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Abstract During the COVID-19 outbreak, the European Reference Network on Rare Bone Diseases (ERN BOND) coordination team and Italian rare bone diseases healthcare professionals created the “COVID-19 Helpline for Rare Bone Diseases” in an attempt to provide high-quality information and expertise on rare bone diseases remotely to patients and healthcare professionals. The present position statement describes the key characteristics of the Helpline initiative, along with the main aspects and topics that recurrently emerged as central for rare bone diseases patients and professionals. The main topics highlighted are general recommendations, pulmonary complications, drug treatment, trauma, pregnancy, children and elderly people, and patient associations role. The successful experience of the “COVID-19 Helpline for Rare Bone Diseases” launched in Italy could serve as a primer of gold-standard remote care for rare bone diseases for the other European countries and globally. Furthermore, similar COVID-19 helplines could be considered and applied for other rare diseases in order to implement remote patients’ care.

Abstract Introduction The objective of this study was to evaluate treatment patterns in patients with rheumatoid arthritis (RA), with a focus on the utilization of baricitinib, an oral highly selective Janus kinase 1 and 2 inhibitor, in an Italian real-world setting. Methods This observational retrospective analysis was based on data collected in selected Italian administrative databases. Patients aged ≥ 18 years with a diagnosis of RA defined by hospitalization discharge diagnosis (International Classification of Diseases, Ninth Revision, Clinical Modification code 714.0) or by disease exemption code 006 for RA in 2018 were included. The index date (ID) was defined as the date of first prescription for a drug indicated for RA during the inclusion period. Patients without a prescription for biologic/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) before the ID were considered to be b/tsDMARD naïve. A further analysis was performed on patients only receiving baricitinib. Results A total of 41,290 RA patients were enrolled, of whom 55.6% were not treated with conventional synthetic DMARDs (csDMARDs) or b/tsDMARDs, 39.4% were receiving therapy with csDMARDs, and 5.0% were using b/tsDMARDs. In the latter group, 2.7% (n = 56) were receiving therapy with baricitinib. In 2018, 13.2% of csDMARD-treated patients switched to b/tsDMARDs, of whom 4.3% (n = 93) of these switched to baricitinib. In total, 149 patients (mean age ± standard deviation 57.6 ± 12.1; 12.8% male) had a baricitinib prescription, of whom 51% were b/tsDMARD naïve. At baseline, 61.7% of baricitinib users were receiving combination therapy with csDMARDs plus corticosteroids, 26.2% were receiving combination therapy with corticosteroids, and 8.1% were receiving combination therapy with csDMARDs; 4% were receiving baricitinib monotherapy. During follow-up, the proportion of patients receiving baricitinib monotherapy increased to 38.9%, while 26.9, 18.8, and 15.4% of baricitinib users received combination therapy with corticosteroids, csDMARDs plus corticosteroids, and csDMARDs, respectively. Conclusion This study provides a current view of the treatment patterns in Italian patients with RA in a real-world setting of daily clinical practice, with a focus on baricitinib utilization.

Valentina Perrone,1 Elisa Giacomini,1 Diego Sangiorgi,1 Margherita Andretta,2 Anna Michela Menti,2 Mariantonietta Naclerio,3 Daniela Ritrovato,3 Luca Degli Esposti1 1CliCon S.r.l. Health, Economics & Outcomes Research, Ravenna, Italy; 2Health Technology Assessment Unit, Azienda Zero, Padova, Italy; 3Novartis Farma Italy, Origgio, VA, ItalyCorrespondence: Valentina PerroneClicon Srl, Health, Economics and Outcomes Research, Via Salara, 36, 48100, Ravenna, ItalyTel +39 544 38393Fax +39 544 212699Email valentina.perrone@clicon.itPurpose: To analyze the treatment patterns of psoriatic arthritis (PSA) or ankylosing spondylitis (AS) patients under biological therapies and to evaluate in this population the health-care resource consumption and related costs.Patients and Methods: A retrospective analysis was performed on administrative databases of the Veneto region. Patients ≥ 18 years with at least one prescription of biological drugs and a diagnosis at any level for PSA or AS from January 1, 2011 to December 31, 2016 (inclusion period) were included. Index date (ID) was defined as date of first biological drug prescription during inclusion period. Patients were characterized the year before ID and followed-up for one year after ID. The drug utilization profile in terms of adherence, persistence and therapeutic regimen changes, and the health-care resource consumption was analyzed during follow-up.Results: A total of 2602 patients were included: 1857 with PSA and 745 with AS. In the PSA cohort, 40.3% of patients were prescribed adalimumab, 35.6% etanercept, 8.0% golimumab, 7.5% infliximab, 5.6% ustekinumab and 3.0% certolizumab. Percentage of PSA patients adherent to treatment was higher among ustekinumab patients (91.3%) and lower among etanercept users (54.3%). Persistence ranged from 53.2% (infliximab) to 70.3% (etanercept). Regarding AS cohort, 45.5% of patients were prescribed adalimumab, 26% etanercept, 17.3% infliximab, 9.7% golimumab and 1.5% certolizumab. Adherence ranged from 46.9% (etanercept) to 90.9% (certolizumab) and persistence from 62.8% (adalimumab) to 81.8% (certolizumab). Mean annual health-care costs (including costs for drug treatment, diagnostic services, specialist visits and hospital admissions) ranged from € 9727 (certolizumab) to € 14,994 (ustekinumab) among PSA patients and from € 9875 (infliximab) to € 12,991 (golimumab) among AS patients.Conclusion: This study in Veneto region gave a picture of biological treatment patterns among PSA and AS patients in a real-world setting. Our findings showed the high degree of variability concerning utilization of each biological drug and provided insight on the economic burden of both diseases.Keywords: psoriatic arthritis, ankylosing spondylitis, biologic drugs, drug utilization, real-world

Carlotta Lunghi,1– 3 Ippazio Cosimo Antonazzo,2 Sofia Burato,2 Emanuel Raschi,2 Violetta Zoffoli,2 Emanuele Forcesi,2 Elisa Sangiorgi,4 Marco Menchetti,5 Pasquale Roberge,3,6 Elisabetta Poluzzi2 1Department of Health Sciences, Université Du Québec À Rimouski, Lévis, Québec, Canada; 2Department of Medical and Surgical Sciences, Pharmacology Unit, Alma Mater Studiorum, University of Bologna, Bologna, Italy; 3Groupe De Recherche PRIMUS, Centre De Recherche Du CHUS, Université De Sherbrooke, Sherbrooke, Canada; 4Drug Policy Service, Emilia Romagna Region Health Authority, Bologna, Italy; 5Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy; 6Faculty of Medicine and Health Sciences, Université De Sherbrooke, Sherbrooke, Québec, CanadaCorrespondence: Carlotta LunghiDepartment of Health Sciences, Université Du Québec À Rimouski, 1595 Boulevard Alphonse Desjardins, Lévis, Québec G6V 0A6, CanadaTel +1 418-833-8800 Ext. 3275Email Carlotta_Lunghi@uqar.caPurpose: Antidepressant consumption has risen in recent years, driven by longer treatment duration. The objective of this study was to measure the prevalence of antidepressant long-term and chronic use in the Bologna area, Italy, and to identify their main determinants.Materials and Methods: We conducted a retrospective claims-based cohort study by using the Bologna Local Health Authority data. A cohort of 18,307 incident users of antidepressant drugs in 2013 was selected, and subjects were followed for three years. A long-term utilization was defined as having at least one prescription claimed during each year of follow-up, while chronic utilization was defined as claiming at least 180 defined daily doses per year. Factors associated with chronic and long-term use were identified by univariate and multivariate logistic regressions.Results: In our cohort, 5448 (29.8%) and 1817 (9.9%) subjects were dispensed antidepressants for a long-term course and in a chronically way, respectively. Older age, antidepressant polytherapy, polypharmacy, and being prescribed the first antidepressant by a hospital physician were all factors independently associated with chronic and long-term prescriptions of antidepressant drugs. Results were reported separately for men and women.Conclusion: Antidepressant long-term and chronic prescriptions are common in the Bologna area. Because longer treatment should be clinically motivated, these results strongly prompt the need to evaluate the actual relevance, as they may indicate potentially inappropriate prescription patterns.Keywords: antidepressants, depression, anxiety, anxiety disorders, primary care, pharmacotherapy, adherence, epidemiology, pharmacoepidemiology, treatment

