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PURPOSE To study for the first time the incidence of adult-onset CNS tumors in Southern Sardinia, Italy. METHODS Clinical records of patients > 18 years old who were diagnosed with primary CNS tumors during 2016-2019 in the study area were reviewed. Meningiomas, cranial/paraspinal nerve tumors, lymphomas, and pituitary tumors were excluded. Cases were classified according to the 2016 WHO classification of CNS tumors and to the morphology codes from the International Classification of Diseases-Oncology, third edition. Age-adjusted incidence rates were calculated by the direct method to the 2011-2020 European standard population. Kulldorff's spatial scan statistic was used to identify geographic clusters of patients who shared increased/decreased tendency to develop CNS tumors. RESULTS CNS tumors were diagnosed in 234 incident patients, but histological diagnosis was available in 222/234 patients (95%) aged 64.3 ± 13.5 years at diagnosis. Crude incidence rate was 7.1 per 100,000 persons-year (95% CI, 6.2-8.1), 6.2 per 100,000 persons-year (95% CI, 5.4-7.0) when age-adjusted. CNS tumors were more frequent in men and after age 40. Glioblastoma accounted for 76% of the total (adjusted rate, 4.7 per 100,000 persons-year; 95% CI, 4.0-5.4). Spatial analysis revealed geographic variations of glioblastoma incidence within the study area. CONCLUSION Although the distribution of tumor diagnoses in Sardinia reflects expected age and gender-related patterns in western populations, our findings would indicate a slightly higher incidence of glial tumors, glioblastoma in particular, in Sardinia than in other European countries. The identification of spatial clusters of high/low risk will serve as a resource for etiological research.

Objectives Although neuropsychiatric involvement in SLE (NPSLE) is one of the most complex and troubling manifestations of the disease, validated outcome instruments to be used as sensitive endpoints in controlled clinical trials are lacking. We performed a systematic literature review (SLR) to identify outcome measurement instruments and domains used to assess NPSLE. Methods The Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were used. Articles available in English (1967–2020), listed in PubMed, Embase, PsycINFO, Cochrane Library and the EULAR outcome measures library were screened. All domains and outcome measurement instruments were characterized according to the OMERACT Filter 2.1, considering core areas (manifestations/abnormalities, life impact, death/lifespan, societal/resource use) and contextual factors. Results Of 3392 abstracts evaluated, 83 studies were included in the SLR (15 974 patients, females 89.9%). Eligible studies included domains and instruments pertinent to all core areas defined by the OMERACT, except for ‘societal/resource use’. The most common core areas were ‘manifestations/abnormalities’, covering 10 domains pertinent to laboratory and instrumental markers, indexes and neuropsychiatric dimension (cognitive, neurologic and psychiatric field), and ‘life impact’, covering 7 domains related to physical function (from both the perspective of the patient and the physician), pain and quality of life. Conclusion Our study revealed great heterogeneity in the instruments derived from populations with NPSLE and none of these had high-quality evidence. This supports the need to develop and further validate a core domain set and outcome measurement instruments to promote clinical research in this field, enhancing comparability across studies.

A systematic review and meta-analysis were conducted, according to the PRISMA methodology, to summarize current evidence on the prevalence and predictors of long-term glucocorticoid (GC) treatment and disease relapses in the real-life management of polymyalgia rheumatica (PMR).Out of 5442 retrieved studies, 21 were eligible for meta-analysis and 24 for qualitative analysis. The pooled proportions of patients still taking GCs at 1, 2, and 5 years were respectively 77% (95%CI 71–83%), 51% (95%CI 41–61%), and 25% (95CI% 15–36%). No significant difference was recorded by distinguishing study cohorts recruited before and after the issue of the international recommendations in 2010. The pooled proportion of patients experiencing at least one relapse at 1 year from treatment initiation was 43% (95%CI 29–56%). Female gender, acute-phase reactants levels, peripheral arthritis, starting GCs dosage, and tapering speed were the most frequently investigated potential predictors of prolonged GC treatment and relapse, but with inconsistent results. Only a few studies and with conflicting results evaluated the potential role of early treatment with methotrexate in reducing the GC exposure and the risk of relapse in PMR.This study showed that a high rate of prolonged GC treatment is still recorded in the management of PMR. The relapse rate, even remarkable, can only partially explain the long-term GC treatment, suggesting that other and not yet identified factors may be involved. Additional research is needed to profile patients with a higher risk of long-term GC treatment and relapse and identify more effective steroid-sparing strategies.Key Points:• High rate of long-term glucocorticoid (GC) treatment is recorded in polymyalgia rheumatica (PMR), being 77%, 51%, and 25% of patients still on GCs after respectively 1, 2, and 5 years.• A pooled relapse rate of 43% at 1 year, even remarkable, can only partially explain the long-term GC treatment in PMR.• Several studies have attempted to identify potential predictors of prolonged treatment with GCs and relapse, but with inconsistent results.• Additional research is needed to profile patients with a higher risk of long-term GC treatment and relapse and identify more effective steroid-sparing strategies.

Background Nursing home (NH) residents have been dramatically affected by COVID-19, with extremely high rates of hospitalization and mortality. Aims To describe the features and impact of an assistance model involving an intermediate care mobile medical specialist team (GIROT, Gruppo Intervento Rapido Ospedale Territorio) aimed at delivering “hospital-at-nursing home” care to NH residents with COVID-19 in Florence, Italy. Methods The GIROT activity was set-up during the first wave of the pandemic (W1, March–April 2020) and became a structured healthcare model during the second (W2, October 2020–January 2021). The activity involved (1) infection transmission control among NHs residents and staff, (2) comprehensive geriatric assessment including prognostication and geriatric syndromes management, (3) on-site diagnostic assessment and protocol-based treatment of COVID-19, (4) supply of nursing personnel to understaffed NHs. To estimate the impact of the GIROT intervention, we reported hospitalization and infection lethality rates recorded in SARS-CoV-2-positive NH residents during W1 and W2. Results The GIROT activity involved 21 NHs (1159 residents) and 43 NHs (2448 residents) during W1 and W2, respectively. The percentage of infected residents was higher in W2 than in W1 (64.5% vs. 38.8%), while both hospitalization and lethality rates significantly decreased in W2 compared to W1 (10.1% vs 58.2% and 23.4% vs 31.1%, respectively). Discussion Potentiating on-site care in the NHs paralleled a decrease of hospital admissions with no increase of lethality. Conclusions An innovative “hospital-at-nursing home” patient-centred care model based on comprehensive geriatric assessment may provide a valuable contribution in fighting COVID-19 in NH residents.

PURPOSE Cord lipomas can clinically resemble groin hernias and missed cord lipomas can potentially result in persistent symptoms. However, no international guideline exists concerning the management of cord lipomas found during inguinal hernia surgery. This study aimed to gain insight into how surgeons typically manage cord lipomas found during inguinal hernia surgery. METHODS A questionnaire was sent to all general surgeons in Denmark performing unsupervised laparoscopic inguinal hernia repair and Lichtenstein repair. The survey contained questions about demographic details and questions about how surgeons would handle cord lipomas. The questionnaire was created by the research team and face-validated on general surgeons. RESULTS A total of 58 surgeons (60%) responded to the questionnaire. The majority agreed that cord lipomas should not be left untouched. During laparoscopic repairs, 53% of the surgeons recommended that cord lipomas should be resected and removed if the anatomical circumstances allowed it. During Lichtenstein repair, the surgeons recommended that cord lipomas should always be resected and removed (49%) or that resection should depend on the size of the lipoma (44%). CONCLUSION When asking surgeons about their preferred handling of cord lipomas, they answered that the management of cord lipomas found during inguinal hernia surgery depends on anatomical circumstances such as the pedicle appearance, the lipoma mobility, and its size. If the cord lipoma is left untouched, the patients' hernia resembling symptoms could persist, why the surgeons predominantly preferred to resect and remove cord lipomas.

