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Background: VEXAS syndrome, a recently identified systemic autoinflammatory disorder, poses new diagnostic and management challenges. Based on experience with other autoinflammatory diseases, anti-interleukin (IL)-1, anti-IL-6, anti-tumor necrosis factor (TNF) biotechnological agents, and Janus kinase inhibitors (JAKis) have been widely employed in VEXAS patients. The aim of this study is to evaluate the global effectiveness and safety of biotechnological agents and JAKis using data from the real-world context., Methods: Clinical, laboratory, and therapeutic data from VEXAS patients were obtained from the international AIDA Network VEXAS registry., Results: In total, 69 VEXAS patients were enrolled in the study. Among them, 12 patients (13 treatment courses) received IL-1 inhibitors, 12 patients (13 treatment courses) were administered anti-IL-6 agents, 8 patients (9 treatment courses) were treated with anti-TNF agents, and 16 patients (17 treatment courses) were treated with JAKis. A complete response was observed in 3 patients (23%) treated with anti-IL-1 agents, 2 patients (15%) receiving IL-6 inhibitors, 1 patient (11%) receiving TNF inhibitors, and 4 patients (23.5%) treated with JAKis. The mean prednisone (or equivalent) dosage significantly decreased during anti-IL-1 treatment (p = 0.01), while glucocorticoids changed during anti-IL-6, anti-TNF, and JAKi treatment in a non-significant fashion. A total of 21 patients experienced adverse events, 3 of which led to death (gut perforation, Legionnaires' disease, and infectious pneumonia) while on JAKis; treatment withdrawal was required for 8 out of 21 patients., Conclusion: IL-1 and IL-6 inhibitors, along with JAKis, represent promising therapeutic options for VEXAS patients, albeit careful monitoring is mandatory to control disease activity and ensure safety., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2025 Vitale, Caggiano, Leone, Hinojosa-Azaola, Martín-Nares, Guaracha-Basañez, Torres-Ruiz, Kawakami-Campos, Hissaria, Callisto, Beecher, Dagna, Campochiaro, Tomelleri, Frassi, Franceschini, Crisafulli, Hernández-Rodríguez, Gómez-Caverzaschi, Araújo, Sfriso, Bindoli, Baggio, Sota, Tufan, Kucuk, Piga, Cauli, D’Agostino, De Paulis, Mormile, Giardini, Cordeiro, Lopalco, Iannone, Monti, Montecucco, Ruiz-Irastorza, Soto-Peleteiro, Triggianese, Gurnari, Viapiana, Bixio, Vitetta, Rovera, Conticini, La Torre, Portincasa, Jaber, Ragab, Maher, Batu, Ozen, Wiesik-Szewczyk, de-la-Torre, Balistreri, Frediani, Fabiani and Cantarini.)

Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of autoimmune diseases characterised by skeletal muscle inflammation and frequently by other organs involvement, in particular lung and skin, but also joints, heart and gastrointestinal tract.Although they are rare diseases, the literature on IIMs has been growing rapidly and many studies have been published in order to clarify the pathogenesis and to better define diagnosis, clinical manifestations (muscular and extra-muscular) and treatment. The purpose of this review is to summarise the most relevant contributions published over the last year on this topic.

Objectives: To assess the lung involvement in patients with Still's disease, an inflammatory disease assessing both children and adults. To exploit possible associated factors for parenchymal lung involvement in these patients., Methods: A multicentre observational study was arranged assessing consecutive patients with Still's disease characterized by the lung involvement among those included in the AIDA (AutoInflammatory Disease Alliance) Network Still's Disease Registry. Still's disease-lung involvement was defined by the presence of pleuritis, parenchymal features, acute respiratory distress syndrome (ARDS), and/or pulmonary arterial hypertension., Results: In total, 90 patients with Still's disease and lung involvement were assessed (mean age 36.3 ± 17.8 years, 35.6% male sex). Among them, 13.3% of patients were paediatrics. These patients with lung involvement mainly showed pleuritis in 72.2% of cases, parenchymal features in 34.4%, ARDS in 9.5%, and pulmonary arterial hypertension in 2.3%. After that we focused on patients characterised by parenchymal lung involvement, which is an emergent issue of clinical concern. These patients with parenchymal lung disease were significantly characterized by sore throat, pericarditis, and higher values of systemic score than others. Finally, the administration of both IL-1 or IL-6 inhibitors was not associated with the presence of parenchymal lung involvement., Conclusion: The clinical characteristics of patients with Still's disease and lung involvement were described in the AIDA network. We also provided a clinical profile of patients with parenchymal lung involvement considering its prognostic relevance. Although providing a clinical landscape of these patients, further studies are needed to fully clarify this issue., (© The Author(s) 2025. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: The current knowledge about the role of comorbidities in systemic sclerosis (SSc) is limited. Therefore, the aim of this study was to evaluate the prevalence of comorbidities and their impact on disease activity and prognosis in the Systemic sclerosis PRogression INvestiGation (SPRING) registry., Methods: SSc patients from the SPRING registry, fulfilling the ACR/EULAR 2013 classification criteria, with complete data on baseline comorbidities were enrolled. The Charlson comorbidity index (CCI) was used to quantify the overall comorbidity burden. The disease activity was calculated using the revised EUSTAR activity index (AI). The impact of SSc features on CCI, the effect of CCI on SSc disease activity and mortality were tested with multivariable regression models., Results: Among 1910 SSc patients enrolled, 67.3 % had at least one comorbidity at baseline. The most frequent comorbidities were systemic arterial hypertension (23.7 %), osteoporosis (12.9 %) and dyslipidemia (11 %). The mean value of CCI score was 2.0 ± 1.8. When patients were grouped according to increasing levels of CCI, a clear separation in the distribution of SSc-related clinical features could be observed. Among over 900 patients with available follow-up, no association between baseline CCI and changes in disease activity was observed. Conversely, the risk of death over time was independently predicted by both CCI and AI., Conclusions: Comorbidities and disease activity independently impact on the prognosis of SSc patients. This suggests that the management of comorbidities, together with the reduction of disease activity, is fundamental to improve patient survival., Competing Interests: Declaration of competing interest Orlandi M, Bellando-Randone S, Ferri C, Foti R, Codullo V, De Angelis R, Cuomo G, Campochiaro C, Luca Magnani, Cacciapaglia F, Ariani A, Giuggioli D, and Guiducci S have no conflict of interest to declare. Matucci-Cerinic M received fees from Actelion, Janssen, Inventiva, Bayer, Biogen, Boehringer, CSL Behring, Corbus, Galapagos, Mitsubishi, Samsung, Regeneron, Acceleron, MSD, Chemomab, Lilly, Pfizer, Roche. Bruni C received consulting fees and/or honoraria from Eli-Lilly, Boehringer Ingelheim, Research grants from Gruppo Italiano Lotta alla Sclerodermia (GILS), European Scleroderma Trials and Research Group (EUSTAR), Scleroderma Clinical Trials Consortium (SCTC), Scleroderma Research Foundation (SRF), Novartis foundation for biomedical research. Congress supports from Boehringer-Ingelheim. Educational grants from AbbVie and Wellcome Trust., (Copyright © 2024. Published by Elsevier B.V.)