During the early phase of an accident with the release of radioactive material to the environment at the local or transboundary scale, a rapid and continuous system of information exchange, including real-time monitoring data to competent authorities and the public, is critical for setting up countermeasures. This information and data exchange must be carried out in a harmonized and consistent manner to facilitate its interpretation and analysis. After the Chernobyl accident in 1986, and in order to avoid the competent authorities being unprepared again for a similar event, the European Commission (EC) defined and put in place a directive (Council Decision 87/600/EURATOM, 1987) which essentially obliges a member state that decides to implement widespread countermeasures to protect its population to notify the European Commission without delay. The same Council Decision also specifies that the results of radiological monitoring must be made available to the European Commission and all potentially affected member states. Over the past 30 years, the European Commission has invested resources in developing and improving a complete system to carry out this delicate task, currently composed of two platforms: the European Community Urgent Radiological Information Exchange (ECURIE) and the European Radiological Data Exchange Platform (EURDEP). This paper aims to increase knowledge of the latter system as a valuable tool for understanding and analysing the radioactivity levels in Europe. Commencing with background information, in this paper, we will describe the EURDEP system in detail, with an emphasis on its status, data availability, and how these data are diffused depending on the audience. Within the scope of this publication, we describe an example of measurements available in the EURDEP system, which to be used for scientific purposes. We provide two complete datasets (air-concentration samples – https://doi.org/10.2905/23CBC7C4-4FCC-47D5-A286-F8A4EDC8215F; De Cort et al., 2019a; and gamma dose rates – https://doi.org/10.2905/0F9F3E2D-C8D7-4F46-BBE7-EACF3EED1560; De Cort et al., 2019b) for the recent radiological release of 106Ru in Europe, which occurred between the end of September and early October 2017. Records stored are publicly accessible through an unrestricted repository called COLLECTION belonging to the JRC Data Public Catalogue (https://data.jrc.ec.europa.eu, last access: 1 July 2019).

High photocatalytic performances of inkjet printed patterns has been achieved by a green formulation of water-based suspension including commercial TiO2 nanoparticles (NPs). The reaction rate constant (k > 3.79 × 10−3min−1cm-2) of the manufactured patterns presented competitive photoresponses in comparison with others complex formulations based on sol-gel process. Optimized conditions of the colloidal dispersion and stabilization of TiO 2 NPs using diethylene glycol as cosolvent, allowed a constant and homogeneous jetting flow, fitting the surface tension and viscosity values suitable for the piezo-driven technology selected. The nanostructure-based pattern printed with micro-resolution achieved the 90% methyl orange degradation after 9h of light exposition and the 100% after 13h in a stirred tank reactor. Moreover, the reusability of printed patterns has been also proved since they preserve their photocatalytic activity and microstructure after sequential tests.This new finding is expected to be particularly useful to industrial fabrication of microdesign and immobilized patters onto different substrates-types.

Rare diseases (RDs) are complicated health conditions that are difficult to be managed at several levels. The scarcity of available data chiefly determines an intricate scenario even for experts and specialized clinicians, which in turn leads to the so called “diagnostic odyssey” for the patient. This situation calls for innovative solutions to support the decision process via quantitative and automated tools. Machine learning brings to the stage a wealth of powerful inference methods; however, matching the health conditions with advanced statistical techniques raises methodological, technological, and even ethical issues. In this contribution, we critically point to the specificities of the dialog of rare diseases with machine learning techniques concentrating on the key steps and challenges that may hamper or create actionable knowledge and value for the patient together with some on-field methodological suggestions and considerations.

The role of antibiotics as adjunctive therapy in the non-surgical treatment of peri-implantitis is uncertain. The aim of this systematic review of randomized controlled trials was to assess the efficacy of antibiotic therapy, local or systemic, as an adjunctive to the non-surgical therapy of peri-implantitis. Primary outcomes were: implant success rate and complications, changes in radiographic bone level, probing pocket depth (PPD), probing attachment level (PAL), bleeding on probing (BOP) and peri-implantitis resolution. Six studies were included: two using topical and four systemic antibiotics. Adjunctive local antibiotics improved PPD (mean difference (MD) = 0.6 mm; 95% CI 0.42–0.78), BOP (MD = 0.15% (95% CI 0.10, 0.19)) and the success rate (risk ratio = 9.89; 95% CI 2.39–40.84). No significant difference in bone level and success rate were found with the use of systemic antibiotics, although they appeared to improve PPD (MD = 1.15 mm; 95% CI 0.31–1.99) and PAL (MD = 1.10 mm; 95% CI 0.13–2.08). Within the limitations of this review, the adjunctive local antibiotics showed improved outcomes in terms of success rate, PPD and BOP, while adjunctive systemic antibiotics improved PPD and PAL only. Peri-implantitis resolution was about 20–30% using adjunctive local antibiotics, whilst it ranged from 2% to 65% with adjunctive systemic antibiotics. Findings are still controversial, since they are based on few studies with high heterogeneity, at the uncertain or high risk of bias and involve few patients. Non-surgical debridement and maintenance periodontal support therapy remain pivotal and the adjunctive use of antibiotics for peri-implantitis cannot be routinely recommended, even considering the increasing concern on antibiotic resistance.

Osteopetrosis (from the Greek “osteo”: bone; “petrosis”: stone) is a clinically and genetically heterogeneous group of rare diseases of the skeleton, sharing the same main characteristic of an abnormally increased bone density. Dense bones in radiological studies are considered the hallmark of these diseases, and the reason for the common term used: “Marble bone disease”. Interestingly, a radiologist, Dr. Albers-Schonberg, described this disease for the first time in Germany in 1904. Indeed, radiology has a key role in the clinical diagnosis of osteopetrosis and is fundamental in assessing the disease severity and complications, as well as in follow-up controls and the evaluation of the response to treatment. Osteopetrosis includes a broad spectrum of genetic mutations with very different clinical symptoms, age onset, and prognosis (from mild to severe). This diversity translates into different imaging patterns related to specific mutations, and different disease severity. The main recognized types of osteopetrosis are the infantile malignant forms with autosomal recessive transmission (ARO—including the rarer X-linked recessive form); the intermediate autosomal recessive form (IAO); and the autosomal dominant ones ADO, type I, and type II, the latter being called ‘Albers-Schonberg’ disease. Imaging features may change among those distinct types with different patterns, severities, skeletal segment involvement, and speeds of progression. There are several classical and well-recognized radiological features related to osteopetrosis: increased bone density (all types with different degrees of severity assuming a ‘Marble Bone Appearance’ especially in the ARO type), different metaphyseal alterations/enlargement including the so-called ‘Erlenmeyer flask deformity’ (particularly of femoral bones, more frequent in ADO type 2, and less frequent in ARO and IAO), ‘bone in bone’ appearance (more frequent in ADO type 2, less frequent in ARO and IAO), and ‘rugger-jersey spine’ appearance (typical of ADO type 2). After conducting an overview of the epidemiological and clinical characteristic of the disease, this review article aims at summarizing the main radiological features found in different forms of osteopetrosis together with their inheritance pattern.