Patients with rheumatoid arthritis (RA), a chronic and disabling autoimmune condition that is characterized by articular and extra-articular manifestations and a pro-inflammatory and pro-oxidant state, suffer from premature atherosclerosis and excessive cardiovascular disease burden. A key step in the pathogenesis of atherosclerosis is impaired synthesis of the endogenous messenger nitric oxide (NO) by endothelial cells which, in turn, alters local homeostatic mechanisms and favors vascular damage and plaque deposition. While the exact mechanisms of endothelial dysfunction in RA remain to be established, there is good evidence that RA patients have relatively high circulating concentrations of the methylated arginine asymmetric dimethylarginine (ADMA), a potent endogenous inhibitor of endothelial NO synthase (eNOS). This review discusses the biological and pathophysiological role of ADMA, the interplay between ADMA, inflammation and oxidative stress, and the available evidence on the adverse impact of ADMA on endothelial function and atherosclerosis and potential ADMA-lowering therapies in RA patients.

Purpose Focusing on two beer festivals held in Nottingham, England, this study aims to evaluate their indirect impact on the performance of city hotels. This study builds on theoretical insights from the revenue management literature to shed empirical light on the potentially beneficial effects of events on the hotels’ performance. This study investigates the impact of the differential support offered by the destination management organisation (DMO) over two years. Design/methodology/approach Using online prices posted in advance of the events on an online travel agent, the authors assess hotel performance for each day of the events relative to the same day of the week in a week with no event. A similar comparison is made to assess the impact across two different years. In both cases, an ordinary least squares methodology was used. Findings Both events appear not to have had a strong impact on hotel prices and occupancy in 2016, i.e. when the DMO’s promotional effort was more proactive. Instead, in 2017, one event registered higher hotel prices and occupancy both relative to the year before and to the “business as usual” week. Practical implications The study identifies the existence of an indirect positive economic impact of the events on the hospitality sector. Originality/value The investigation adopts a more naturalistic experimental design to collect the data, which allows the authors to control for both the impact on prices and occupancy at the level of the single hotel. The evidence is therefore micro-founded. Moreover, results shed light on the role played by the DMO.

This paper deals with the relationship between regulatory compliance, bureaucratic corruption, lobbying and the industrial structure of a country. We show that lobbying and bureaucratic corruption can coexist at the macro level when we allow for heterogeneity in firm size. Countries with similar level of development are often characterized by very different industrial structures: we show the implications this has for the level of compliance, corruption and lobbying in that country. Welfare implications of our model point toward encouraging policies that support the small business sector of an economy and toward flexible regulatory policies meant to suppress regulation for small enough firms.

The maintenance of mitochondrial DNA (mtDNA) relies on proteins encoded by nuclear genes. Mutations in their coding sequences result in heterogenous clinical presentations featuring mtDNA instability in affected tissues. DNA2 is a multi‐catalytic protein involved in the removal of single strand DNA during mtDNA replication or Long Patch Base Excision Repair pathway. We have previously described DNA2 mutations in adult patients affected with familial and sporadic forms of mitochondrial myopathy. Here we describe four novel probands presenting with limb weakness associated with novel DNA2 molecular defects. Biochemical assays were established to investigate the functional effects of these variants.

Objective Our objective was to update the understanding of the development of paradoxical immune-mediated glomerular disorders (IGDs) in patients with rheumatic diseases treated with biologics and targeted synthetic drugs (ts-drugs). Methods A systematic literature review was performed by searching PubMed for articles published between 1 January 2014 and 1 January 2020 reporting on the development of IGD in adult patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis or systemic lupus erythematosus (SLE) who were receiving biologics or ts-drugs. IGDs were classified on the basis of clinical, laboratory and histopathological data as (1) glomerulonephritis associated with systemic vasculitis (GNSV), (2) isolated autoimmune renal disorder (IARD) or (3) glomerulonephritis in SLE and in lupus-like syndrome (GNLS). The World Health Organization-Uppsala Monitoring Centre (WHO-UMC) system for standardized case causality assessment was applied to evaluate the causal relationship between IGD and specific drugs. The classification was based on a six-category scale, where the “certain” and “probable” categories were deemed clinically relevant relationships. Results The literature search retrieved 875 articles. Of these, 16 articles reported IGD data, for a total of 25 cases. According to the WHO-UMC assessment, the strength of the causal relationship between IGDs and investigated drugs was higher for anti-tumor necrosis factor-α agents (a clinically relevant relationship was found in four of six cases), abatacept (one of two cases), tocilizumab (two cases), ustekinumab (one case) and tofacitinib (one case) than for rituximab (nine cases), belimumab (three cases) or secukinumab (one case), which showed a weak causal relationship with these paradoxical events. No cases associated with apremilast or baricitinib were found. The retrieved cases were classified as 11 GNLS, seven IARD and seven GNSV. Conclusions Biologics and ts-drugs can cause IGDs. These events are rare, and the causative effect of a specific drug is hard to establish. When a patient is suspected of having an IGD, the drug should be discontinued, and treatment for the new-onset renal disorder should be promptly started.

Summary Background The accuracy of current prediction tools for ischaemic and bleeding events after an acute coronary syndrome (ACS) remains insufficient for individualised patient management strategies. We developed a machine learning-based risk stratification model to predict all-cause death, recurrent acute myocardial infarction, and major bleeding after ACS. Methods Different machine learning models for the prediction of 1-year post-discharge all-cause death, myocardial infarction, and major bleeding (defined as Bleeding Academic Research Consortium type 3 or 5) were trained on a cohort of 19 826 adult patients with ACS (split into a training cohort [80%] and internal validation cohort [20%]) from the BleeMACS and RENAMI registries, which included patients across several continents. 25 clinical features routinely assessed at discharge were used to inform the models. The best-performing model for each study outcome (the PRAISE score) was tested in an external validation cohort of 3444 patients with ACS pooled from a randomised controlled trial and three prospective registries. Model performance was assessed according to a range of learning metrics including area under the receiver operating characteristic curve (AUC). Findings The PRAISE score showed an AUC of 0·82 (95% CI 0·78–0·85) in the internal validation cohort and 0·92 (0·90–0·93) in the external validation cohort for 1-year all-cause death; an AUC of 0·74 (0·70–0·78) in the internal validation cohort and 0·81 (0·76–0·85) in the external validation cohort for 1-year myocardial infarction; and an AUC of 0·70 (0·66–0·75) in the internal validation cohort and 0·86 (0·82–0·89) in the external validation cohort for 1-year major bleeding. Interpretation A machine learning-based approach for the identification of predictors of events after an ACS is feasible and effective. The PRAISE score showed accurate discriminative capabilities for the prediction of all-cause death, myocardial infarction, and major bleeding, and might be useful to guide clinical decision making. Funding None.

This paper presents a linear dynamical operator described in terms of a rational transfer function, endowed with a well-defined and efficient back-propagation behavior for automatic derivatives computation. The operator enables end-to-end training of structured networks containing linear transfer functions and other differentiable units by exploiting standard deep learning software. Two relevant applications of the operator in system identification are presented. The first one consists in the integration of prediction error methods in deep learning. The dynamical operator is included as the last layer of a neural network in order to obtain the optimal one-step-ahead prediction error. The second one considers identification of general block-oriented models from quantized data. These block-oriented models are constructed by combining linear dynamical operators with static nonlinearities described as standard feed-forward neural networks. A custom loss function corresponding to the log-likelihood of quantized output observations is defined. For gradient-based optimization, the derivatives of the log-likelihood are computed by applying the back-propagation algorithm through the whole network. Two system identification benchmarks are used to show the effectiveness of the proposed methodologies.