VEXAS syndrome is a recently described monogenic autoinflammatory disease capable of manifesting itself with a wide array of organs and tissues involvement. Orbital/ocular inflammatory manifestations are frequently described in VEXAS patients. The objective of this study is to further describe orbital/ocular conditions in VEXAS syndrome while investigating potential associations with other disease manifestations. In the present study, twenty-seven out of 59 (45.8 %) VEXAS patients showed an inflammatory orbital/ocular involvement during their clinical history. The most frequent orbital/ocular affections were represented by periorbital edema in 8 (13.6 %) cases, episcleritis in 5 (8.5 %) patients, scleritis in 5 (8.5 %) cases, uveitis in 4 (6.8 %) cases, conjunctivitis in 4 (6.8 %) cases, blepharitis in 3 (5.1 %) cases, orbital myositis in 2 (3.4 %) cases. A diagnosis of systemic immune-mediated disease was observed in 15 (55.6 %) cases, with relapsing polychondritis diagnosed in 12 patients. A significant association was observed between relapsing polychondritis and orbital/ocular involvement in VEXAS syndrome (Relative Risk: 2.37, 95 % C.I. 1.03-5.46, p = 0.048). Six deaths were observed in the whole cohort of patients after a median disease duration of 1.2 (IQR=5.35) years, 5 (83.3 %) of which showed orbital/ocular inflammatory involvement. In conclusion, this study confirms that orbital/ocular inflammatory involvement is a common finding in VEXAS patients, especially when relapsing polychondritis is diagnosed. This makes ophthalmologists a key figure in the diagnostic process of VEXAS syndrome. The high frequency of deaths observed in this study seems to suggest that patients with orbital/ocular involvement may require increased attention and more careful follow-up., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest for this work., (Copyright © 2024. Published by Elsevier Inc.)

Objectives: The aim of this study was to evaluate the effectiveness and safety profile of filgotinib, a JAK1 preferential inhibitor, in rheumatoid arthritis (RA) patients included in Italian GISEA (Group for the Study of Early Arthritis) registry., Methods: Data from RA patients treated with filgotinib, recorded in the GISEA registry, were analysed. Disease activity scores and patient-reported outcomes (PROs) were assessed at baseline, as well as during 12-month follow-up. A difficult-to-treat (D2T) RA patient was defined according with EULAR criteria. Retention rate of filgotinib was estimated by the Kaplan-Meier method and factors influencing drug discontinuation were estimated by Cox regression models., Results: 246 RA patients (female 89%, 57.6±12.2 years old) started filgotinib, mostly as second (22%) or further (43.9%) b/tsDMARDs line of treatment. At 3 and 12 months, 18.8% and 27.5% of patients achieved Clinical Diseases Activity Index based remission and 30.1% and 37.7% obtained a visual analogue scale of pain ≤20 (all p<0.01 vs. baseline). Filgotinib survival rate was 84.5% at the 6-month and 75.8% at 12-month follow-up, and was comparable either in monotherapy or combination therapy, and irrespective of glucocorticoid intake. b/tsDMARD naive patients had the lowest hazard ratio (HR) of filgotinib discontinuation (HR 0.29, 95%CI 0.14-0.64), while D2T-RA the highest (HR 1.82, 95%CI 1.01-3.3). Eight patients (3.3%) discontinued filgotinib due to adverse events., Conclusions: In an Italian real-life setting, filgotinib is confirmed to be safe and with a good effectiveness profile both in monotherapy and without glucocorticoids.

Background: The identification of patients surviving an acute intracerebral hemorrhage who are at a long-term risk of arterial thrombosis is a poorly defined, crucial issue for clinicians., Methods: In the setting of the MUCH-Italy (Multicenter Study on Cerebral Haemorrhage in Italy) prospective observational cohort, we enrolled and followed up consecutive 30-day intracerebral hemorrhage survivors to assess the long-term incidence of arterial thrombotic events, to assess the impact of clinical and radiological variables on the risk of these events, and to develop a tool for estimating such a risk at the individual level. Primary end point was a composite of ischemic stroke, myocardial infarction, or other arterial thrombotic events. A point-scoring system was generated by the β-coefficients of the variables independently associated with the long-term risk of arterial thrombosis, and the predictive MUCH score was calculated as the sum of the weighted scores., Results: Overall, 1729 patients (median follow-up time, 43 months [25th to 75th percentile, 69.0]) qualified for inclusion. Arterial thrombotic events occurred in 169 (9.7%) patients. Male sex, diabetes, hypercholesterolemia, atrial fibrillation, and personal history of coronary artery disease were associated with increased long-term risk of arterial thrombosis, whereas the use of statins and antithrombotic medications after the acute intracerebral hemorrhage was associated with a reduced risk. The area under the receiver operating characteristic curve of the MUCH score predictive validity was 0.716 (95% CI, 0.56-0.81) for the 0- to 1-year score, 0.672 (95% CI, 0.58-0.73) for the 0- to 5-year score, and 0.744 (95% CI, 0.65-0.81) for the 0- to 10-year score. C statistic for the prediction of events that occur from 0 to 10 years was 0.69 (95% CI, 0.64-0.74)., Conclusions: Intracerebral hemorrhage survivors are at high long-term risk of arterial thrombosis. The MUCH score may serve as a simple tool for risk estimation., Competing Interests: Disclosures Dr Ciccone reports grants from Daiichi Sankyo, Italfarmaco, and Alexion Pharmaceuticals. Dr Paciaroni reports compensation from Sanofi-Aventis U.S. LLC, Pfizer Canada, Inc, iRhythm Technologies, Daiichi Sankyo Europe GmbH, and Bristol Myers Squibb for other services. The other authors report no conflicts.

