCs); the data were fused with operational taxonomic units (OTUs) from 16S RNA targeted-metagenomics and classified by chemometric models. Non-VOCs did not characterize JIA patients nor JIA activity stages compared to CTRLs. The core of VOCs, (Ethanol, Methyl-isobutyl-ketone, 2,6-Dimethyl-4-heptanone and Phenol) characterized patients at baseline and inactive disease stages, while the OTUs represented by Ruminococcaceae, Lachnospiraceae and Clostridiacea discriminated between JIA inactive stage and CTRLs. No differences were highlighted amongst JIA activity stages. Finally, the fused data discriminated inactive and baseline stages versus CTRLs, based on the contribution of the invariant core of VOCs while Ruminococcaceae concurred for the inactive stage versus CTRLs comparison. In conclusion, the GM signatures enabled to distinguish the inactive disease stage from CTRLs.

This work aims to identify the damping properties of a commercial viscoelastic material that can be embedded and cured between the layers of composite laminates. The material may be adopted for reducing the vibration response of composite panels, typically used in automotive and aerospace applications, e.g., as vehicle body shell components. In order to objectively estimate the actual potential to enhance the noise vibration and harshness aspects, the effects of the viscoelastic material on the modal parameters of carbon/epoxy thin panels are quantitatively assessed through experimental modal analysis. Two different experiments are conducted, namely impact hammer tests and shaker excitation measurements. Based on the results of the experimental campaign, the investigated material is confirmed as a promising solution for possibly reducing the severity of vibrations in composite panels, thanks to its high damping properties. Indeed, the presence of just one layer proves to triple the damping properties of a thin panel. An approximate damping model is derived from the measured data in order to effectively simulate the dynamic response of new design solutions, including thin composite panels featuring the viscoelastic material.

This study investigates the dynamic behavior of a recently developed counterbalance forklift truck. The final objective is creating virtual testing tools based on numerical multibody models to evaluate the dynamic stresses experienced by the forklift family of interest during a reference operating cycle, defined by the manufacturer’s testing protocols. This work aims at defining sufficiently accurate and easy-to-implement modelling approaches and validation procedures. It focuses on a specific test, namely the passage of a speed-bump-like obstacle at high velocity, which represents one of the most severe conditions within the reference cycle. Indeed, unlike most of the other wheeled vehicles, forklifts typically do not have advanced suspension systems and their dynamic response is significantly affected by ground irregularities. To this end, a preliminary model of the complete forklift, featuring rigid bodies and a simplified tire–ground contact model, is implemented with a commercial software. Experimental tests are conducted on the forklift to measure the vehicle vibrations when running on the obstacle, for model validation purposes. After model updating, the results provided by the numerical simulations match the experimental data satisfactorily. Hence, the modelling and validation strategies are proven viable and effective.

Primary immunodeficiencies with selective susceptibility to EBV infection are rare conditions associated with severe lymphoproliferation. We followed a patient, son of consanguineous parents, referred to our center for recurrent periodic episodes of fever associated with tonsillitis and adenitis started after an infectious mononucleosis and responsive to oral steroid. An initial diagnosis of periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome was done. In the following months, recurrent respiratory infections and episodes of keratitis were also observed, together with a progressive reduction of immunoglobulin levels and an increase of CD20+ cells. Cell sorting and EBV PCR showed 25,000 copies for 100,000 leukocytes with predominant infection of B lymphocytes. Lymph node’s biopsy revealed reactive lymphadenopathy with paracortical involvement consistent with a chronic EBV infection. Molecular analysis of XIAP, SHA2D1A, ITK, and CD27 genes did not detect any pathogenic mutation. The patients underwent repeated courses of anti-CD20 therapy with only a partial control of the disease, followed by stem cell transplantation with a complete normalization of clinical and immunological features. Whole exome sequencing of the trio was performed. Among the variants identified, a novel loss of function homozygous c.163-2A>G mutation of the CD70 gene, affecting the exon 2 AG-acceptor splice site, fit the expected recessive model of inheritance. Indeed, deficiency of both CD27, and, more recently, of its ligand CD70, has been reported as a cause of EBV-driven lymphoproliferation and hypogammaglobulinemia. Cell surface analysis of patient-derived PHA-T cell blasts and EBV-transformed lymphoblastoid cell lines confirmed absence of CD70 expression. In conclusion, we describe a case of severe chronic EBV infection caused by a novel mutation of CD70 presenting with recurrent periodic fever.