OBJECTIVES This study aimed to establish the rate, etiology, and short-term outcome of hypoglycemia in infants and children accessing an emergency department of a tertiary care pediatric hospital. METHODS The study was retrospectively conducted on the clinical records of children with hypoglycemia aged 15 days to 17 years who were admitted consecutively to the emergency department during a 6-year period for various clinical conditions. Hypoglycemia was defined as a venous plasma glucose level lower than 45 mg/dL. RESULTS Hypoglycemia was detected in 402 patients (female-to-male ratio, 1.26; mean age, 2.6 ± 1.8 years), with a rate of 0.99 per 1000 children. Plasma glucose levels ranged from 3 to 45 (mean, 37.48 ± 7.44) mg/dL. Hypoglycemia was associated with gastroenteritis or other infectious diseases causing protracted fasting in 86.32% of cases, whereas hypoglycemia related to a different etiology (HDE) was observed in 13.68% of hypoglycemic children. Most HDE patients had a final diagnosis of ketotic hypoglycemia, whereas metabolic defects were a rare (1.49%) but nonnegligible etiologic cause. A severe triage code was more frequent in the HDE group (P < 0.001). Factors significantly and independently associated with HDE were impaired level of consciousness, assessed with the AVPU scale (A, alert; V, responding to verbal; P, responding to pain; U, unresponsive; adjusted odds ratio, 2.50; P = 0.025) and clinical onset within 12 hours (adjusted odds ratio, 3.98; P < 0.001). CONCLUSIONS In a nonnegligible number of critically ill children, hypoglycemia can be detected. In a minority of cases, hypoglycemia was due to metabolic disorders that should be suspected on the basis of the severity of hypoglycemia, and the recent onset and the presence of neuroglycopenic symptoms.

This study aimed to evaluate the intensity and characteristics of pain, which was assessed at home by children with cancer or their parents using an app for mobile devices, for a 1-month poststudy enrollment. The participants of this observational prospective study were outpatients at the hematology/oncology department of an academic hospital in Italy, aged between 0 and 21 years, and receiving hospital-at-home care. Patients or their parents were asked to assess pain levels for one month at home using the Faces, Legs, Arms, Cry, and Consolability (FLACC) scale for patients aged

OBJECTIVE To compare the effect of achievement and maintenance of Lupus Low Disease Activity State (LLDAS) and clinical remission (CR) in preventing early damage accrual in patients with systemic lupus erythematosus (SLE). METHODS In a monocentric cohort of 116 newly diagnosed SLE patients, LLDAS and CR achievement at 6 months (T1) after treatment initiation and their maintenance over the next 12 months were assessed. Early damage was recorded after 18 months of follow-up (T2) using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index. Univariate and multivariate analyses were performed to evaluate the association of LLDAS and CR with early damage. RESULTS LLDAS was significantly more attained than CR both at T1 (42.2% versus 21.6% of patients; P < 0.001) and T2 (46.6% versus 31.9%; P = 0.022). The overlap rate between persistent LLDAS and persistent CR was 41.7% (n = 15). On multivariate analysis, achievement of CR (odds ratio [OR] 0.07 [95% confidence interval (95% CI) 0.01-0.59], P = 0.015) and LLDAS (OR 0.25 [95% CI 0.06-0.99], P = 0.049) at T1 were independently associated with lower accrual of early damage. Patients who achieved LLDAS (including CR) at T1 and steadily persisted in this condition until T2 developed significantly less damage compared to those who failed to maintain it during the T1-T2 interval (P = 0.003), those who achieved it later than T1 (P < 0.001), or those who had never been in this condition (P < 0.001). CONCLUSION Although CR is recommended as the primary treatment target in SLE, LLDAS represents a valid alternative in the early stage of SLE management. LLDAS and CR maintenance should be targeted to prevent damage.

Background: Electronic surveillance using clinical and administrative data from multiple sources has been reported as a tool for surveillance of surgical site infections (SSIs), but experiences are limited. In this study, we aimed to assess the accuracy of a text-searching algorithm to detect SSIs in children based on the application of regular expressions of unstructured clinical notes collected through different information systems. Methods: We developed an information system data warehouse that integrates data provided by electronic health and administrative records for patients who underwent surgical procedures in index weeks when active SSIs surveillances was conducted. To capture whether the patient developed an SSI, we developed a customized application to analyze clinical notes and code descriptions applying a pattern-matching algorithm based on regular expressions. We described the SSI cases detected by the active surveillance and the text-searching algorithm. To assess the accuracy in identifying the SSIs through the two methods, we adopted a reference standard that calculated the total number of SSIs as those detected by active surveillance plus those derived by the text-searching algorithm that was missed by active surveillance. Results: Compared with the total number of SSIs used as a reference standard, both methods had a specificity of 100%, a positive predictive value of 100%, and a negative predictive value >99.5%. Sensitivity was 70% for the text-mining algorithm and 60% for the active surveillance. Accuracy was >99% with both methods. The kappa value was 0.46. Conclusions: Compared with conventional surveillance of SSIs, a text-searching algorithm is a valid tool for case finding that has the potential to reduce drastically the workload of conventional surveillance, which involved direct contact with all families.

Background People increasingly search online for health information. Particularly, parents of patients often use the Internet as a source for health information. We conducted a survey to investigate the online searching behavior of parents of patients Methods The cross-sectional survey was nested in a prospective cohort study on surgical procedures. Parents of patients undergoing surgical procedures at Bambino Gesù Children’s Hospital, Rome, Italy, were enrolled and contacted by phone after the procedure. We recorded socio-demographic data, sex, length of stay following surgery, proximity of residence to the hospital, use of the internet to search for information on the surgery before and after the intervention and effect of information found online. Results The majority (91%) of parents of children undergoing surgical intervention used the internet. Of these, 74.3% of parents searched for information before surgery, and 26.1% searched for information after. Most parents searched for information on the care provider’s website. Two thirds of parents reported that information found online had increased their understanding of the child’s condition. Multivariate analyses indicated that families living far from the hospital (> 43 km) were more likely to search for health information (OR 2.3; 95% CI 1.34–4.00), as were families of patients undergoing a major surgery (OR = 2.1; 95% CI 1.04–4.11). Conclusions Parents of children undergoing surgery often search online for information on their child’s intervention, in particular those whose child is scheduled for a major surgery and those living far from the hospital. A survey like the present one allows to understand parents’ information needs, to better guide them in online information seeking and to better tailor information provided on the care provider’s website.

ObjectiveThe Physician Global Assessment (PGA) is a visual analogue score that reflects the clinician’s judgement of overall SLE disease activity. The aim of this systematic literature review is to describe and analyse the psychometric properties of the PGA.MethodsThis systematic literature review was conducted by two independent reviewers in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. All articles published through 1 July 2019 in PubMed were screened, with no limitation on year of publication, language or patients’ age. Psychometric properties data were analysed according to the OMERACT Filter methodology version 2.1.ResultsThe literature search identified 91 studies. Face validity was reported in all the articles retrieved in which the PGA was used alone or as part of composite indices (Systemic Responder Index, Safety of Estrogen in Lupus Erythematosus National Assessment Flare Index, Lupus Low Disease Activity State, Definitions of Remission in Systemic Lupus Erythematosus criteria). Content validity was reported in 89 studies. Construct validity was demonstrated by a good correlation (r ≥ 0.50) between the PGA with the SLEDAI (12 studies), SLAM (4 studies), LAI, BILAG and ECLAM (2 studies each). Criterion validity was assessed exploring the PGA correlation with quality of life measurements, biomarker levels and treatment changes in 28 studies, while no study has evaluated correlation with damage. A good responsiveness for PGA was shown in eight studies. A high variability in scales was found, causing a wide range of reliability (intraclass correlation coefficient 0.67–0.98).ConclusionPGA is a valid, responsive and feasible instrument, though its reliability was impacted by the scale adopted, suggesting the major need for standardization of its scoring.

Glioblastoma is a lethal primary brain tumor lacking effective therapy. The secluded onset site, combined with the infiltrative properties of this tumor, require novel targeted therapies. In this scenario, the use of oncolytic viruses retargeted to glioblastoma cells and able to spread across the tumor cells represent an intriguing treatment strategy. Here, we tested the specificity, safety and efficacy of R-613, the first oncolytic HSV fully retargeted to EGFRvIII, a variant of the epidermal growth factor receptor carrying a mutation typically found in glioblastoma. An early treatment with R-613 on orthotopically transplanted EGFRvIII-expressing human glioblastoma significantly increased the median survival time of mice. In this setting, the growth of human glioblastoma xenotransplants was monitored by a secreted luciferase reporter and showed that R-613 is able to substantially delay the development of the tumor masses. When administered as late treatment to a well-established glioblastomas, R-613 appeared to be less effective. Notably the uninfected tumor cells derived from the explanted tumor masses were still susceptible to R-613 infection ex vivo, thus suggesting that multiple treatments could enhance R-613 therapeutic efficacy, making R-613 a promising oncolytic HSV candidate for glioblastoma treatment.