Biotechnological monoclonal antibodies and receptor antagonists capable of targeting specific inflammatory actors, such as cytokines, cytokines receptors, co-stimulatory molecules or leukocyte populations, have emerged as an alternative to conventional therapies for treating systemic inflammatory diseases with immune pathogenesis. However, there is no doubt that, with a frequency that is not exceptionally high but also not negligible, immunotherapies can favour the development of systemic and organ-specific immune-mediated disorders. It has become increasingly evident that interference with a specific immune pathway may favour the activation of opposing compensatory signalling, which may exacerbate underlying subclinical disorders or cause immune-mediated diseases completely different from the underlying disease. The 'compensatory immunological switch' has emerged primarily in patients treated with tumor necrosis factor (TNF) -α inhibitors, the first biological drugs approved for treating systemic inflammatory diseases with immune pathogenesis. In this Review, we describe the clinical features and predisposing factors of the main TNF-α inhibitor-related autoimmune disorders, organising them into subclinical serological autoimmunity, autoimmune disorders other than those for which TNF-α inhibitors are indicated, and paradoxical reactions. We also discuss the underlying pathogenetic mechanisms and precautions for use in the therapeutic management of these patients. Better understanding of the complex phenomenon of the 'compensatory immunological switch', which TNF-α inhibitors and other biological drugs might trigger, can help not only appropriately managing immune-mediated disorders, but also better interpreting the heterogeneity of the pathogenetic mechanisms underlying certain chronic inflammatory conditions that, although different from each other, are arbitrarily placed in the context of overly generic nosological entities., Competing Interests: Declaration of Competing Interest CM reports grant/research support from AbbVie, Eli Lilly, Roche and Novartis, and personal fees from AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Galapagos, MSD, Novartis, Pfizer, Roche, Janssen. SB reports grant/research support from Pfizer and personal fees from AbbVie, Bristol-Myers Squibb, Eli Lilly, Galapagos, Pfizer and Novartis. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Serena Bugatti, Carlomaurizio Montecucco reports a relationship with AbbVie Inc. that includes: consulting or advisory and speaking and lecture fees. Serena Bugatti, Carlomaurizio Montecucco reports a relationship with Bristol-Myers Squibb Company that includes: consulting or advisory and speaking and lecture fees. Serena Bugatti, Carlomaurizio Montecucco reports a relationship with Eli Lilly and Company that includes: consulting or advisory and speaking and lecture fees. Serena Bugatti, Carlomaurizio Montecucco reports a relationship with Galapagos that includes: consulting or advisory and speaking and lecture fees. Serena Bugatti, Carlomaurizio Montecucco reports a relationship with Janssen Pharmaceuticals Inc. that includes: consulting or advisory and speaking and lecture fees. Serena Bugatti, Carlomaurizio Montecucco reports a relationship with Novartis that includes: consulting or advisory and speaking and lecture fees. Serena Bugatti, Carlomaurizio Montecucco reports a relationship with Pfizer that includes: consulting or advisory and speaking and lecture fees., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Benign liver lesions are increasingly diagnosed in daily clinical practice due to the growing use of imaging techniques for the study of the abdomen in patients who have non-specific symptoms and do not have an increased risk of hepatic malignancy. They include simple or parasitic hepatic cysts and solid benign tumors which differ widely in terms of prevalence, clinical relevance, symptoms and natural history and often lead to significant clinical problems relating to diagnosis and clinical management. Following the need to have updated guidelines on the management of benign focal liver lesions, the Scientific Societies mainly involved in their management have promoted the drafting of a new dedicated document. This document was drawn up according to the present Italian rules and methodologies necessary to produce clinical, diagnostic, and therapeutic guidelines based on evidence. Here we present the second part of the guideline, concerning the diagnosis and clinical management of hemangioma, focal nodular hyperplasia, and hepatocellular adenoma., Competing Interests: Declaration of Competing Interest The Authors declare no conflict of interest., (Copyright © 2022. Published by Elsevier Ltd.)

The outbreak of COVID-19, beginning in 2019 and continuing through the time of writing, has led to renewed interest in the mathematical modeling of infectious disease. Recent works have focused on partial differential equation (PDE) models, particularly reaction-diffusion models, able to describe the progression of an epidemic in both space and time. These studies have shown generally promising results in describing and predicting COVID-19 progression. However, people often travel long distances in short periods of time, leading to nonlocal transmission of the disease. Such contagion dynamics are not well-represented by diffusion alone. In contrast, ordinary differential equation (ODE) models may easily account for this behavior by considering disparate regions as nodes in a network, with the edges defining nonlocal transmission. In this work, we attempt to combine these modeling paradigms via the introduction of a network structure within a reaction-diffusion PDE system. This is achieved through the definition of a population-transfer operator, which couples disjoint and potentially distant geographic regions, facilitating nonlocal population movement between them. We provide analytical results demonstrating that this operator does not disrupt the physical consistency or mathematical well-posedness of the system, and verify these results through numerical experiments. We then use this technique to simulate the COVID-19 epidemic in the Brazilian region of Rio de Janeiro, showcasing its ability to capture important nonlocal behaviors, while maintaining the advantages of a reaction-diffusion model for describing local dynamics., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 Elsevier B.V. All rights reserved.)