The current paper discusses the most recent advancements in automated vehicle (AV) certification and how existing regulations/best practices from the nuclear field helped make AVs a reality. In particular, three main pillars differentiate the newly devised certification frameworks from previous automotive regulations: the introduction of a safety management system, the adoption of in-service monitoring and reporting data logging systems, and the use of virtual testing to demonstrate the safety of the AV; a set of pillars that are also found in the nuclear practice. The argumentation is informed by relevant literature and shared experiences from the nuclear power plant and transportation fields where there are established safety practices to manage safety-critical cyber-physical systems. Although the nuclear and transportation fields might seem unrelated, strong synergies were found, including risk management approaches and operational data collection procedures, which supported the timely drafting of the new regulation for AVs. Nonetheless, some open challenges remain due to peculiar aspects of AVs that will need to be addressed in the near future. Namely, practical methodologies for the residual-risk calculation for the various Operational Design Domains (ODDs), the design of scalable monitoring techniques, and the definition of detailed procedures for the virtual testing tool qualification.

The bisimulation proof method can be enhanced by employing `bisimulations up-to' techniques. A comprehensive theory of such enhancements has been developed for first-order (i.e., CCS-like) labelled transition systems (LTSs) and bisimilarity, based on abstract fixed-point theory and compatible functions. We transport this theory onto languages whose bisimilarity and LTS go beyond those of first-order models. The approach consists in exhibiting fully abstract translations of the more sophisticated LTSs and bisimilarities onto the first-order ones. This allows us to reuse directly the large corpus of up-to techniques that are available on first-order LTSs. The only ingredient that has to be manually supplied is the compatibility of basic up-to techniques that are specific to the new languages. We investigate the method on the pi-calculus, the lambda-calculus, and a (call-by-value) lambda-calculus with references.

Genetic disorders of the skeleton encompass a diverse group of bone diseases differing in clinical characteristics, severity, incidence and molecular etiology. Of particular interest are the monogenic rare bone mass disorders, with the underlying genetic defect contributing to either low or high bone mass phenotype. Extensive, deep phenotyping coupled with high-throughput, cost-effective genotyping is crucial in the characterization and diagnosis of affected individuals. Massive parallel sequencing efforts have been instrumental in the discovery of novel causal genes that merit functional validation using in vitro and ex vivo cell-based techniques, and in vivo models, mainly mice and zebrafish. These translational models also serve as an excellent platform for therapeutic discovery, bridging the gap between basic science research and the clinic. Altogether, genetic studies of monogenic rare bone mass disorders have broadened our knowledge on molecular signaling pathways coordinating bone development and metabolism, disease inheritance patterns, development of new and improved bone biomarkers, and identification of novel drug targets. In this comprehensive review we describe approaches to further enhance the innovative processes taking discoveries from clinic to bench, and then back to clinic in rare bone mass disorders. We highlight the importance of cross laboratory collaboration to perform functional validation in multiple model systems after identification of a novel disease gene. We describe the monogenic forms of rare low and high rare bone mass disorders known to date, provide a roadmap to unravel the genetic determinants of monogenic rare bone mass disorders using proper phenotyping and genotyping methods, and describe different genetic validation approaches paving the way for future treatments.

Abstract The Dacian Basin was uniquely situated to record late Miocene hydrological changes that influenced depositional environments and faunal dispersal patterns in Central Eurasia's mega‐lake Paratethys. Differences between the high strontium isotope ratio (87Sr/86Sr) of the waters from Lake Pannon and local Carpathian rivers and low 87Sr/86Sr of the Eastern Paratethys (Black Sea ‒ Caspian Sea) allow a thorough investigation of connectivity and water fluxes in the transient Dacian Basin. We present a detailed 87Sr/86Sr record for the Dacian Basin, which provides an exceptional record of basin connectivity from the latest Tortonian (ca. 7.7 Ma) until the early Pleistocene (ca. 1.8 Ma). Data show that a late Tortonian transgression (7.6–7.4 Ma) started with an incursion of Eastern Paratethys waters into the Dacian Basin, after which local rivers became the dominant source for the mostly freshwater environments of the early Messinian. The regional Maeotian‐Pontian transitional interval (6.3–5.9 Ma) records a second incursion of Eastern Paratethys waters, but this time with an additional marine (Mediterranean) influx coinciding with a short‐lived salinity incursion. During the Messinian Salinity Crisis of the Mediterranean, the Dacian Basin progressively connected with the Eastern Paratethys (5.9–5.5 Ma), after which it became restricted during the peak Mediterranean lowstand (5.5 Ma) and filled with Lake Pannon and local river water (5.5–5.3 Ma). During the Plio‐Pleistocene, the Dacian Basin reconnected with the, at that time isolated, Black Sea, which shows similar 87Sr/86Sr as in the Last Glacial Maximum.

Low-density lipoprotein cholesterol (LDL-C) plays a crucial role in the development of atherosclerosis. Statin therapy is the standard treatment for lowering LDL-C in primary and secondary prevention. However, some patients do not reach optimal LDL-C target levels or do not tolerate statins, especially when taking high doses long-term. Combining statins with different therapeutic approaches and testing other new drugs is the future key to reducing the burden of cardiovascular disease (CVD). Recently, several new cholesterol-lowering drugs have been developed and approved; others are promising results, enriching the pharmacological armamentarium beyond statins. Triglycerides also play an important role in the development of CVD; new therapeutic approaches are also very promising for their treatment. Familial hypercholesterolemia (FH) can lead to CVD early in life. These patients respond poorly to conventional therapies. Recently, however, new and promising pharmacological strategies have become available. This narrative review provides an overview of the new drugs for the treatment of dyslipidemia, their current status, ongoing clinical or preclinical trials, and their prospects. We also discuss the new alternative therapies for the treatment of dyslipidemia and their relevance to practice.

Through this structured review of the published literature, we aimed to provide an up-to-date description of strategies (human-related) and tools (mainly from the digital field) facilitating the appropriateness of drug use in older adults. The evidence of each strategy and tool’s effectiveness and sustainability largely derives from local and heterogeneous experiences, with contrasting results. As a general framework, three main steps should be considered in implementing measures to improve appropriateness: prescription, acceptance by the patient, and continuous monitoring of adherence and risk-benefit profile. Each step needs efforts from specific actors (physicians, patients, caregivers, healthcare professionals) and dedicated supporting tools. Moreover, how to support the appropriateness also strictly depends on the particular setting of care (hospital, ambulatory or primary care, nursing home, long-term care) and available economic resources. Therefore, it is urgent assigning to each approach proposed in the literature the following characteristics: level of effectiveness, strength of evidence, setting of implementation, needed resources, and issues for its sustainability.