Ryanodine receptor type 1-related congenital myopathies are the most represented subgroup among congenital myopathies (CMs), typically presenting a central core or multiminicore muscle histopathology and high clinical heterogeneity. We evaluated a cohort of patients affected with Ryanodine receptor type 1-related congenital myopathy (RYR1-RCM), focusing on four patients who showed a severe congenital phenotype and underwent a comprehensive characterization at few months of life. To date there are few reports on precocious instrumental assessment. In two out of the four patients, a muscle biopsy was performed in the first days of life (day 5 and 37, respectively) and electron microscopy was carried out in two patients detecting typical features of congenital myopathy. Two patients underwent brain MRI in the first months of life (15 days and 2 months, respectively), one also a fetal brain MRI. In three children electromyography was performed in the first week of life and neurogenic signs were excluded. Muscle MRI obtained within the first years of life showed a typical pattern of RYR1-CM. The diagnosis was confirmed through genetic analysis in three out of four cases using Next Generation Sequencing (NGS) panels. The development of a correct and rapid diagnosis is a priority and may lead to prompt medical management and helps optimize inclusion in future clinical trials.

Several cardiovascular (CV) risk algorithms are available to predict CV events in the general population. However, their performance in patients with rheumatoid arthritis (RA) might differ from the general population. This cross-sectional multicentre study aimed to estimate the 10-year CV risk using two different algorithms in a large RA cohort and in patients with osteoarthritis (OA).In a consecutive series of RA patients and matched OA controls without prior CV events, clinical and serologic data and traditional CV risk factors were recorded. The 10-year CV risk was assessed with the Systematic COronary Risk Evaluation (SCORE) and the "Progetto Cuore" algorithms.1,467 RA patients and 342 OA subjects were included. RA patients were more frequently diabetic (9.9% vs 6.4%; p=0.04) and smokers (20.4% vs 12.5%; p=0.002) but had lower prevalence of obesity (15% vs 21%; p=0.003). Dyslipidaemia was more prevalent in OA (32.5% vs 21.7%; p0.0001). The 10-year estimated CV risk was 1.6% (95%CI 1.3-1.9) in RA and 1.4% (95%CI 1.3-1.6) in OA (p=0.002) according to SCORE and 6.5% (95%CI 6.1-6.9) in RA and 4.4% (95%CI 3.9-5.1) in OA (p0.001) according to "Progetto Cuore". Regardless of the score used, RA patients had a 3- to-4-fold increased 10-year risk of CV events compared to OA subjects.RA patients have a significantly higher 10-year risk of CV events than OA subjects. In addition to effective disease control and joint damage prevention, specific protective measures targeting modifiable traditional CV risk factors should be implemented in RA.

β-thalassemia is an inherited disease causing an impaired hemoglobin production, eventually leading to a severe chronic anemia. Resolutive treatments are still limited to a small number of patients and blood transfusions still represent the standard of care. In this scenario, luspatercept is the first approved drug able to significantly modify the disease phenotype. Developed as a fusion protein, it binds TGF-β ligands, contributing to a reduction of ineffective erythropoiesis. As shown by clinical trials in thalassemia, this effect determines an increase in mean hemoglobin levels and/or a decrease in transfusion burden. While some potential indications are still being evaluated in trials, luspatercept has recently entered the clinical practice for transfusion-dependent thalassemia patients.

Fine needle aspiration (FNA) is the reference standard for the diagnosis of thyroid nodules. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) has been successfully used to discriminate the proteomic profiles of benign and malignant thyroid FNAs within the scope of providing support to pathologists for the classification of morphologically borderline cases. However, real FNAs provide a limited amount of material due to sample collection restrictions. Ex vivo FNAs could represent a valuable alternative, increasing sample size and the power of statistical conclusions. In this study, we compared the real and ex vivo MALDI-MSI proteomic profiles, extracted from thyrocyte containing regions of interest, of 13 patients in order to verify their similarity. Statistical analysis demonstrated the mass spectra similarity of the proteomic profiles by performing intra-patient comparison, using statistical similarity systems. In conclusion, these results show that post-surgical FNAs represent a possible alternative source of material for MALDI-MSI proteomic investigations in instances where pre-surgical samples are unavailable or the number of cells is scarce. Supplementary Information The online version contains supplementary material available at 10.1007/s00216-020-03088-4.

Background: Although numerous patient specific co-factors have been shown to be associated with worse outcomes in COVID-19, the prognostic value of thalasemic syndromes in COVID-19 patients remains poorly understood. Aims: We studied the outcomes of 137 COVID-19 patients with a history of Transfusion Dependent Thalassemia (TDT) and non-Transfusion Dependent Thalassemia (NTDT) extracted from a large international cohort and compared them with the outcomes from a matched cohort of COVID-19 patients with no history of thalasemia. Results: The mean age of thalassemia patients included in our study was 41±16 years (48.9% male). Almost 81% of these patients suffered from TDT requiring blood transfusions on a regular basis. 38.7% of patients were blood group O. Cardiac iron overload was documented in 6.8% of study patients, whereas liver iron overload was documented in 35% of study patients. 25% of thalassemia patients had a history of splenectomy. 27.7% of study patients required hospitalization due to COVID-19 infection. Amongst the hospitalized patients, one patient died (0.7%) and one patient required intubation. Continuous positive airway pressure (CPAP) was required in almost 5% of study patients. After adjustment for age-, sex- and other known risk factors (cardiac disease, kidney disease and pulmonary disease), the rate of in-hospital complications (supplemental oxygen use, admission to the an intensive care unit for CPAP therapy or intubation) and all-cause mortality was significantly lower in the thalassemia group compared to the matched cohort with no history of thalassemia. Amongst thalassemia patients in general, the NTDT group exhibited a higher rate of hospitalization compared to the TDT group (p=0.001). In addition, the rate of complications such as acute kidney injury and need for supplemental oxygen was significantly higher in the NTDT group compared to the TDT group. In the multivariable logistic regression analysis, age and history of heart or kidney disease were all found to be independent risk factors for increased in-hospital, all-cause mortality, whereas the presence of thalassemia (either TDT or NTDT) was found to be independently associated with reduced all-cause mortality. Conclusions: The presence of thalassemia in COVID-19 patients was independently associated with lower in-hospital, all-cause mortality and few in-hospital complications in in our study. The pathophysiology of this is unclear and needs to be studied in vitro and in animal models. Trial Registration for sources of data extraction: NCT: 04334291, 04746066 Funding Statement: This study was funded by a non-conditioned grant from FUNDACION INTERHOSPITALARIA PARA LA INVESTIGACION CARDIOVASCULAR, FIC. (Madrid, Spain). This nonprofit institution had no role in the study design, the collection, analysis and interpretation of data, the writing of the report, or the decision to submit the paper for publication. Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: The study was approved by the Ethics Committees in all of the centers involved (Banjarmasin, Bari, Cagliari, Catania, Ferrara, Gela, Genoa, Getafe, Guadalajara, Legan, Madrid, Mannheim, Milan, Monza, Naples, Olbia, Padua, Pavia, Ragusa, Rome, Salerno, Turin, Valladolid and Verona).