Increasing environmental demands, alongside the planned penetration of natural gas as marine fuel, have rendered dual-fuel engines as an attractive prime mover alternative. In this context, knowing the specific fuel consumption is essential to selecting the most efficient engine. The specific fuel consumption can be approached by simulation models with varying levels of complexity that are either implemented by basic programming languages or simulated by dedicated packages. This study aims to develop a simplified model to predict the specific fuel consumption of dual-fuel two-stroke marine engines driving fixed or controllable pitch propellers. The model relies on clear trends approachable by polynomials that were revealed by normalizing specific fuel consumption. This model requires only the value of specific fuel consumption at a nominal maximum continuous rating to predict the engine consumption at any specified rating, including at partial engine load. The outcome of the study shows that the maximum deviations regarding the two simulated engines did not exceed −3.6%. In summary, the proposed model is a fast and effective tool for optimizing the selection of dual-fuel, two-stroke Diesel engines regarding fuel consumption.

Reducing losses in water distribution networks is a worldwide challenge and all utilities are developing proper strategies for the active control of leaks. Temporary or permanent grids of units for the continuous monitoring of pipelines through vibro-acoustic measurements are probably the most commonly adopted leak detection systems. Such systems generally rely on the definition of proper thresholds to detect increments in the vibration levels associated with leaks. Since the thresholds are strongly dependent on the local boundary conditions of the monitored network, the initial setup is costly and time consuming, and the risk of undetected leaks or false alarms increases. This work aims to investigate leak detection methods based on the inherent properties of the measured signals instead of their relative amplitude. In particular, the possibility of detecting water leaks in small-diameter plastic pipes by analyzing the autocorrelation function of vibro-acoustic signals is assessed. An experimental campaign is conducted in a full-scale test facility that simulates the actual network. The measurements concerning artificially generated leaks are attained by two accelerometers and one hydrophone. The experimental results confirm the effectiveness of the proposed approach, which is therefore proven as a promising tool for leak detection.

Immunoglobulin (Ig) isotype diversification by class switch recombination (CSR) is an essential process for mounting a protective humoral immune response. Ig CSR deficiencies in humans can result from an intrinsic B cell defect; however, most of these deficiencies are still molecularly undefined and diagnosed as common variable immunodeficiency (CVID). Here, we show that extracellular adenosine critically contributes to CSR in human naive and IgM memory B cells. In these cells, coordinate stimulation of B cell receptor and toll-like receptors results in the release of ATP stored in Ca2+-sensitive secretory vesicles. Plasma membrane ectonucleoside triphosphate diphosphohydrolase 1 CD39 and ecto-5′-nucleotidase CD73 hydrolyze ATP to adenosine, which induces CSR in B cells in an autonomous fashion. Notably, CVID patients with impaired class-switched antibody responses are selectively deficient in CD73 expression in B cells, suggesting that CD73-dependent adenosine generation contributes to the pathogenesis of this disease.

The implementation of strategies for controlling water leaks is essential in order to reduce losses affecting distribution networks of drinking water. This paper focuses on leak detection by using vibration monitoring techniques. The long-term goal is the development of a system for automatic early detection of burst leaks in service pipes. An experimental campaign was started to measure vibrations transmitted along water pipes by real burst leaks occurring in actual water supply networks. The first experimental data were used for assessing the leak detection performance of a prototypal algorithm based on the calculation of the standard deviation of acceleration signals. The experimental campaign is here described and discussed. The proposed algorithm, enhanced by means of proper signal filtering techniques, was successfully tested on all monitored leaks, thus proving effective for leak detection purpose.

The implementation of effective strategies to manage leaks represents an essential goal for all utilities involved with drinking water supply in order to reduce water losses affecting urban distribution networks. This study concerns the early detection of leaks occurring in small-diameter customers’ connections to water supply networks. An experimental campaign was carried out in a test bed to investigate the sensitivity of Acoustic Emission (AE) monitoring to water leaks. Damages were artificially induced on a polyethylene pipe (length 28 m, outer diameter 32 mm) at different distances from an AE transducer. Measurements were performed in both unburied and buried pipe conditions. The analysis permitted the identification of a clear correlation between three monitored parameters (namely total Hits, Cumulative Counts and Cumulative Amplitude) and the characteristics of the examined leaks.