Benign liver lesions are increasingly diagnosed in daily clinical practice due to the growing use of imaging techniques for the study of the abdomen in patients who have non-specific symptoms and do not have an increased risk of hepatic malignancy. They include simple or parasitic cysts and solid benign tumors which differ widely in terms of prevalence, clinical relevance, symptoms and natural history and often lead to significant clinical problems relating to diagnosis and clinical management. Following the need to have updated guidelines on the management of benign focal liver lesions, the Scientific Societies mainly involved in their management have promoted the drafting of a new dedicated document. This document was drawn up according to the present Italian rules and methodologies necessary to produce clinical, diagnostic, and therapeutic guidelines based on evidence. Here we present the first part of the guideline, concerning the characterization of focal hepatic lesions detected by ultrasound, and the diagnosis and clinical management of simple and parasitic hepatic cysts, and of polycystic liver disease., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Patient-reported outcomes (PROs) are currently poorly integrated in the clinical evaluation of disease activity in patients with ANCA-associated vasculitis (AAV)., Objectives: To assess the distribution of the Patient Global Assessment (PtGA) in patients with AAV in stable remission, and to identify correlates of PtGA; to assess the discordance between PtGA score and Physician Global Assessment (PhGA)., Methods: Patients with a diagnosis of AAV in stable remission (BVAS=0) and with a Physician Global Assessment (PhGA)=0 were included. The following PROs on a 0-100 visual analogue scale (VAS) were assessed: PtGA, fatigue, pain, general health, sleep quality, and chronic damage according to the patient's opinion. The Cragg Hurdle model was used to assess the predictors of PtGA., Results: 65 patients were included, female 57%, mean age 61±12 years. Median disease duration 6 years (IQR 3-12). Vasculitis damage index (VDI) was 4.4±2.3. Despite having been classified as being in remission, PtGA was elevated in 37% of patients. The PtGA was not associated with older age, comorbidities, educational level, the type of AAV diagnosis, number of organ-systems involved, previous relapses, disease duration, nor higher VDI. Female sex was significantly associated with PtGA: 51% of female patients reported an elevated PtGA compared to 18% of males (p=0.009). PtGA significantly correlated with all the other assessed PROs. Pain and fatigue were the main determinants of an elevated PtGA., Conclusions: A significant proportion of patients with AAV considered to be in remission by the physician still declares to have persistent aspects of uncontrolled disease. PtGA is significantly influenced by pain and fatigue, which should receive more attention in the future assessment of patients with AAV., Competing Interests: Declaration of Competing Interest None to declare., (Copyright © 2022. Published by Elsevier Inc.)

COVID-19 tide had shattered on European countries with three distinct and tough waves, from March and April, 2020; October and November, 2020 and March and April, 2021 respectively. We observed a 50% reduction in the hazard of death during both wave II and III compared with wave I (HR 0.54, 95%CI 0.39-0.74 and HR 0.57, 95%CI 0.41-0.80, respectively). Sex and age were independent predictors of death. We compare in-hospital mortality of COVID-19 patients admitted at our Referral Hospital of Northern Italy during the different waves, discuss the reasons of the observed differences and suggest approaches to the challenges ahead., Competing Interests: The authors declare no conflict of interest., (© 2022 Published by Elsevier Ltd.)

Background and Purpose: Observational studies have suggested a link between fibromuscular dysplasia and spontaneous cervical artery dissection (sCeAD). However, whether patients with coexistence of the two conditions have distinctive clinical characteristics has not been extensively investigated., Methods: In a cohort of consecutive patients with first-ever sCeAD, enrolled in the setting of the multicenter IPSYS CeAD study (Italian Project on Stroke in Young Adults Cervical Artery Dissection) between January 2000 and June 2019, we compared demographic and clinical characteristics, risk factor profile, vascular pathology, and midterm outcome of patients with coexistent cerebrovascular fibromuscular dysplasia (cFMD; cFMD+) with those of patients without cFMD (cFMD-)., Results: A total of 1283 sCeAD patients (mean age, 47.8±11.4 years; women, 545 [42.5%]) qualified for the analysis, of whom 103 (8.0%) were diagnosed with cFMD+. In multivariable analysis, history of migraine (odds ratio, 1.78 [95% CI, 1.13-2.79]), the presence of intracranial aneurysms (odds ratio, 8.71 [95% CI, 4.06-18.68]), and the occurrence of minor traumas before the event (odds ratio, 0.48 [95% CI, 0.26-0.89]) were associated with cFMD. After a median follow-up of 34.0 months (25th to 75th percentile, 60.0), 39 (3.3%) patients had recurrent sCeAD events. cFMD+ and history of migraine predicted independently the risk of recurrent sCeAD (hazard ratio, 3.40 [95% CI, 1.58-7.31] and 2.07 [95% CI, 1.06-4.03], respectively) in multivariable Cox proportional hazards analysis., Conclusions: Risk factor profile of sCeAD patients with cFMD differs from that of patients without cFMD. cFMD and migraine are independent predictors of midterm risk of sCeAD recurrence.

The commerce of illegal and counterfeit medicinal products on internet is a serious criminal problem. Drugs for erectile dysfunction such as phosphodiesterase type 5 inhibitor are the most commonly counterfeited medicines in Europe. The search of possible toxic chemical substances in seized products is needed. Moreover, the profiling of the material can be the source of relevant forensic information. For the first time a combined approach based on liquid chromatography (LC) coupled to high resolution mass spectrometry (HRMS) and instrumental neutron activation analysis (INAA) is proposed and tested, allowing characterisation of both authentic and illegal pharmaceuticals containing sildenafil seized in Italy. LC-HRMS allowed the detection and identification of unknown impurities not reported on labels in illegal products and the quantitation of the sildenafil. INAA showed to be suitable to provide both qualitative and quantitative information for forensic purposes on 23 elements, allowing discrimination between legal and illegal products., (© 2019 The Author(s).)