Eosinophilic Granulomatosis with Polyangiitis (EGPA, Churg-Strauss syndrome) is a rare anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) characterised by respiratory manifestations and systemic organ involvement [1]. Particularly, cardiac manifestations occur in 40–60% of patients, representing the leading cause of mortality [2]. Recent reports suggest that venous thromboembolic events might also represent a consistent burden of disease [3, 4], as already known for the other AAVs [5–7], possibly due to eosinophil-mediated vascular inflammation [5]. Nevertheless, the occurrence of arterial and venous thrombotic events (AVTE) has never been systematically explored in EGPA. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Alessandra Bettiol Conflict of interest: Renato Alberto Sinico Conflict of interest: Franco Schiavon Conflict of interest: Sara Monti Conflict of interest: Enrica Paola Bozzolo Conflict of interest: Franco Franceschini Conflict of interest: Marcello Govoni Conflict of interest: Claudio Lunardi Conflict of interest: Giuseppe Guida Conflict of interest: Giuseppe Lopalco Conflict of interest: Giuseppe Paolazzi Conflict of interest: Angelo Vacca Conflict of interest: Gina Gregorini Conflict of interest: Pietro Leccese Conflict of interest: Matteo Piga Conflict of interest: Fabrizio Conti Conflict of interest: Paolo Fraticelli Conflict of interest: Luca Quartuccio Conflict of interest: Federico Alberici Conflict of interest: Carlo Salvarani Conflict of interest: Silvano Bettio Conflict of interest: Simone Negrini Conflict of interest: Carlo Selmi Conflict of interest: Savino Sciascia Conflict of interest: Gabriella Moroni Conflict of interest: Loredana Colla Conflict of interest: Carlo Manno Conflict of interest: Maria Letizia Urban Conflict of interest: Alfredo Vannacci Conflict of interest: Maria Rosa Pozzi Conflict of interest: Paolo Fabbrini Conflict of interest: Stefano Polti Conflict of interest: Mara Felicetti Conflict of interest: Maria Rita Marchi Conflict of interest: Roberto Padoan Conflict of interest: Paolo Delvino Conflict of interest: Roberto Caporali Conflict of interest: Carlomaurizio Montecucco Conflict of interest: Lorenzo Dagna Conflict of interest: Adriana Cariddi Conflict of interest: Paola Toniati Conflict of interest: Dr. Tamanini reports other from Glaxo Smith Kline, outside the submitted work. Conflict of interest: Federica Furini Conflict of interest: Alessandra Bortoluzzi Conflict of interest: Elisa Tinazzi Conflict of interest: Lorenzo Delfino Conflict of interest: Iuliana Badiu Conflict of interest: Giovanni Rolla Conflict of interest: Vincenzo Venerito Conflict of interest: Florenzo Iannone Conflict of interest: Alvise Berti Conflict of interest: Roberto Bortolotti Conflict of interest: Vito Racanelli Conflict of interest: Guido Jeannin Conflict of interest: Angela Padula Conflict of interest: Alberto Cauli Conflict of interest: Roberta Priori Conflict of interest: Armando Gabrielli Conflict of interest: Milena Bond Conflict of interest: Martina Tedesco Conflict of interest: Giulia Pazzola Conflict of interest: Paola Tomietto Conflict of interest: Marco Pellecchio Conflict of interest: Chiara Marvisi Conflict of interest: Federica Maritati Conflict of interest: Alessandra Palmisano Conflict of interest: Christian Dejaco Conflict of interest: Johann Willeit Conflict of interest: Stefan Kiechl Conflict of interest: Iacopo Olivotto Conflict of interest: Peter Willeit Conflict of interest: Domenico Prisco Conflict of interest: Augusto Vaglio Conflict of interest: Giacomo Emmi

Biallelic TYMP variants result in the mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), a juvenile-onset disorder with progressive course and fatal outcome. Milder late-onset (>40 years) form has been rarely described. Gene panel sequencing in a cohort of 60 patients featuring muscle accumulation of mitochondrial DNA (mtDNA) deletions detected TYMP defects in three subjects (5%), two of them with symptom onset in the fifth decade. One of the patients only displayed ptosis and ophthalmoparesis. Biochemical and molecular studies supported the diagnosis. Screening of TYMP is recommended in adult patients with muscle mtDNA instability, even in the absence of cardinal MNGIE features.

This study explores demographic, clinical, and therapeutic features of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) in a cohort of 80 patients recruited from 19 Italian referral Centers. Patients’ data were collected retrospectively and then analyzed according to age groups (disease onset before or after 16 years) and genotype (high penetrance (HP) and low penetrance (LP) TNFRSF1A gene variants). Pediatric- and adult-onset were reported, respectively, in 44 and 36 patients; HP and LP variants were found, respectively, in 32 and 44 cases. A positive family history for recurrent fever was reported more frequently in the pediatric group than in the adult group (p<0.05). With reference to clinical features during attacks, pericarditis and myalgia were reported more frequently in the context of adult-onset disease than in the pediatric age (with p<0.01 and p<0.05, respectively), while abdominal pain was present in 84% of children and in 25% of adults (p<0.01). Abdominal pain was significantly associated also to the presence of HP mutations (p<0.01), while oral aphthosis was more frequently found in the LP variant group (p<0.05). Systemic amyloidosis occurred in 25% of subjects carrying HP variants. As concerns laboratory features, HP mutations were significantly associated to higher ESR values (p<0.01) and to the persistence of steadily elevated inflammatory markers during asymptomatic periods (p<0.05). The presence of mutations involving a cysteine residue, abdominal pain, and lymphadenopathy during flares significantly correlated with the risk of developing amyloidosis and renal impairment. Conversely, the administration of colchicine negatively correlated to the development of pathologic proteinuria (p<0.05). Both NSAIDs and colchicine were used as monotherapy more frequently in the LP group compared to the HP group (p<0.01). Biologic agents were prescribed to 49 (61%) patients; R92Q subjects were more frequently on NSAIDs monotherapy than other patients (p<0.01); nevertheless, they required biologic therapy in 53.1% of cases. At disease onset, the latest classification criteria for TRAPS were fulfilled by 64/80 (80%) patients (clinical plus genetic items) and 46/80 (57.5%) patients (clinical items only). No statistically significant differences were found in the sensitivity of the classification criteria according to age at onset and according to genotype (p<0.05). This study describes one of the widest cohorts of TRAPS patients in the literature, suggesting that the clinical expression of this syndrome is more influenced by the penetrance of the mutation rather than by the age at onset itself. Given the high phenotypic heterogeneity of the disease, a definite diagnosis should rely on both accurate working clinical assessment and complementary genotype.

Liquid biopsies, as blood and urine, could offer an invaluable, easily accessible source of biomarkers, and evidences for elucidating the pathological processes. Only few studies integrated the proteomes driven by more than one biofluid. Furthermore, it is not clear which biofluid better mirrors the alterations triggered by disease. Venous infiltrating RCC(Renal Cell Carcinoma) could represent an advantageous model for exploring this aspect. Herein, we investigate how blood and urine “proteomically” reflect the changes occurring during RCC infiltration into renal vein(RV) by label-free nLC-ESI-MS/MS. We found 574 and 58 differentially expressed proteins(DEPs) in response to vascular involvement. To the augment of vascular involvement, the abundance of only three proteins in urine(UROM,RALA,CNDP1) and two in plasma(APOA1,K2C1) diminished while increased for twenty-six urinary proteins. 80 proteins were found both in urine and plasma, among which twenty-eight were DEPs. A huge overlap between the two biofluids was highlighted, as expected, being urine the filtrate of blood. However, this consistency decreases when RV-occlusion occurs suggesting alternative protein releases, and a loss of kidney architecture. Moreover, several proteomic and functional signatures were biofluid-specific. In conclusion, the complementarity between the specimens allowed to achieve a deeper level of molecular complexity of the RCC venous infiltration. Significance: Although plasma and urine are strongly interconnected, only few proteomic studies investigated the complementarity of these fluids as bio-sources of information. Moreover, none of them was focused to their analysis and comparison in the context of vascular infiltration of renal cancer. Herein, new insights were gained regarding the impact into urinary and plasma proteome of the changes triggered by the ccRCC invasion into vascular system and renal vein. Furthermore, the integration of the information driven by the two liquid biopsies permits to unravel biological processes otherwise lost.