The aim of this article is to describe a novel approach combining muco-gingival, regenerative and prosthetics concepts for immediate implant insertion that overcomes the limits traditionally considered as contraindications for Type 1 flapless implant positioning, simultaneously obtaining soft- and hard-tissue augmentation. After pre-surgical CBCT evaluation, the surgical technique consisted in the execution of a lateral-approach coronally advanced envelope flap, with oblique submarginal interproximal incisions directed towards the flap’s center of rotation (the tooth to be extracted); after buccal-flap elevation, the atraumatic extraction of the tooth was performed. Following guided implant insertion, a mixture of biomaterial and autologous bone was placed, stabilized by a pericardium membrane and a connective-tissue graft sutured in the inner aspect of the buccal flap. The peri-implant soft tissues were conditioned with a provisional crown until the shape and position for the mucosal scallop to resemble the gingival margin of the adjacent corresponding tooth were obtained; then, the definitive screw-retained restoration was placed. Within the limitations of this case report, the proposed immediate implant placement approach combining CTG application and buccal bone regeneration showed the possibility of obtaining 1-year-follow-up implant success, stable bone level, good esthetic results and high patient satisfaction.

The very first line of defense in humans is innate immunity, serving as a critical strongpoint in the regulation of inflammation. Abnormalities of the innate immunity machinery make up a motley group of rare diseases, named ‘autoinflammatory’, which are caused by mutations in genes involved in different immune pathways. Self-limited inflammatory bouts involving skin, serosal membranes, joints, gut and other districts of the human body burst and recur with variable periodicity in most autoinflammatory diseases (ADs), often leading to secondary amyloidosis as a long-term complication. Dysregulated inflammasome activity, overproduction of interleukin (IL)-1 or other IL-1-related cytokines and delayed shutdown of inflammation are pivotal keys in the majority of ADs. The recent progress of cellular biology has clarified many molecular mechanisms behind monogenic ADs, such as familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome (or ‘autosomal dominant familial periodic fever’), cryopyrin-associated periodic syndrome, mevalonate kinase deficiency, hereditary pyogenic diseases, idiopathic granulomatous diseases and defects of the ubiquitin-proteasome pathway. A long-lasting history of recurrent fevers should require the ruling out of chronic infections and malignancies before considering ADs in children. Little is known about the potential origin of polygenic ADs, in which sterile cytokine-mediated inflammation results from the activation of the innate immunity network, without familial recurrency, such as periodic fever/aphthous stomatitis/pharyngitis/cervical adenopathy (PFAPA) syndrome. The puzzle of febrile attacks recurring over time with chameleonic multi-inflammatory symptoms in children demands the inspection of the mixture of clinical data, inflammation parameters in the different disease phases, assessment of therapeutic efficacy of a handful of drugs such as corticosteroids, colchicine or IL-1 antagonists, and genotype analysis to exclude or confirm a monogenic origin.

Considering the future shortage of natural aggregates, various researchers have promoted the recycling of by-products into various asphalt pavement types. This paper promoted a double-recycling technique, where thermally treated waste silt was used as a filler for the bituminous skeleton and grouting material of a geopolymer-based semiflexible pavement. Semiflexible pavements (SFP) inherit the flexibility of common asphalt pavements and simultaneously benefit from the rigidity of cement concrete pavements. For this purpose, waste silt obtained from a local asphalt plant was thermally treated at 750 °C and was used as the filler to produce the porous skeleton. Two different materials, including conventional cement-based and a geopolymer-based cement, were used as the grouting material. The geopolymer grout was produced by mixing metakaolin (MK), potassium-based liquid hardener and calcined silt as filler. The porous and grouted samples were characterized in terms of indirect tensile strength (ITS), the indirect tensile strength modulus (ITSM) and moisture sensitivity. The use of thermally treated waste silt as filler in porous asphalt demonstrated promising results and was comparable to the control samples produced with limestone as the filler. However, the control samples grouted with cement-based material outperformed the geopolymer grout in all aspects. Moreover, the addition of calcined silt improved the low-temperature fatigue performance of porous and grouted asphalt pavements.

Background: To investigate the effects of the COVID-19 lockdowns on the vasculopathic population. Methods: The Divisions of Vascular Surgery of the southern Italian peninsula joined this multicenter retrospective study. Each received a 13-point questionnaire investigating the hospitalization rate of vascular patients in the first 11 months of the COVID-19 pandemic and in the preceding 11 months. Results: 27 out of 29 Centers were enrolled. April-December 2020 (7092 patients) vs. 2019 (9161 patients): post-EVAR surveillance, hospitalization for Rutherford category 3 peripheral arterial disease, and asymptomatic carotid stenosis revascularization significantly decreased (1484 (16.2%) vs. 1014 (14.3%), p = 0.0009; 1401 (15.29%) vs. 959 (13.52%), p = 0.0006; and 1558 (17.01%) vs. 934 (13.17%), p < 0.0001, respectively), while admissions for revascularization or major amputations for chronic limb-threatening ischemia and urgent revascularization for symptomatic carotid stenosis significantly increased (1204 (16.98%) vs. 1245 (13.59%), p < 0.0001; 355 (5.01%) vs. 358 (3.91%), p = 0.0007; and 153 (2.16%) vs. 140 (1.53%), p = 0.0009, respectively). Conclusions: The suspension of elective procedures during the COVID-19 pandemic caused a significant reduction in post-EVAR surveillance, and in the hospitalization of asymptomatic carotid stenosis revascularization and Rutherford 3 peripheral arterial disease. Consequentially, we observed a significant increase in admissions for urgent revascularization for symptomatic carotid stenosis, as well as for revascularization or major amputations for chronic limb-threatening ischemia.

I Would like to express my sincere gratitude – and the gratitude of the Electron Device Society (EDS) community at large – to Colin McAndrew, A. G. Unil Perera, and Krishna Shenai, for their commitment, dedication, and hard work during their nine plus years of service on the Journal of the Electron Devices editorial board. They were part of the initial team that launched J-EDS and made it the internationally renowned, open access, vibrant publication of these days. I will miss their knowledge, wisdom, and responsiveness! Our very best wishes to them in their future endeavors.

Collagen type I mutations are related to wide phenotypic expressions frequently causing an overlap of clinical manifestations, in particular between Osteogenesis Imperfecta (OI) and Ehlers-Danlos syndrome (EDS). Both disorders present inter- and intra-familial clinical variability and several clinical signs are present in both diseases. Recently, after the observation that some individuals first ascertained by a suspicion of EDS resulted then carriers of pathogenic variants of genes known to primarily cause OI, some authors proposed the term “COL1-related overlap disorder” to describe these cases. In this paper, we report clinical, molecular, and biochemical information about an individual with a diagnosis of EDS with severe joint hypermobility who carries a pathogenic heterozygous variant in COL1A2 gene, and a benign variant in COL1A1 gene. The pathogenic variant, commonly ascribed to OI, as well as the benign variant, has been inherited from the individual's mother, who presented only mild signs of OI and the diagnosis of OI was confirmed only after molecular testing. In addition, we reviewed the literature of similar cases of overlapping syndromes caused by COL1 gene mutations. The reported case and the literature review suggest that the COL1-related overlap disorders (OI, EDS and overlapping syndromes) represent a continuum of clinical phenotypes related to collagen type I mutations. The spectrum of COL1-related clinical manifestations, the pathophysiology and the underlying molecular mechanisms support the adoption of the updated proposed term “COL1-related overlap disorder” to describe the overlapping syndromes.