Because of the demographic shift and the increased proportion of patients surviving acute critical illnesses, the number of people living with severely disabling chronic diseases and, consequently, the demand for rehabilitation are expected to increase sharply over time. As underscored by the World Health Organization, there is substantial evidence that the provision of inpatient rehabilitation in specialized rehabilitation units to people with complex needs is effective in fostering functional recovery, improving health-related quality of life, increasing independence, reducing institutionalization rate, and improving prognosis. Recent studies in the real world setting reinforce the evidence that patients with ischemic heart disease or stroke benefit from rehabilitation in terms of improved prognosis. In addition, there is evidence of the effectiveness of rehabilitation for the prevention of functional deterioration in patients with complex and/or severe chronic diseases. Given this evidence of effectiveness, rehabilitation should be regarded as an essential part of the continuum of care. Nonetheless, rehabilitation still is underdeveloped and underused. Efforts should be devoted to foster healthcare professional awareness of the benefits of rehabilitation and to increase referral and participation., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

In the present paper, the biological effects of three different naphthalene diimides (NDIs) G-quadruplex (G4) ligands (H-NDI-Tyr, H-NDI-NMe2, and tetra-NDI-NMe2) were comparatively evaluated to those exerted by RHPS4, a well-characterized telomeric G4-ligand, in an in vitro model of glioblastoma. Data indicated that NDIs were very effective in blocking cell proliferation at nanomolar concentrations, although displaying a lower specificity for telomere targeting compared to RHPS4. In addition, differently from RHPS4, NDIs failed to enhance the effect of ionizing radiation, thus suggesting that additional targets other than telomeres could be involved in the strong NDI-mediated anti-proliferative effects. In order to test telomeric off-target action of NDIs, a panel of genes involved in tumor progression, DNA repair, telomere maintenance, and cell-cycle regulation were evaluated at transcriptional and translational level. Specifically, the compounds were able to cause a marked reduction of TERT and BCL2 amounts as well as to favor the accumulation of proteins involved in cell cycle control. A detailed cytofluorimetric analysis of cell cycle progression by means of bromodeoxyuridine (BrdU) incorporation and staining of phospho-histone H3 indicated that NDIs greatly reduce the progression through S-phase and lead to G1 accumulation of BrdU-positive cells. Taken together, these data indicated that, besides effects on telomeres and oncogenes such as Tert and Bcl2, nanomolar concentrations of NDIs determined a sustained block of cell proliferation by slowing down cell cycle progression during S-phase. In conclusion, our data indicate that NDIs G4-ligands are powerful antiproliferative agents, which act through mechanisms that ultimately lead to altered cell-cycle control., (© 2018 Federation of European Biochemical Societies.)

Whether to resume antithrombotic treatment after oral anticoagulant-related intracerebral haemorrhage (OAC-ICH) is debatable. In this study, we aimed at investigating long-term outcome associated with OAC resumption after warfarin-related ICH, in comparison with secondary prevention strategies with platelet inhibitors or antithrombotic discontinuation. Participants were patients who sustained an incident ICH during warfarin treatment (2002-2014) included in the Multicenter Study on Cerebral Hemorrhage in Italy. Primary end-point was a composite of ischemic stroke/systemic embolism (SE) and all-cause mortality. Secondary end-points were ischemic stroke/SE, all-cause mortality and major recurrent bleeding. We computed individual propensity score (PS) as the probability that a patient resumes OACs or other agents given his pre-treatment variables, and performed Cox multivariable analysis using Inverse Probability of Treatment Weighting (IPTW) procedure. A total of 244 patients qualified for the analysis. Unlike antiplatelet agents, OAC resumption was associated with a lower rate of the primary end-point (weighted hazard ratio [HR], 0.21; 95% confidence interval [CI], 0.09-0.45), as well as of overall mortality (weighted HR, 0.17; 95% CI, 0.06-0.45) and ischemic stroke/SE (weighted HR, 0.19; 95% CI, 0.06-0.60) with no significant increase of major bleeding in comparison with patients receiving no antithrombotics. In the subgroup of patients with atrial fibrillation, OACs resumption was also associated with a reduction of the primary end-point (weighted HR, 0.22; 95% CI, 0.09-0.54), and the secondary end-point ischemic stroke/SE (weighted HR, 0.09; 95% CI, 0.02-0.40). In conclusion, in patients who have an ICH while receiving warfarin, resuming anticoagulation results in a favorable trade-off between bleeding susceptibility and thromboembolic risk., Competing Interests: None declared., (Schattauer GmbH Stuttgart.)

The authors present an implant prosthesis procedure that uses screws on one-piece implants connected with a titanium pin at their abutment level and one supporter titanium bar in order to guarantee immediate stabilization. These can be implanted and fitted with customized temporary crowns in a single surgical procedure, restoring function and aesthetics and consenting recovery of the bone deficit with reduced healing times and limited patient discomfort. One-piece wide-diameter titanium screw implants with thread measurements of 2.1 and 2.6 mm (smaller diameter) up to diameter of 4.5 mm with one abutment of 2.0 and 2.5 mm respectively, were positioned and splinted by intraoral welding. One-piece titanium implants were used together with a pin (needle) titanium implant as supporting structure to achieve deep stabilization. The Scialom-like pin has a diameter of 1.2 mm and it is long enough to reach deep cortical bone that is “bicorticalism”. The One-piece implant is tightly connected to the needle implant by means of Mondani intra-oral welding technique. In severely atrophic anterior maxilla, the use of this method allows the immediate loading of a fixed resin prosthesis soon after surgery. These implants yielded satisfactory functional and aesthetic outcome in bone-deficient upper anterior sectors, without invasive regenerative procedures. The low invasiveness of this approach also consents rapid healing, reduced biological burden and greater patient benefit.