INTRODUCTION An accurate diagnostic classification of thyroid lesions remains an important clinical aspect that needs to be addressed in order to avoid 'diagnostic' thyroidectomies. Among the several 'omics' techniques, proteomics is playing a pivotal role in the search for diagnostic markers. In recent years, different approaches have been used, taking advantage of the technical improvements related to mass spectrometry that have occurred. Areas covered: The review provides an update of the recent findings in diagnostic classification, in genetic definition and in the investigation of thyroid lesions based on different proteomics approaches and on different type of specimens: cytological, surgical and biofluid samples. A brief section will discuss how these findings can be integrated with those obtained by metabolomics investigations. Expert commentary: Among the several proteomics approaches able to deepen our knowledge of the molecular alterations of the different thyroid lesions, MALDI-MSI is strongly emerging above all. In fact, MS-imaging has also been demonstrated to be capable of distinguishing thyroid lesions, based on their different molecular signatures, using cytological specimens. The possibility to use the material obtained by the fine needle aspiration makes MALDI-MSI a highly promising technology that could be implemented into the clinical and pathological units.

OBJECTIVES: To describe the prevalence of malocclusions in 2- to 10-year-old children suffering from obstructive sleep apnoea (OSA) and to evaluate the association between occlusal variables and OSA. SETTING AND SAMPLE POPULATION: A total of 2101 consecutive patients referred to an otorhinolaryngology unit were considered for the study. One hundred and fifty-six children (range 2-10 years) with suspected OSA were selected for a sleep study. The final sample consisted of 139 children suffering from OSA and a control group of 137 children. MATERIALS AND METHODS: All patients included in the study underwent a clinical orthodontic examination to record the following occlusal variables: primary canine relationship, presence of a posterior crossbite, overjet and overbite. Odds ratios and 95% confidence intervals, comparing the demographic characteristics and dental parameters in OSA vs non-OSA children, were computed. Multivariable logistic regression models were developed to compare independent variables associated with OSA to non-OSA children. RESULTS: The prevalence of malocclusions in children with OSA was 89.9% compared to 60.6% in the control group (P < 0.001). Factors independently associated with OSA compared to the control group were posterior crossbite (OR = 3.38; 95%CI:1.73-6.58), reduced overbite (OR = 2.43; 95%CI:1.15-5.15.), increased overbite (OR = 2.19; 95%CI:1.12-4.28) and increased overjet (OR = 4.25; 95%CI:1.90-9.48). CONCLUSIONS: This study showed a high prevalence of malocclusion in children with OSA compared to the control group. The posterior crossbite and deviations in overjet and overbite were significantly associated with OSA. The presence of these occlusal features shows the importance of an orthodontic evaluation in screening for paediatric OSA

Heart disease remains a leading cause of morbidity and mortality in transfusion-dependent thalassemia (TDT), which can be attributed to several factors but primarily develops in the setting of iron overload. This was a retrospective cohort study utilizing Webthal® patient data from five major centers across Italy. Patients without heart disease were followed-up for 10 years (2000-2010) and data were collected for demographics, splenectomy status, serum ferritin and hemoglobin levels, and comorbidities associated with heart disease. Among 379 patients analyzed (mean age 22.9 ± 5.1years, 47.8% men), 44 (cumulative incidence: 11.6%) developed heart disease during the period of observation. Splenectomy (p = 0.002) and serum ferritin level (p

Many real-world tasks require multiple agents to work together. When talking about multiple agents in robotics, it is usually referenced to multiple manipulators in collaboration to solve a given task, where each one is controlled by a single agent. However, due to the increasing development of modular and re-configurable robots, it is also important to investigate the possibility of implementing multi-agent controllers that learn how to manage the manipulator’s degrees of freedom (DoF) in separated clusters for the execution of a given application (e.g., being able to face faults or, partially, new kinematics configurations). Within this context, this paper focuses on the decentralization of the robot control action learning and (re)execution considering a generic multi-DoF manipulator. Indeed, the proposed framework employs a multi-agent paradigm and investigates how such a framework impacts the control action learning process. Multiple variations of the multi-agent framework have been proposed and tested in this research, comparing the achieved performance w.r.t. a centralized (i.e., single-agent) control action learning framework, previously proposed by some of the authors. As a case study, a manipulation task (i.e., grasping and lifting) of an unknown object (to the robot controller) has been considered for validation, employing a Franka EMIKA panda robot. The MuJoCo environment has been employed to implement and test the proposed multi-agent framework. The achieved results show that the proposed decentralized approach is capable of accelerating the learning process at the beginning with respect to the single-agent framework while also reducing the computational effort. In fact, when decentralizing the controller, it is shown that the number of variables involved in the action space can be efficiently separated into several groups and several agents. This simplifies the original complex problem into multiple ones, efficiently improving the task learning process.

Evidence on the effectiveness of SARS-CoV-2 vaccines in nursing home (NHs) residents is limited. We examined the impact of the BNT162b2 mRNA SARS-CoV-2 vaccine on the course of the epidemic in NHs in the Florence Health District, Italy, before and after vaccination. Moreover, we assessed survival and hospitalization by vaccination status in SARS-CoV-2-positive cases occurring during the post-vaccination period. We calculated the weekly infection rates during the pre-vaccination (1 October–26 December 2020) and post-vaccination period (27 December 2020–31 March 2021). Cox analysis was used to analyze survival by vaccination status. The study involved 3730 residents (mean age 84, 69% female). Weekly infection rates fluctuated during the pre-vaccination period (1.8%–6.5%) and dropped to zero during the post-vaccination period. Nine unvaccinated (UN), 56 partially vaccinated (PV) and 35 fully vaccinated (FV) residents tested SARS-CoV-2+ during the post-vaccination period. FV showed significantly lower hospitalization and mortality rates than PV and UV (hospitalization: FV 3%, PV 14%, UV 33%; mortality: FV 6%, PV 18%, UV 56%). The death risk was 84% and 96% lower in PV (HR 0.157, 95%CI 0.049–0.491) and FV (HR 0.037, 95%CI 0.006–0.223) versus UV. SARS-CoV-2 vaccination was followed by a marked decline in infection rates and was associated with lower morbidity and mortality among infected NH residents.

The coronavirus disease‐19 (COVID‐19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) challenged globally with its morbidity and mortality. A small percentage of affected patients (20%) progress into the second stage of the disease clinically presenting with severe or fatal involvement of lung, heart and vascular system, all contributing to multiple‐organ failure. The so‐called ‘cytokines storm’ is considered the pathogenic basis of severe disease and it is a target for treatment with corticosteroids, immunotherapies and intravenous immunoglobulin (IVIg). We provide an overview of the role of IVIg in the therapy of adult patients with COVID‐19 disease. After discussing the possible underlying mechanisms of IVIg immunomodulation in COVID‐19 disease, we review the studies in which IVIg was employed. Considering the latest evidence that show a link between new coronavirus and autoimmunity, we also discuss the use of IVIg in COVID‐19 and anti‐SARS‐CoV‐2 vaccination related autoimmune diseases and the post‐COVID‐19 syndrome. The benefit of high‐dose IVIg is evident in almost all studies with a rapid response, a reduction in mortality and improved pulmonary function in critically ill COVID‐19 patients. It seems that an early administration of IVIg is crucial for a successful outcome. Studies’ limitations are represented by the small number of patients, the lack of control groups in some and the heterogeneity of included patients. IVIg treatment can reduce the stay in ICU and the demand for mechanical ventilation, thus contributing to attenuate the burden of the disease.

Quantitative determination of most economic valuable metals in waste is the first fundamental operation of evaluating the feasibility of recycling processes. Field-portable X-ray fluorescence spectrometers (FPXRFs) represent a more practical, efficient, and economic tool in determining the elemental composition of samples with respect to conventional analytical techniques, such as atomic absorption spectrometry (AAS) and inductively coupled plasma emission spectrometry (ICP). In this paper, quick and smart determination of gold content in printed circuit boards (PCBs) of waste mobile phones was studied. The aim of the research was to combine the practicality of FPXRFs with the reliability of quantitative spectrometry analysis and evaluate the error between the two techniques. Several samples (33) of PCBs were ground to a size below 0.5 mm, and then, the powders were analyzed by FPXRFs at different acquisition times with five replications for each sample. The same analyzed samples then underwent chemical attack to determine the quantitative gold content by AAS. The obtained results were associated with FPXRFs response with the purpose of realizing a calibration curve (100–1000 mg/kg Au). The curve was validated for accuracy and precision by other PCBs waste samples, the control samples were added as standards to obtain a more reliable calibration curve. The curve was evaluated with RPD classification, regression linear, and Bolt–Altman analysis.