Objective. To provide estimates of patients with rheumatoid arthritis (RA) eligible for biotechnological therapy and to evaluate their healthcare costs. Method. An observational analysis was performed based on data-linkage between administrative databases of selected Italian Regional/Local healthcare departments. Data were then re-proportioned to the Italian population. Patients with RA diagnosis defined by discharge diagnosis and/or exemption code during 01/01/2013- 31/12/2017 were included. The criteria applied to evaluate the elegibility for biotechnological therapy were: 1) methotrexate (MTX)-treatment failure ≥6 months and start of a different conventional-synthetic diseasemodifying antirheumatic drugs (csDMARD); 2) corticosteroid ≥6 months with dosage ≥7.5 mg/die; 3) MTX-contraindication (therapy or hospitalization for renal damage/interstizial lung disease/hepatic failure). Mean annual costs per patient included drugs, hospitalizations, outpatient services. Results. Data re-proportioned to the Italian population estimated 318,328 RA patients: 43,361 with, 274,967 without biotechnological agents. Among the latter, 26,487(9.6%) patients met ≥1 criteria applied for eligibility: 1,896 had MTX-treatment failure and started another csDMARD; 15,833 received corticosteroid ≥7.5 mg/die; 7,788 had MTX-contraindication. Regarding patients fulfilling two criteria, 107 had MTX-treatment failure followed by another csDMARDs and corticosteroid ≥7.5 mg/die, 53 were treated with another csDMARDs after MTX-treatment failure and also presented MTX-contraindication, 810 had corticosteroid ≥7.5 mg/die and MTX-contraindication. Mean total annual costs for patients estimated eligible for biotechnological therapy was € 3,132, of which € 177 related to drugs indicated for RA and € 2,955 related to other direct costs. Conclusions. According to our estimates, around 10% RA patients not currently treated with biotechnological agents are eligible for such therapies, highlighting a trend of under-use in clinical practice for RA management.

Streptococcus bovis/Streptococcus equinus complex (SBSEC) is a group of non-enterococcal group D Streptococci that colonizes both humans and animals. Due to gastrointestinal disease, they can switch in opportunistic pathogens passing through intestinal mucosal barrier and may cause bacteremia and distant organs damage. Despite infective endocarditis (IE), extra-cardiac manifestations of organs damage include osteoarticular infections, meningitis, and biliary infections among others; moreover, the association with colonic pathological lesions has been largely described. Streptococcus alactolyticus as a species included in SBSEC may share pathophysiological similarities, although it represents an extremely rare cause of distant organ infections, being reported in literature as causative agent of IE in only two other cases. We describe a case of 69-year-old male admitted to our institution due to mild–moderate dyspnea and fever, affected by cervico-brachialgia for 3 weeks. Streptococcus alactolyticus was identified as causative agent of IE on the mitral valve, causing severe regurgitation.

This analysis estimated the number of inflammatory bowel disease (IBD) patients presenting criteria of eligibility for biological therapies in an Italian real-world setting. An observational analysis was performed on administrative databases of a sample of Local Health Units, covering 11.3% of the national population. Adult IBD patients (CD or UC) from 2010 to the end of data availability were included. Eligibility criteria for biologics were the following: Criterion A, steroid-refractory active disease; Criterion B, steroid-dependent patients; Criterion C, intolerance or contraindication to conventional therapies; Criterion D, severe relapsing disease; Criterion E (CD only), highly active CD disease and poor prognosis. Of 26,781 IBD patient identified, 18,264 (68.2%) were treated: 3,125 (11.7%) with biologics and 15,139 (56.5%) non-biotreated. Among non-biotreated, 7,651 (28.6%) met at least one eligibility criterion for biologics, with criterion B (steroid-dependence) and criterion D (relapse) as the most represented (58–27% and 56–76%, respectively). Data reportioned to the Italian population estimated 67,635 patients as potentially eligible for biologics. This real-world analysis showed a trend towards undertreatment with biologics in IBD patients with 28.6% being potentially eligible, suggesting that an unmet medical need still exists among the Italian general clinical practice for IBD management. [ABSTRACT FROM AUTHOR]

Bruno Balbi,1 Claudia Sangiorgi,1 Isabella Gnemmi,1 Ilaria Ferrarotti,2 Davide Vallese,1 Elena Paracchini,1 Lorena Delle Donne,1 Luciano Corda,3 Paolo Baderna,4 Angelo Corsico,2 Mauro Carone,1 Paola Brun,5 Francesco Cappello,6,7 Fabio LM Ricciardolo,8 Paolo Ruggeri,9 Sharon Mumby,10 Ian M Adcock,10 Gaetano Caramori,9 Antonino Di Stefano11Istituti Clinici Scientifici Maugeri, IRCCS, Division of Pneumology and Laboratory of Cytoimmunopathology of the Heart and Lung, Veruno, Italy; 2Department of Internal Medicine and Medical Therapy, University of Pavia, Pavia, Italy; 3Medicina Respiratoria, Seconda Medicina Interna, Spedali Civili, Brescia, Italy; 4Division of Pneumology, Aosta Hospital, Aosta, Italy; 5Department of Molecular Medicine, University of Padova, Padova, Italy; 6Dipartimento di Biomedicina Sperimentale e Neuroscienze Cliniche, Sezione di Anatomia Umana, Università di Palermo, Palermo, Italy; 7Euro-mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy; 8Department of Clinical and Biological Sciences, A.O.U., San Luigi Gonzaga, Orbassano, University of Turin, Turin, Italy; 9UOC Di Pneumologia, Dipartimento di Scienze Biomediche, Odontoiatriche e Delle Immagini Morfologiche e Funzionali (BIOMORF), Università di Messina, Messina, Italy; 10Airways Disease Section, National Heart and Lung Institute, Imperial College London, UKCorrespondence: Antonino Di StefanoIstituti Clinici Scientifici Maugeri Irccs, Via Maugeri, 4, Pavia 27100, ItalyTel +39 032 288 4711Fax +39 032 288 4776Email antonino.distefano@icsmaugeri.itBackground: Airway inflammation may drive the progression of chronic obstructive pulmonary disease (COPD) associated with alpha-1 antitrypsin deficiency (AATD), but the relationship between airway microbiota and inflammation has not been investigated.Methods: We studied 21 non-treated AATD (AATD-noT) patients, 20 AATD-COPD patients under augmentation therapy (AATD-AT), 20 cigarette smoke-associated COPD patients, 20 control healthy smokers (CS) and 21 non-smokers (CON) with normal lung function. We quantified sputum inflammatory cells and inflammatory markers (IL-27, CCL3, CCL5, CXCL8, LTB4, MPO) by ELISA, total bacterial load (16S) and pathogenic bacteria by qRT-PCR.Results: AATD-AT patients were younger but had similar spirometric and DLCO values compared to cigarette smoke-associated COPD, despite a lower burden of smoking history. Compared to cigarette smoke-associated COPD, AATD-noT and AATD-AT patients had lower sputum neutrophil levels (p=0.0446, p=0.0135), total bacterial load (16S) (p=0.0081, p=0.0223), M. catarrhalis (p=0.0115, p=0.0127) and S. pneumoniae (p=0.0013, p=0.0001). Sputum IL-27 was significantly elevated in CS and cigarette smoke-associated COPD. AATD-AT, but not AATD-noT patients, had IL-27 sputum levels (pg/ml) significantly lower than COPD (p=0.0297) and these positively correlated with FEV1% predicted values (r=0.578, p=0.0307).Conclusions: Compared to cigarette smoke-associated COPD, AATD-AT (COPD) patients have a distinct airway inflammatory and microbiological profile. The decreased sputum bacterial load and IL-27 levels in AATD-AT patients suggests that augmentation therapy play a role in these changes.Keywords: alpha-1 antitrypsin deficiency, COPD, chronic airway inflammation, respiratory disability, sputum