Objective: We performed propensity score (PS) models to compare the outcome of patients with myasthenia gravis (MG) submitted to 2 different surgical approaches: extended transsternal (T-3b) or thoracoscopic extended thymectomy (VATET)., Methods: Patients' clinical data were retrieved from the MG database of the C. Besta Neurologic Institute Foundation. In the PS analysis, a matching ratio of 1:1 of the main clinical variables was obtained for the 2 groups of patients and treatment effect was estimated by comparing their outcome., Results: A total of 210 patients met the inclusion criteria, by having a complete set of clinical data, and were included in the PS model; a matched dataset of 122 participants (61 per group) showed an adequate balance of all the covariates. Our analysis demonstrated that 68.9% of patients who had thymectomy by the VATET technique reached the pharmacologic remission/remission status at 2 years from thymectomy compared to 34.4% of those operated on by the T-3b technique ( p < 0.001), had a lower INCB-MG score ( p < 0.001), and had less muscle fatigability ( p = 0.004). Similar results were found considering only nonthymomatous patients with MG. Results were also confirmed by paired statistical tests., Conclusions: Our PS matching analysis showed that VATET is a reliable and effective surgical approach alternative to T-3b in patients with MG who are candidates for thymectomy., Classification of Evidence: This study provides Class IV evidence that for patients with MG, VATET is more effective than T-3b thymectomy., (© 2017 American Academy of Neurology.)

Human nutrition encompasses an extremely broad range of medical, social, commercial, and ethical domains and thus represents a wide, interdisciplinary scientific and cultural discipline. The high prevalence of both disease-related malnutrition and overweight/obesity represents an important risk factor for disease burden and mortality worldwide. It is the opinion of Federation of the Italian Nutrition Societies (FeSIN) that these two sides of the same coin, with their sociocultural background, are related to a low "nutritional culture" secondary, at least in part, to an insufficient academic training for health-care professionals (HCPs). Therefore, FeSIN created a study group, composed of delegates of all the federated societies and representing the different HCPs involved in human nutrition, with the aim of identifying and defining the domains of human nutrition in the attempt to more clearly define the cultural identity of human nutrition in an academically and professionally oriented perspective and to report the conclusions in a position paper. Three main domains of human nutrition, namely, basic nutrition, applied nutrition, and clinical nutrition, were identified. FeSIN has examined the areas of knowledge pertinent to human nutrition. Thirty-two items were identified, attributed to one or more of the three domains and ranked considering their diverse importance for academic training in the different domains of human nutrition. Finally, the study group proposed the attribution of the different areas of knowledge to the degree courses where training in human nutrition is deemed necessary (e.g., schools of medicine, biology, nursing, etc.). It is conceivable that, in the near future, a better integration of the professionals involved in the field of human nutrition will eventually occur based on the progressive consolidation of knowledge, competence, and skills in the different areas and domains of this discipline.

Infant acute leukemia still has a poor prognosis, and allogeneic hematopoietic stem cell transplantation is indicated in selected patients. Umbilical cord blood (UCB) is an attractive cell source for this population because of the low risk of chronic graft-versus-host disease (GVHD), the strong graft-versus-leukemia effect, and prompt donor availability. This retrospective, registry-based study reported UCB transplantation (UCBT) outcomes in 252 children with acute lymphoblastic leukemia (ALL; n = 157) or acute myelogenous leukemia (AML; n = 95) diagnosed before 1 year of age who received a single-unit UCBT after myeloablative conditioning between 1996 and 2012 in European Society for Blood and Marrow Transplantation centers. Median age at UCBT was 1.1 years, and median follow-up was 42 months. Most patients (57%) received a graft with 1 HLA disparity and were transplanted in first complete remission (CR; 55%). Cumulative incidence function (CIF) of day 100 acute GVHD (grades II to IV) was 40% ± 3% and of 4-year chronic GVHD was 13% ± 2%. CIF of 1-year transplant-related mortality was 23% ± 3% and of 4-year relapse was 27% ± 3%. Leukemia-free-survival (LFS) at 4 years was 50% ± 3%; it was 40% and 66% for those transplanted for ALL and AML, respectively (P = .001). LFS was better for patients transplanted in first CR, regardless of diagnosis. In multivariate model, diagnosis of ALL (P = .001), advanced disease status at UCBT (<.001), age at diagnosis younger than 3 months (P = .012), and date of transplant before 2004 were independently associated with worse LFS. UCBT is a suitable option for patients diagnosed with infant acute leukemia who achieve CR. In this cohort, patients with AML had better survival than those with ALL., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for most children with osteopetrosis (OP). Timing of HSCT is critical; therefore, umbilical cord blood transplantation (UCBT) is an attractive option. We analyzed outcomes after UCBT in 51 OP children. Median age at UCBT was 6 months. Seventy-seven percent of the cord blood grafts had 0 or 1 HLA disparity with the recipient. Conditioning regimen was myeloablative (mostly busulfan-based in 84% and treosulfan-based in 10%). Antithymocyte globulin was given to 90% of patients. Median number of total nucleated and CD34 + cells infused was 14 × 10 7 /kg and 3.4 × 10 5 /kg, respectively. Median follow-up for survivors was 74 months. Cumulative incidence (CI) of neutrophil recovery was 67% with a median time to recovery of 23 days; 33% of patients had graft failure, 81% of engrafted patients had full donor engraftment, and 19% had mixed donor chimerism. Day 100 CI of acute graft-versus-host disease (grades II to IV) was 31% and 6-year CI of chronic graft-versus-host disease was 21%. Mechanical ventilation was required in 28%, and veno-occlusive disease was diagnosed in 16% of cases. Six-year overall survival rate was 46%. Comparative studies with other alternative donors should be performed to evaluate whether UCBT remains a valid alternative for children with OP without an HLA-matched donor., (Copyright © 2016 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Vertigo and dizziness are common symptoms in the general population, with an estimated prevalence between 20% and 56%. The aim of our work was to assess the point prevalence of these symptoms in a population of 2672 subjects. Patients were asked to answer a questionnaire; in the first part they were asked about demographic data and previous vertigo and or dizziness. Mean age of the sample was 48.3 ± 15 years, and 46.7% were males. A total of 1077 (40.3%) subjects referred vertigo/dizziness during their lifetime, and the mean age of the first vertigo attack was 39.2 ± 15.4 years; in the second part they were asked about the characteristics of vertigo (age of first episode, rotational vertigo, relapsing episodes, positional exacerbation, presence of cochlear symptoms) and lifetime presence of moderate to severe headache and its clinical features (hemicranial, pulsatile, associated with phono and photophobia, worse on effort). An age and sex effect was demonstrated, with symptoms 4.4 times more elevated in females and 1.8 times in people over 50 years. In the total sample of 2672 responders, 13.7% referred a sensation of spinning, 26.3% relapsing episodes, 12.9% positional exacerbation and 4.8% cochlear symptoms; 34.8% referred headache during their lifetime. Subjects suffering from headache presented an increased rate of relapsing episodes, positional exacerbation, cochlear symptoms and a lower age of occurrence of the first vertigo/dizziness episode. In the discussion, our data are compared with those of previous studies, and we underline the relationship between vertigo/dizziness from one side and headache with migrainous features on the other., (© Copyright by Società Italiana di Otorinolaringologia e Chirurgia Cervico-Facciale, Rome, Italy.)