This paper deals with static balancing of closed-loop mechanisms. The long-term goal of the research is enhancing the performance of parallel robots by means of effective static balancing strategies that take into account the system dynamic behaviour. In this contribution, the influence of mass-balancing on the elastodynamic performance of a four-bar linkage, intended as the simplest example of closed-loop mechanism, is experimentally investigated. The design of the experimental apparatus is discussed and the results of tests on both an unbalanced linkage and its balanced variant are presented. Base-transmitted forces and vibrations are monitored for constant-speed operations and for velocity ramp tests in order to characterize the elastodynamic behaviour of the linkages. The analysis is supported by implementing a flexible multibody model of the experimental apparatus that enhances the interpretation of the experimental data.

T helper 17 cells (T(H)-17) represent a lineage of effector T cells critical in host defence and autoimmunity. In both mouse and human IL-1β has been indicated as a key cytokine for the commitment to T(H)-17 cells. Cryopyrin-associated periodic syndromes (CAPS) are a group of inflammatory diseases associated with mutations of the NLRP3 gene encoding the inflammasome component cryopyrin. In this work we asked whether the deregulated secretion of IL-1β secondary to mutations characterizing these patients could affect the IL-23/IL-17 axis.A total of 11 CAPS, 26 systemic onset juvenile idiopathic arthritis (SoJIA) patients and 20 healthy controls were analyzed. Serum levels of IL-17 and IL-6 serum were assessed by ELISA assay. Frequency of T(H)17 cells was quantified upon staphylococcus enterotoxin B (SEB) stimulation. Secretion of IL-1β, IL-23 and IL-6 by monocyte derived dendritic cells (MoDCs), were quantified by ELISA assay. A total of 8 CAPS and 11 SoJIA patients were also analysed before and after treatment with IL-1β blockade. Untreated CAPS patients showed significantly increased IL-17 serum levels as well as a higher frequency of T(H)17 compared to control subjects. On the contrary, SoJIA patients displayed a frequency of T(H)17 similar to normal donors, but were found to have significantly increased serum level of IL-6 when compared to CAPS patients or healthy donors. Remarkably, decreased IL-17 serum levels and T(H)17 frequency were observed in CAPS patients following in vivo IL-1β blockade. On the same line, MoDCs from CAPS patients exhibited enhanced secretion of IL-1β and IL-23 upon TLRs stimulation, with a reduction after anti-IL-1 treatment.These findings further support the central role of IL-1β in the differentiation of T(H)17 in human inflammatory conditions.

Plasmacytoid dendritic cells (pDCs) are a subset of dendritic cells endowed with the capacity of producing large amounts of IFNα. Here we show that the Leukocyte-Associated Ig-like Receptor-1 (LAIR-1) is abundantly expressed on pDCs (the highest expression among all leukocytes) and its cross-linking inhibits IFNα production in response to Toll-like receptor ligands. Remarkably, LAIR-1 expression in pDCs is down-regulated in the presence of interleukin (IL)-3, thus indicating coordinated functions with NKp44, another pDC inhibitory receptor, which is conversely induced by IL-3. Nevertheless, the expression of NKp44 in pDCs isolated from secondary lymphoid organs, which is thought to be influenced by IL-3, is not coupled to a decreased expression of LAIR-1. Interestingly, pDCs isolated from peripheral blood of systemic lupus erithematosus (SLE) patients express lower levels of LAIR-1 while displaying slight but consistent expression of NKp44, usually undetectable on pDCs derived from healthy donors. Using sera derived from SLE patients, we show that LAIR-1 and NKp44 display synergistic inhibitory effects on IFNα production by interleukin IL-3 cultured pDCs stimulated with DNA immunocomplexes. In conclusion, our results indicate that the inhibitory function of LAIR-1 may play a relevant role in the mechanisms controlling IFNα production by pDCs both in normal and pathological innate immune responses.