Abstract Background By post-transcriptionally regulating multiple target transcripts, microRNAs (miRNAs or miR) play important biological functions. H1 embryonic stem cells (hESCs) and NTera-2 embryonal carcinoma cells (ECCs) are two of the most widely used human pluripotent model cell lines, sharing several characteristics, including the expression of miRNAs associated to the pluripotent state or with differentiation. However, how each of these miRNAs functionally impacts the biological properties of these cells has not been systematically evaluated. Methods We investigated the effects of 31 miRNAs on NTera-2 and H1 hESCs, by transfecting miRNA mimics. Following 3–4 days of culture, cells were stained for the pluripotency marker OCT4 and the G2 cell-cycle marker Cyclin B1, and nuclei and cytoplasm were co-stained with Hoechst and Cell Mask Blue, respectively. By using automated quantitative fluorescence microscopy (i.e., high-content screening (HCS)), we obtained several morphological and marker intensity measurements, in both cell compartments, allowing the generation of a multiparametric miR-induced phenotypic profile describing changes related to proliferation, cell cycle, pluripotency, and differentiation. Results Despite the overall similarities between both cell types, some miRNAs elicited cell-specific effects, while some related miRNAs induced contrasting effects in the same cell. By identifying transcripts predicted to be commonly targeted by miRNAs inducing similar effects (profiles grouped by hierarchical clustering), we were able to uncover potentially modulated signaling pathways and biological processes, likely mediating the effects of the microRNAs on the distinct groups identified. Specifically, we show that miR-363 contributes to pluripotency maintenance, at least in part, by targeting NOTCH1 and PSEN1 and inhibiting Notch-induced differentiation, a mechanism that could be implicated in naïve and primed pluripotent states. Conclusions We present the first multiparametric high-content microRNA functional screening in human pluripotent cells. Integration of this type of data with similar data obtained from siRNA screenings (using the same HCS assay) could provide a large-scale functional approach to identify and validate microRNA-mediated regulatory mechanisms controlling pluripotency and differentiation.

The Radioactivity Environmental Monitoring data bank (REMdb) was created in the aftermath of the Chernobyl accident (1986) by the European Commission (EC) – Directorate-General Joint Research Centre (DG JRC), sited in Ispra (Italy). Since then it has been maintained there with the aim to keep a historical record of the Chernobyl accident and to store the radioactivity monitoring data gathered through the national environmental monitoring programs of the member states (MSs). The legal basis is the Euratom Treaty, Chapter III Health and Safety, Articles 35 and 36, which clarify that MSs shall periodically communicate to the EC information on environmental radioactivity levels. By collecting and validating this information in REMdb, JRC supports the DG for Energy in its responsibilities in returning qualified information to the MSs (competent authorities and general public) on the levels of radioactive contamination of the various compartments of the environment (air, water, soil) on the European Union scale. REMdb accepts data on radionuclide concentrations from EU MSs in both environmental samples and foodstuffs from 1984 onwards. To date, the total number of data records stored in REMdb exceeds 5 million, in this way providing the scientific community with a valuable archive of environmental radioactivity topics in Europe. Records stored in REMdb are publicly accessible until 2011 through an unrestricted repository “REM data bank – Years 1984–2006” https://doi.org/10.2905/jrc-10117-10024 (De Cort et al., 2007) and “REM data bank – Years 2007–2011” https://doi.org/10.2905/de42f259-fafe-4329-9798-9d8fabb98de5 (De Cort et al., 2012). Access to data from 2012 onwards is granted only after explicit request, until the corresponding monitoring report is published. Each data record contains information describing the sampling circumstances (sampling type, begin and end time), measurement conditions (value, nuclide, apparatus, etc.), location and date of sampling, and original data reference. In this paper the scope, features and extension of REMdb are described in detail.

The morphology of dinoflagellate cysts (dinocysts) is related not only to the genetics of the motile dinoflagellate from which it derives, but is also dependent on a range of environmental factors including salinity, temperature and nutrient status. Although this knowledge improves our understanding of the drivers behind dinocyst morphological variations, it makes the taxonomy governing their description somewhat complex. In basins such as the Black Sea, where environmental change can be extreme and occurs on relatively short (millennial) timescales, taxonomy becomes particularly challenging. Morphological continua can be observed between described forms, displaying a large range of intermediate phenotypes that do not necessarily correspond to any genetic difference. As these morphological nuances may preserve information about palaeoenvironments, it is important to find a systematic method of characterising morphotypes. Here, we show a dinocyst matrix within which dinocysts are described according to their similarity to (or difference from) described forms based on key descriptive parameters. In the example set out here, cyst shape and degree of process and/or ectophragm development are taken as two key parameters in Pyxidinopsis psilata and Spiniferites cruciformis, and can allow the description of intermediate forms even though the definitions do not overlap. We review some frequently occurring morphotypes and propose that using matrices to show the gradual variation between endmember forms is the most pragmatic approach until cyst–theca studies and genetic sequencing can be used to demonstrate relationships between genotypes and morphotypes. As prior studies propose salinity to be a primary driver of intraspecific variability, the endmembers presented may represent salinity extremes within an overall brackish environment. Although we cannot assign each morphotype to a value or a range of an environmental parameter (e.g. salinity) as the different morphotypes can occur in the same sample, using this matrix allows preservation of information about morphological variability without creating taxonomic categories that are likely to require alteration if genetic evidence becomes available.

L Degli Esposti,1 V Perrone,1 D Sangiorgi,1 D Alessandrini,1 S Buda,1 F Cantini,2 E Mazzini,3 C Toma,3 F De Solda3 1CliCon S.r.l. Health, Economics & Outcomes Research, Ravenna, Italy; 2Division of Rheumatology, Hospital of Prato, Azienda USL Toscana Centro, Prato, Italy; 3Bristol-Myers Squibb, Roma, Italy Purpose: The purpose of this study was to analyze the therapeutic strategies and estimate the health care resource consumption in patients with psoriatic arthritis (PsA). Patients and methods: An observational retrospective cohort analysis of administrative databases of six Italian Local Health Units was performed. Patients ≥18 years with a hospitalization discharge diagnosis of PsA (International Classification of Diseases, Ninth Revision code: 696.0) or exemption code (045.696.0) for PsA from January 1, 2010 to December 31, 2015 (inclusion period), with at least one prescription of any therapy used for PsA were included. The index date (ID) was the first date matching with at least one of the inclusion criteria during the inclusion period. All patients were followed up after the ID until the end of data availability. Baseline C-reactive protein (CRP) levels (±6 months in relation to the ID) were also analyzed. Results: A total of 2,408 (prevalence 0.83 per 1,000) patients with PsA (male 52%; median age 54 years) were included in the study; patients were already treated for PsA in 42.4% of cases. At 1 year of follow-up, 73% of the patients received one systemic drug, while 22% of patients received two systemic drugs; in addition, our results show an increase in the number of add-on or switches in a longer follow-up period. The utilization of biologic agents was higher among patients with previous PsA treatment, showing a progression of the pathology. Overall, a medium/high level of CRP at baseline was observed among more than half of the overall sample, with slight changes across subgroups in analysis. The average health care costs were €1,966.4 and €13,914 per year for patients treated with conventional systemic therapy and biological agents, respectively. Conclusion: A better knowledge of prescription therapeutic scheme and economic burden of PsA could stimulate the rational development of health programs aimed at potentiating services for its management. Keywords: psoriatic arthritis, drug utilization, real-world data, treatment patterns