Background: The hypopharynx is the site with the worst prognosis among head and neck squamous cell carcinomas (SCCs). The purpose of this study was to evaluate the oncologic outcomes of hypopharyngeal SCCs to identify the major clinical predictive factors and to compare the different primary therapeutic modalities., Methods: The medical records of 123 consecutive patients diagnosed with primary resectable hypopharyngeal SCC were reviewed. The correlations of oncologic endpoints with tumor parameters and primary treatment were evaluated., Results: The overall survival (OS) rate was 76% and the disease-specific survival (DSS) rate was 80% at 3 years in the entire group. Sex and T and N classifications significantly influenced survival in both univariate and multivariate analyses. Seventy-four percent of our patients underwent both surgery and radiotherapy (RT), and the temporal sequence of the 2 modalities did not affect prognosis., Conclusion: The primary treatment modality in patients with resectable hypopharyngeal SCC did not affect prognosis in univariate and multivariate analyses for any stage considered., (© 2015 Wiley Periodicals, Inc.)

We analyzed the impact of human cytomegalovirus infection on the development of natural killer cells in 27 pediatric patients affected by hematological malignancies, who had received a HLA-haploidentical hematopoietic stem cell transplantation, depleted of both α/β+ T cells and B cells. In line with previous studies in adult recipients of umbilical cord blood transplantation, we found that human cytomegalovirus reactivation accelerated the emergence of mature natural killer cells. Thus, most children displayed a progressive expansion of a memory-like natural killer cell subset expressing NKG2C, a putative receptor for human cytomegalovirus, and CD57, a marker of terminal natural killer cell differentiation. NKG2C(+)CD57(+) natural killer cells were detectable by month 3 following hematopoietic stem cell transplantation and expanded until at least month 12. These cells were characterized by high killer Ig-like receptors (KIRs) and leukocyte inhibitory receptor 1 (LIR-1) and low Siglec-7, NKG2A and Interleukin-18Rα expression, killed tumor targets and responded to cells expressing HLA-E (a NKG2C ligand). In addition, they were poor Interferon-γ producers in response to Interleukin-12 and Interleukin-18. The impaired response to these cytokines, together with their highly differentiated profile, may reflect their skewing toward an adaptive condition specialized in controlling human cytomegalovirus. In conclusion, in pediatric patients receiving a type of allograft different from umbilical cord blood transplantation, human cytomegalovirus also induced memory-like natural killer cells, possibly contributing to controlling infections and reinforcing anti-leukemia effects., (Copyright© Ferrata Storti Foundation.)

Clinical trials aimed at improving results of hematopoietic cell transplantation (HCT) by adjuvant cell-based interventions in children have been limited by small numbers and pediatric-specific features. The need for a larger number of pediatric HCT centers to participate in trials has resulted in a demand for harmonization of disease-specific clinical trials and immune-monitoring. Thus far, most phase I/II trials select different end points evaluated at disparate time points, making inter-study comparisons difficult and, sometimes, impossible. In this review, we discuss the various aspects that are important to consider for harmonizing clinical trial design as well as the critical elements for standardized (immune)-monitoring protocols in cell-based intervention trials in the context of HCT. Comparison data from trials applying harmonized trial design will lead to optimized immunotherapeutic treatment protocols to maximize clinical efficacy while minimizing toxicity., (Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Among taphonomical modifications during decomposition processes, little is known about the action of high or low pH to human tissues and bones. Moreover, acid or basic solutions are seldom used to ease decomposition and wrecking of the body. In this study a total of 60 samples of porcine bones on which two cut marks were produced before the beginning of the experiment, were put in six different solutions with different pH (1, 3, 5, 9, 12, 14) and analyzed every five days over a period of 70 days. Surveys were carried out macroscopically, with stereomicroscopy and with light microscopy on thin sections. Only the specimens exposed to extremely acid (<1) or basic (>12) pH showed evident modifications of the bone's structure, as witnessed by the analyses with stereomicroscopy as well. Many samples showed a detachment of the periosteum; cut marks became soon unrecognizable with pH 14 but still detectable in all the other samples. The information gained from the present study can be of great help in detecting the exposure of human tissues to high or low environmental pH and in understanding the effects that these solutions can exert on human bones., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Introduction: The green areas play an important role in improving the environmental quality and climate of the city. However, despite the undoubted importance of these areas, the benefits to public health are still under investigation., Results: The Authors perform a review of studies on the relationship between health and green areas and describe the main areas for which evidence on this relationship is currently available. They include: effects on air quality, on social cohesion, on mental health, with particular reference to the stress, and on physical activity., Conclusions: Most of the evidence comes from cross-sectional and descriptive studies and the approaches used to measure the association show themselves to be often unsatisfactory. The Authors conclude the review stressing the need for greater integration between the different professionals involved in urban planning and in health care analysis in order to identify research approaches more appropriate to understand such complex issues, striving toward a planning design of green areas that will satisfy both environmental sustainability and health requirements.