Whole-body magnetic resonance imaging is constantly gaining more importance in rheumatology, particularly for what concerns the diagnosis, follow-up, and treatment response evaluation. Initially applied principally for the study of ankylosing spondylitis, in the last years, its use has been extended to several other rheumatic diseases. Particularly in the pediatric population, WB-MRI is rapidly becoming the gold-standard technique for the diagnosis and follow-up of both chronic recurrent multifocal osteomyelitis and juvenile spondyloarthritis. In this review, we analyze the benefits and limits of this technique as well as possible future applications.

Objectives The study aimed to evaluate the emergency department (ED) presentation of children with a diagnosis of osteomyelitis, septic arthritis, or both. Methods A retrospective single-center study was conducted on all children aged between 1 month and 18 years evaluated in the ED over a 7-year period and having a final diagnosis of osteoarticular infection. One hundred seventeen patients were enrolled. Results Only 39.3% of patients were admitted after the first evaluation, and only 45.3% had a proper diagnosis of admission. Pain was the only symptom reported by all. White cell count, C-reactive protein level, and erythrocytes sedimentation rate were normal in 49.5%, 21.4%, and 17.1% of children, respectively. X-ray findings were unremarkable in 48% of cases. Clinical and bone structural sequelae were described in 19.23% and 56.86% of all cases. No statistically significant differences were found among osteomyelitis, arthritis, and the combination of both regarding all considered variables, except for structural outcomes resulting more significant in the third group. Significant differences were evident in clinical manifestations, blood examinations, and findings of osteolysis between patients diagnosed within and after 1 week since the disease onset. Finally, questionable differences between white blood cells and C-reactive protein level were found among patients younger than 5 years and older ones, whereas a history of trauma was more often reported in the second group. Conclusions The difficulty in recognizing osteoarticular infection in a pediatric ED can be due to the possible lack of the classic signs and symptoms, and the absence of specific laboratory and radiologic findings.

Increasing age is a strong, independent risk factor for atherosclerosis and cardiovascular disease. Key abnormalities driving cardiovascular risk in old age include endothelial dysfunction, increased arterial stiffness, blood pressure, and the pro-atherosclerotic effects of chronic, low-grade, inflammation. The identification of novel therapies that comprehensively target these alterations might lead to a major breakthrough in cardiovascular risk management in the older population. Systematic reviews and meta-analyses of observational studies have shown that methotrexate, a first-line synthetic disease-modifying anti-rheumatic drug, significantly reduces cardiovascular morbidity and mortality in patients with rheumatoid arthritis, a human model of systemic inflammation, premature atherosclerosis, and vascular aging. We reviewed in vitro and in vivo studies investigating the effects of methotrexate on endothelial function, arterial stiffness, and blood pressure, and the potential mechanisms of action involved. The available evidence suggests that methotrexate might have beneficial effects on vascular homeostasis and blood pressure control by targeting specific inflammatory pathways, adenosine metabolism, and 5' adenosine monophosphate-activated protein kinase. Such effects might be biologically and clinically relevant not only in patients with rheumatoid arthritis but also in older adults with high cardiovascular risk. Therefore, methotrexate has the potential to be repurposed for cardiovascular risk management in old age because of its putative pharmacological effects on inflammation, vascular homeostasis, and blood pressure. However, further study and confirmation of these effects are essential in order to adequately design intervention studies of methotrexate in the older population.

To explore the significance of the association between treatment with methotrexate (MTX) and liver stiffness in rheumatoid arthritis (RA) patients.We enrolled 140 consecutive RA patients under MTX treatment (MTX-treated RA; mean treatment duration: 6.2 years; mean MTX cumulative dose: 4.67 g), 33 RA patients naive to MTX (MTX-naive RA) and 100 age and sex-matched healthy blood donors (HD). Liver stiffness was assessed by real time two-dimensional shear wave elastography, with values ≥7.1 Kilopascals (kPa) defining significant liver fibrosis.kPa values in HD (4.32 ± 0.7) were lower than that in MTX-naive RA (4.92 ± 0.8) and MTX-treated RA (4.85 ± 0.9, p .0005 for trend). On the contrary, the difference in kPa between MTX-naive and MTX-treated RA was not significant (p = .89). Similarly, liver stiffness was not significantly different across strata of cumulative MTX dose (4.95 ± 0.7 kPa in MTX1 g, 4.90 ± 1.1 kPa in MTX 1-3 g and 4.80 ± 0.9 in MTX3 g, p = .610). Significant liver fibrosis was diagnosed in 4 patients in the MTX-treated RA (highest kPa value = 7.6; no liver function test abnormalities or clinical signs of hepatic failure) and in none in both the MTX-naive RA and HD groups (p = .145).Liver stiffness values, although within the normal range, are significantly higher in RA patients vs. controls, irrespective of MTX treatment. RA patients taking MTX do not have a higher prevalence of significant liver fibrosis when compared to MTX naive RA patients and the general population.

Purpose To explore the potential role of circulating endothelial cells (CECs) and their progenitors (EPCs) as biomarkers of disease activity and damage accrual in patients with Behcet's syndrome (BS), by using a standardised and reliable flow cytometry protocol. Patients and methods CECs and EPCs were assessed in 32 BS patients and 11 gender/age/smoking habits matched healthy controls (HC). They were identified by flow cytometry as alive/nucleated/CD45-negative/CD34-bright/CD146-positive and alive/nucleated/CD45-negative/CD34-bright/CD309-positive events, respectively. In BS patients, demographic and clinical features, including disease activity (assessed by Behcet's disease current disease activity form, BDCAF) and irreversible damage accrual (by the vasculitis damage index, VDI) were recorded. Uni- and multivariate analysis were performed to compare the CECs and EPCs concentrations in BS vs HC and to identify potential associations with demographic or clinical features. Results The CECs concentration was significantly higher in the BS patients than HCs [median (IQR) 15.0 (7.5-23.0) vs 6.0 (2.0-13.0) CECs/mL, p=0.024]. In BS patients, no significant associations were found between CECs and demographic features, present and past clinical manifestations, BDCAF score and ongoing treatment. A significant association was observed between CECs and organ damage, as assessed by the VDI (rho 0.356, p=0.045). Higher levels of CECs were especially associated with vascular damage [median (IQR) 23.0 (14.0-47.0) vs 13.0 (6.0-19.0) CECs/mL, p=0.011], including arterial aneurysm and stenosis, complicated venous thrombosis, cerebrovascular accident. The concentration of EPCs did not significantly differ between the BS and HC [median 26.5 (13.0-46.0) vs 19.0 (4.0-42.0) EPCs/mL, p=0.316] and no significant associations were observed between their levels and any clinical characteristic. Conclusion Our study suggests that the CECs concentration is significantly higher in BS than healthy subjects, and it mainly correlates with vascular damage. A longitudinal extension of the present study on a wider cohort would be useful to validate the potential role of CECs as a marker or, hopefully, predictor of vascular damage in BS.