(1) Background: The Pediatric Outcomes Data Collection Instrument (PODCI) is an English-language questionnaire specifically designed to assess health-related quality of life in children and adolescents with musculoskeletal disorders. This scoring system has been translated into several languages. Given the lack of an Italian version of the PODCI, this study aimed to translate, cross-culturally adapt, and assess the psychometric properties of the PODCI score in the Italian pediatric population. (2) Methods: The PODCI questionnaire was culturally adapted to Italian patients in accordance with the literature guidelines. The study included 59 participants from a single orthopedic institution who underwent orthopedic surgery for various skeletal conditions. The questionnaire was administered to participants at multiple time-points (T0, T1, T2). Internal consistency was evaluated using Cronbach’s alpha. Reproducibility was assessed using the intraclass correlation coefficient (ICC) between T0 and T1 assessment. Criterion validity was assessed using Spearman’s correlation coefficients between PODCI and the Hospital for Special Surgery Pediatric Functional Activity Brief Scale (HSS Pedi-FABS). Responsiveness was evaluated by the difference between T0 and T2 using the effect size (ES) and the standardized response mean (SRM) calculation. (3) Results: Cronbach’s alpha was acceptable in both the self- and parent-reported versions with values of 0.78 (0.68–0.90) and 0.84 (0.60–0.92), respectively. The ICC fluctuated between 0.31 and 0.89 for self-reported and 0.49 to 0.87 for pediatrics. The Spearman’s r showed a moderate correlation between HSS Pedi-FABS and the “Sport & Physical Functioning” and “Global Functioning” domains. ES and SRM varied from small to moderate across all the domains. (4) Conclusions: This study demonstrates that the Italian version of the PODCI, translated following the international standardized guidelines, is reliable, valid, and responsive in pediatric patients who underwent orthopedic surgery.

Real world data are becoming a crucial tool to understand how cancer is treated in routine daily practice. This real-world analysis aims to describe the characteristics of patients with CML in 2nd or ≥3rd tyrosine kinase inhibitors (TKI) lines of therapy, to evaluate their treatment sequence and utilization in settings of Italian clinical practice in Italy. A retrospective analysis was performed using an administrative databases covering around 15.3 million cases. All adult patients prescribed with TKI as 2nd or ≥3rd lines (L) of therapy for CML during January 2015–December 2018 were included. A total of 491 patients in 2nd and 144 in ≥3rd L was included. In both cohorts, hypertension was the most reported comorbidity, followed by metabolic and blood count alterations. In each calendar inclusion year, an increment of 97.6% was observed in the number of patients treated in ≥3rd L. In the 2nd L cohort, 18.7% had a switch to 3rd L, while 26.4% of ≥3rd L patients switched to a subsequent line. Around 40% in both lines discontinued their treatment after a median time of 5.5 (2nd L) and 4.3 (≥3rd L) years. The results provided insights into CML management clinical practice, indicating a heavy disease burden for patients in later lines that showed an increasing complex management, and suggest that a need for novel treatment strategies might exists.

About 35% of patients affected by erectile dysfunction (ED) do not respond to oral phosphodiesterase-5 inhibitors (PDE5i) and more severe vasculogenic refractory ED affects diabetic patients. Innovative approaches, such as regenerative therapies, including stem cell therapy (SCT) and platelet-rich plasma (PRP), are currently under investigation. Recent data point out that the regenerative capacity of stem cells is strongly influenced by local immune responses, with macrophages playing a pivotal role in the injury response and as a coordinator of tissue regeneration, suggesting that control of the immune response could be an appealing approach in regenerative medicine. A new generation of autologous cell therapy based on immune cells instead of stem cells, which could change regenerative medicine for good, is discussed. Increasing safety and efficacy data are coming from clinical trials using peripheral blood mononuclear cells to treat no-option critical limb ischemia and diabetic foot. In this review, ongoing phase 1/phase 2 stem cell clinical trials are discussed. In addition, we examine the mechanism of action and rationale, as well as propose a new generation of regenerative therapies, evolving from typical stem cell or growth factor to immune cell-based medicine, based on autologous peripheral blood mononuclear cells (PBMNC) concentrates for the treatment of ED.

The present study has been developed to investigate the effect of freeze and thaw (F–T) cycles on the characteristics of highly rubberised asphalt materials to be used as impact-absorbing pavement (IAP) in urban road infrastructures. The tested samples were produced in the laboratory following the dry process incorporation. Two main types of crumb rubber particles in the range of 0–4 mm were used. Moreover, two types of binders, one warm and one cold, were utilised to prove the feasibility of cold-produced admixtures. The temperature range of the F–T procedure was comprised between −18 ± 2 °C (dry freezing), and 4 ± 2 °C (in water), and the cycles were repeated, on the samples, 10 times. At 0, 1, 5, and 10 cycles, the samples were tested with non-destructive and destructive testing methods, including air voids content, ITSM, ITS, and Cantabro loss. The waters of the thawing period were collected, and the pH, electric conductivity, and particle loss were measured. A consequent change in mechanical behaviour has been recorded between warm and cold produced samples. However, the tests found that the F–T cycles had limited influence on the deterioration of the highly rubberised samples. The loss of particles in the thaw waters were identified as being potentially caused by the temperature stresses. The research suggested various ways to optimise the material to enhance the cold-produced layer mechanical performances, aiming at a fume and smell-free industrialised solution and reducing the potential leaching and particle losses.

Luca Degli Esposti,1 Valentina Perrone,1 Diego Sangiorgi,1 Stefano Buda,1 Margherita Andretta,2 Maurizio Rossini,3 Giampiero Girolomoni4 1CliCon Srl, Health Economics and Outcomes Research, Ravenna, Italy; 2Pharmaceutical Department Local Health Unit, ULSS 9 Scaligera, Verona, Italy; 3Department of Medicine, Section of Rheumatology, University of Verona, Verona, Italy; 4Department of Medicine, Section of Dermatology and Venereology, University of Verona, Verona, Italy Objectives: To describe the therapeutic pathways of patients with psoriasis (PSO) and psoriatic arthritis (PsA) before and after treatment with biological therapies in a real-world setting and to determine the relative consumption of health care resources.Design: Retrospective observational study.Setting: Real-life clinical setting in 5 Italian local health units.Participants: A total of 351 male and female patients with at least 1 prescription for a biological drug from January 1, 2010 to December 31, 2013; patients with concomitant rheumatoid arthritis, ankylosing spondylitis, or Crohn’s disease were excluded.Results: The major health care cost (excluding drug costs) was represented by hospitalizations, mainly related to PSO /PsA-associated disorders and cardiometabolic disorders. Use of conventional drugs among biologics-naïve patients reached 50% in PSO and 80% in PsA; their use decreased following initiation of biological therapy. After the start of biological treatment, the incidence of hospitalization decreased both for PSO (from 12.3% to 3.2% in day hospital regimen and from 2.4% to 0.4% for conventional admission) and for PsA (from 11.1% to 8.1% and from 10.1% to 3.0%, respectively). Mean annual costs for hospitalization before biological treatment were €217 and €537 for PSO and PsA, respectively, while mean annual cost for concomitant drugs slightly increased after biologics initiation: from €249.8 to €269.4 for PSO and from €331.8 to €346.9 for PsA. The major consumption of health care resources occurred in the quarter preceding the beginning of biological treatment.Conclusion: The consumption of health resources is mostly related to hospitalization, seems to peak during the quarter before the beginning of biologics therapies, and subsequently decreases after biologics initiation. Further studies should focus on prescription scheme and economic burden of PSO and PsA in Italy to help optimize health care resources and potentiate services for patients. Keywords: psoriasis, psoriatic arthritis, biological treatment, health care costs, hospitalization