Study Design: Marjolin's ulcer is a squamous cell carcinoma that develops in posttraumatic scars and chronic wounds. Suspicion of such lesions should be raised in chronic wounds demonstrating characteristic changes. We have reported the peculiar phenomenon of malignant transformation of chronic pressure sores that occurred in a paraplegic patient., Objectives: The aim of this study was to cover the extensive defects by a last resort reconstructive option., Setting: Department of Plastic and Reconstructive Surgery, Università Politecnica delle Marche, Ancona, Italy., Methods and Results: A 40-year-old paraplegic man, with multiple hemangioblastomas of the brain and spinal cord due to Von Hippel Lindau syndrome developed pressure ulcers with unstable healing over the sacral, trochanteric, bilateral, and ischiatic areas after 15 years from neurosurgery. The biopsy result showed an invasive squamous carcinoma. Carcinomas in pressure sores are highly aggressive, and they need to be treated more radically. In our case we opted for a demolitive surgical treatment including musculocutaneous rotational flap harvested from total left thigh to cover the extensive defects. The limb was previously disarticulated., Conclusion: In Marjolin's ulcer, multiple biopsies are the first-line modality for the early diagnosis as they are a safe method with high rate of accuracy. First-line treatment is surgery consisting of radical excision with lymph node dissection, if they are involved. Adjuvant radiation therapy may be used in selected patients. Management of massive pelvic defects can be a challenging problem. The pedicled lower limb flap offers a technique that can be considered as a last resort procedure for extensive defects where other options are insufficient or not available anymore. In our case the patient is disease-free after 2 years of follow-up.

The production of jets associated to bottom quarks is measured for the first time in PbPb collisions at a center-of-mass energy of 2.76 TeV per nucleon pair. Jet spectra are reported in the transverse momentum (p(T)) range of 80-250  GeV/c, and within pseudorapidity |η|<2. The nuclear modification factor (R(AA)) calculated from these spectra shows a strong suppression in the b-jet yield in PbPb collisions relative to the yield observed in pp collisions at the same energy. The suppression persists to the largest values of p(T) studied, and is centrality dependent. The R(AA) is about 0.4 in the most central events, similar to previous observations for inclusive jets. This implies that jet quenching does not have a strong dependence on parton mass and flavor in the jet p(T) range studied.

Background Aims: Celiac disease is caused by a dysregulated immune response toward dietary gluten, whose only treatment is a lifelong gluten-free diet. We investigated the effects of mesenchymal stromal cells (MSCs) on gliadin-specific T cells, which are known to induce intestinal lesions, in view of a possible use as new therapy., Methods: Bone marrow-derived MSCs and gliadin-specific T-cell lines were obtained from allogeneic donors and mucosal specimens of celiac patients, respectively. The immunosuppressant effect of MSCs was evaluated in terms of proliferative response and interferon (IFN)-γ production upon gliadin stimulation of long-term T-cell lines; the immunomodulant effect was assessed in terms of apoptotic rate, immunophenotype and cytokine profile of short-term T-cell lines generated in the presence of MSCs. Different MSC:T-cell ratios were applied, and statistics were performed as appropriate., Results: MSCs inhibited both proliferative response and IFN-γ production of long-term T-cell lines in a dose-dependent manner while limiting the expansion of short-term T-cell lines by increasing the apoptotic rate. Moreover, a reduction of the CD4(+) population and expansion of the regulatory FoxP3+ subset were found in T-cell lines cultured with MSCs, in which a significant decrease of interleukin (IL)-21, IFN-γ and IL-10 paralleled by an upregulation of transforming growth factor-β1, IL-6 and IL-8 were observed. Finally, an increase of the indoleamine 2,3-dioxygenase activity was found, possibly playing a key role in mediating these effects., Conclusions: MSCs exert potent immunomodulant effects on gliadin-specific T cells, which may be exploited for future therapeutic application in celiac disease., (Copyright © 2014 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Objective: To assess the efficacy, safety and tolerability of sodium valproate (800mg/die) compared with placebo in medication-overuse headache patients with a history of migraine without aura., Methods: This is a multicenter, randomized, double-blind, placebo-controlled study enrolled medication-overuse headache patients for a 3-month treatment period with sodium valproate (800mg/day) or placebo after a 6 day outpatient detoxification regimen, followed by a 3-month follow-up. Primary outcome was defined by the proportion of patients achieving ≥50% reduction in the number of days with headache per month (responders) from the baseline to the last 4 weeks of the 3-month treatment. Multivariate logistic regression models were used on the primary endpoint, adjusting for age, sex, disease duration, comorbidity and surgery. The last-observation-carried-forward method was used to adjust for missing values., Results: Nine sites enrolled 130 patients and, after a 6-day detoxification phase, randomized 88 eligible patients. The 3-month responder rate was higher in the sodium valproate (45.0%) than in the placebo arm (23.8%) with an absolute difference of about 20% (p=0.0431). Sodium valproate had safety and tolerability profiles comparable to placebo., Conclusions: The present study supports the efficacy and safety of sodium valproate in the treatment of medication overuse headache with history of migraine after detoxification., (Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.)

The 2011 collaborative exercise of the ISFG Italian Working Group GeFI was aimed at validating the five ENFSI/EDNAP miniSTR loci D1S1656, D2S441, D10S1248, D12S391 and D22S1045. The protocol required to type at least 50 multilocus profiles from locally resident individuals and two blind bloodstains in duplicate (i.e., using at least two different commercial kits), and to send the electropherograms to the Organizing Committee. Nineteen laboratories distributed across Italy participated, collecting a total of 960 samples. Full concordance was found for the five new miniSTRs as observed from the comparison of 13,150 alleles. The inspection of the electropherograms allowed the identification of a very limited number of mistypings in the miniSTR genotypes thus contributing to the establishment of an high quality Italian database of frequencies., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)