BACKGROUND: Whole-body MRI (WB-MRI) could be an alternative to multimodality staging of colorectal cancer, but its diagnostic accuracy, effect on staging times, number of tests needed, cost, and effect on treatment decisions are unknown. We aimed to prospectively compare the diagnostic accuracy and efficiency of WB-MRI-based staging pathways with standard pathways in colorectal cancer.METHODS: The Streamline C trial was a prospective, multicentre trial done in 16 hospitals in England. Eligible patients were 18 years or older, with newly diagnosed colorectal cancer. Exclusion criteria were severe systemic disease, pregnancy, contraindications to MRI, or polyp cancer. Patients underwent WB-MRI, the result of which was withheld until standard staging investigations were complete and the first treatment decision made. The multidisciplinary team recorded its treatment decision based on standard investigations, then on the WB-MRI staging pathway (WB-MRI plus additional tests generated), and finally on all tests. The primary outcome was difference in per-patient sensitivity for metastases between standard and WB-MRI staging pathways against a consensus reference standard at 12 months, in the per-protocol population. Secondary outcomes were difference in per-patient specificity for metastatic disease detection between standard and WB-MRI staging pathways, differences in treatment decisions, staging efficiency (time taken, test number, and costs), and per-organ sensitivity and specificity for metastases and per-patient agreement for local T and N stage. This trial is registered with the International Standard Randomised Controlled Trial registry, number ISRCTN43958015, and is complete.FINDINGS: Between March 26, 2013, and Aug 19, 2016, 1020 patients were screened for eligibility. 370 patients were recruited, 299 of whom completed the trial; 68 (23%) had metastasis at baseline. Pathway sensitivity was 67% (95% CI 56 to 78) for WB-MRI and 63% (51 to 74) for standard pathways, a difference in sensitivity of 4% (-5 to 13, p=0·51). No adverse events related to imaging were reported. Specificity did not differ between WB-MRI (95% [95% CI 92-97]) and standard pathways (93% [90-96], p=0·48). Agreement with the multidisciplinary team's final treatment decision was 96% for WB-MRI and 95% for the standard pathway. Time to complete staging was shorter for WB-MRI (median, 8 days [IQR 6-9]) than for the standard pathway (13 days [11-15]); a 5-day (3-7) difference. WB-MRI required fewer tests (median, one [95% CI 1 to 1]) than did standard pathways (two [2 to 2]), a difference of one (1 to 1). Mean per-patient staging costs were £216 (95% CI 211-221) for WB-MRI and £285 (260-310) for standard pathways.INTERPRETATION: WB-MRI staging pathways have similar accuracy to standard pathways and reduce the number of tests needed, staging time, and cost.FUNDING: UK National Institute for Health Research.

We review the importance of the revenue management (RM) system in the airline industry, focusing on cost-leader companies. We show that RM of low-cost carriers, which looks simple at a first glance, is indeed quite a sophisticated tool for extracting value from different demand segments, and thus, it is, for all intents and purposes, a capability in the resource-based view.

WOS: 000478608100031, PubMed ID: 31148155, Transfusion-dependent thalassaemia (TDT) requires red blood cell concentrates (RBCC) to prevent complications of anaemia, but carries risk of infection. Pathogen reduction of RBCC offers potential to reduce infectious risk. We evaluated the efficacy and safety of pathogen-reduced (PR) Amustaline-Glutathione (A-GSH) RBCC for TDT. Patients were randomized to a blinded 2-period crossover treatment sequence for six transfusions over 8-10 months with Control and A-GSH-RBCC. The efficacy outcome utilized non-inferiority analysis with 90% power to detect a 15% difference in transfused haemoglobin (Hb), and the safety outcome was the incidence of antibodies to A-GSH-PR-RBCC. By intent to treat (80 patients), 12 center dot 5 +/- 1 center dot 9 RBCC were transfused in each period. Storage durations of A-GSH and C-RBCC were similar (8 center dot 9 days). Mean A-GSH-RBCC transfused Hb (g/kg/day) was not inferior to Control (0 center dot 113 +/- 0 center dot 04 vs. 0 center dot 111 +/- 0 center dot 04, P = 0 center dot 373, paired t-test). The upper bound of the one-sided 95% confidence interval for the treatment difference from the mixed effects model was 0 center dot 005 g/kg/day, within a non-inferiority margin of 0 center dot 017 g/kg/day. A-GSH-RBCC mean pre-transfusion Hb levels declined by 6 center dot 0 g/l. No antibodies to A-GSH-RBCC were detected, and there were no differences in adverse events. A-GSH-RBCCs offer potential to reduce infectious risk in TDT with a tolerable safety profile., Ege University Hospital Blood Centre, Izmir, Turkey

Introduction Psoriasis is a chronic inflammatory disease characterized by the presence of erythematosquamous lesions. A wide variety of topical treatments for therapy of this pathology are available, including sodium bicarbonate (SB). A few papers reported in literature focus on use of SB baths for treatment of psoriasis, but none assess evidence concerning the efficacy of SB topical preparations. This study aimed to determine the effectiveness of a galenic SB in lanette vax formulation compared with lanette vax base in mild to moderate stable plaque psoriasis. Methods A randomized, double-blind, intrapatient, controlled study was performed in 28 days. Thirty patients of both genders were selected for testing. A blinded investigator evaluated the patients’ psoriasis using a modified Psoriasis Area and Severity Index (PASI), body surface area (BSA), and objective parameters using sensors (Multiprobe Adapter MPA5; Courage & Khazaka Electronic GmbH, Cologne, Germany). Results Data analysis of objective parameters highlighted that use of the SB topical preparation led to no improvement in skin hydration, no reduction in transepidermal water loss, and no decrease of erythema. The modified PASI and BSA did not change from baseline. Conclusions The results obtained show that use of the studied product did not improve psoriatic lesions.

Today, the 10-year cardiovascular risk largely relies on conventional cardiovascular risk factors (CCVRFs) and suffers from the effect of atherosclerotic wall changes. In this study, we present a novel risk calculator AtheroEdge Composite Risk Score (AECRS1.0), designed by fusing CCVRF with ultrasound image-based phenotypes. Ten-year risk was computed using the Framingham Risk Score (FRS), United Kingdom Prospective Diabetes Study 56 (UKPDS56), UKPDS60, Reynolds Risk Score (RRS), and pooled composite risk (PCR) score. AECRS1.0 was computed by measuring the 10-year five carotid phenotypes such as IMT (ave., max., min.), IMT variability, and total plaque area (TPA) by fusing eight CCVRFs and then compositing them. AECRS1.0 was then benchmarked against the five conventional cardiovascular risk calculators by computing the receiver operating characteristics (ROC) and area under curve (AUC) values with a 95% CI. Two hundred four IRB-approved Japanese patients' left/right common carotid arteries (407 ultrasound scans) were collected with a mean age of 69 ± 11 years. The calculators gave the following AUC: FRS, 0.615; UKPDS56, 0.576; UKPDS60, 0.580; RRS, 0.590; PCRS, 0.613; and AECRS1.0, 0.990. When fusing CCVRF, TPA reported the highest AUC of 0.81. The patients were risk-stratified into low, moderate, and high risk using the standardized thresholds. The AECRS1.0 demonstrated the best performance on a Japanese diabetes cohort when compared with five conventional calculators. Graphical abstract AECRS1.0: Carotid ultrasound image phenotype-based 10-year cardiovascular risk calculator. The figure provides brief overview of the proposed carotid image phenotype-based 10-year cardiovascular risk calculator called AECRS1.0. AECRS1.0 was also benchmarked against five conventional cardiovascular risk calculators (Framingham Risk Score (FRS), United Kingdom Prospective Diabetes Study 56 (UKPDS56), UKPDS60, Reynolds Risk Score (RRS), and pooled composite risk (PCR) score).

Tactile sensing represents a valuable source of information in robotics for perception of the state of objects and their properties. Modern soft tactile sensors allow perceiving orthogonal forces and, in some cases, relative motions along the surface of the object. Detecting and measuring this kind of lateral motion is fundamental to react to possibly uncontrolled slipping and sliding of the object being manipulated. Object slip detection and prediction have been extensively studied in the robotic community leading to solutions with good accuracy and suitable for closed-loop grip stabilization. However, algorithms for object perception, such as in-hand object pose estimation and tracking algorithms, often assume no relative motion between the object and the hand and rarely consider the problem of tracking the pose of the object subjected to slipping and sliding motions. In this work, we propose a differentiable Extended Kalman filter that can be trained to track the position and the velocity of an object under translational sliding regime from tactile observations alone. Experiments with several objects, carried out on the iCub humanoid robot platform, show that the proposed approach allows achieving an average position tracking error in the order of 0.6 cm, and that the provided estimate of the object state can be used to take control decisions using tactile feedback alone. A video of the experiments is available as Supplementary Material.