Integrated Ocean Drilling Program (IODP) Expedition 318 recovered a ∼ 170 m long Holocene organic-rich sedimentary sequence at Site U1357. Located within the narrow but deep Adélie Basin close to the Antarctic margin, the site accumulated sediments at exceptionally high sedimentation rates, which resulted in extraordinary preservation of the organic sedimentary component. Here, we present an overview of 74 different mainly marine microfossil taxa and/or types found within the organic component of the sediment, which include the remains of unicellular and higher organisms from three eukaryotic kingdoms (Chromista, Plantae, and Animalia). These remains include phytoplanktonic (phototrophic dinoflagellates and prasinophytes) and very diverse zooplanktonic (heterotrophic dinoflagellates, tintinnids, copepods) organisms. We illustrate each marine microfossil taxon or type identified by providing morphological details and photographic images, which will help with their identification in future studies. We also review their ecological preferences to aid future (palaeo)ecological and (palaeo)environmental studies. The planktonic assemblage shows a high degree of endemism related to the strong influence of the sea-ice system over Site U1357. In addition, we found the remains of various species of detritus feeders and bottom-dwelling scavengers (benthic foraminifers and annelid worms) indicative of high export productivity at Site U1357. This study shows the potential of organic microfossil remains for reconstructing past environmental conditions, such as sea-ice cover and (export) productivity.

This paper deals with the fundamental differences between industrial and paving-grade bituminous binders. The paper is presented in two main sections: 1) a review of the materials’ colloidal structure and the required properties for the industrial and paving applications; 2) a wide range of experimental tests with which the bituminous binders were studied and compared. In this research, a 160/220 industrial bitumen was studied and compared to a paving-grade bitumen with the same penetration and with a lower penetration, 70/100 one. The research consisted of physical, chemical, thermal, microstructural, and rheological analysis to provide a comprehensive understanding of these bituminous binders of diverse applications. Overall, the comparison of the tests’ results indicated that while the asphaltene content and its characteristics have a great influence on the bitumen’s properties, it is not the only fundamental factor. During the study of the chemical structures via Atomic Force Microscopy (AFM), it was found that the Peri phase (attributed to the resins) also plays an important role, defining the bitumen’s physical visco-elastic properties. In fact, from a microstructural point of view using AFM a significant difference was notified between the industrial bitumen and the paving-grade ones. These differences allow the paving-grade bitumens to be more elastic and ductile compared to the industrial bitumen.

Gelatine is a well-known and extensively studied biopolymer, widely used in recent decades to create biomaterials in many different ways, exploiting its molecular resemblance with collagen, the main constituent of the extra-cellular matrix, from which it is derived. Many have employed this biopolymer in tissue engineering and chemically modified (e.g., gelatin methacryloyl) or blended it with other polymers (e.g., alginate) to modulate or increase its performances and printability. Nevertheless, little is reported about its use as a stand-alone material. Moreover, despite the fact that multiple works have been reported on the realization of mould-casted and three-dimensional printed scaffolds in tissue engineering, a clear comparison among these two shaping processes, towards a comparable workflow starting from the same material, has never been published. Herein, we report the use of gelatine as stand-alone material, not modified, blended, or admixed to be processed or crosslinked, for the realization of suitable scaffolds for tissue engineering, towards the two previously mentioned shaping processes. To make the comparison reliable, the same pre-process (e.g., the gelatin solution preparation) and post-process (e.g., freeze-drying and crosslinking) steps were applied. In this study, gelatine solution was firstly rheologically characterized to find a formulation suitable for being processed with both the shaping processes selected. The realized scaffolds were then morphologically, phisico-chemically, mechanically, and biologically characterized to determine and compare their performances. Despite the fact that the same starting material was employed, as well as the same pre- and post-process steps, the two groups resulted, for most aspects, in diametrically opposed characteristics. The mould-casted scaffolds that resulted were characterized by small, little-interconnected, and random porosity, high resistance to compression and slow cell colonization, while the three-dimensional printed scaffolds displayed big, well-interconnected, and geometrically defined porosity, high elasticity and recover ability after compression, as well as fast and deep cell colonization.

Patients with Chronic Obstructive Pulmonary Disease (COPD) periodically experience acute exacerbation (AECOPD). Carbocysteine represents a valid add on therapy in COPD by exerting antioxidant and anti-inflammatory activities. The in vivo effects of carbocysteine on inflammatory markers are not yet fully understood. The aims of this study were to assess: (i) miR-21, IL-8, soluble Receptor for Advanced Glycation End Products (sRAGE), and fluorescent Advanced Glycation End Products (fAGEs) in control subjects (n = 9), stable (n = 9), and AECOPD patients (n = 24); and (ii) whether carbocysteine modifies these markers and the functional parameters in mild AECOPD patients. Mild AECOPD patients received or not carbocysteine along with background inhalation therapy for 20 days. At the onset and at the end of the observation period, the following parameters were evaluated: FEV1, FEF25–75%, CAT questionnaire; miR-21 by Real Time PCR; IL-8 and sRAGE by ELISA; and fAGEs by spectro-fluorescence method. COPD patients showed higher levels of miR-21, IL-8, fAGEs and lower levels of sRAGE compared to that of controls. miR-21 inversely correlated with FEV1. IL-8 and fAGEs were significantly different in stable and exacerbated COPD patients. Carbocysteine improved symptoms, FEV1 and FEF25–75%, increased sRAGE, and reduced miR-21, IL-8, and fAGEs in mild AECOPD patients. The present study provides compelling evidence that carbocysteine may help to manage mild AECOPD by downregulating some parameters of systemic inflammation.

The research on the possibilities of using biowaste from urban green areas is scarce. In this work, four plants, widely distributed in urban parks in Central Europe (Lotus corniculatus, Medicago lupulina, Knautia arvensis and Plantago major) were extracted using eco-friendly solvents based either on aqueous cyclodextrin solutions (hydroxypropyl-β-cyclodextrin or γ-cyclodextrin) or natural deep eutectic solvents based on glycerol, betaine and glucose. Metal content was determined using total reflection X-ray fluorescence (TXRF). The content of selected metabolites was determined using UV-VIS spectrophotometric methods and HPLC. Skin-related bioactivity was assessed using tyrosinase and elastase inhibition assays. The selected plants contained metals beneficial for skin health, such as zinc and calcium, while having a low content of toxic heavy metals. The extracts contained the bioactive phenolics such as quercetin, kaempferol, luteolin and apigenin. L. corniculatus was the most potent tyrosinase inhibitor, while K. arvensis showed the most pronounced elastase inhibitory activity. The employed solvents actively contributed to the observed bioactivity. The results indicate that the biowaste obtained from urban parks represents an ecologically acceptable alternative to conventional cultivation for the preparation of ecologically acceptable, high-value cosmetic products.