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Objective: To evaluate the long-term effectiveness, safety, and tolerability of erenumab in a real-world migraine population, looking for putative predictors of responsiveness. Background: Erenumab proved to be effective, safe, and well tolerated in the prevention of episodic migraine (EM) and chronic migraine (CM) in long-term extension studies of double-blind, placebo-controlled trials in patients with no more than two (EM) or three (CM) prior preventive treatment failures. Methods: A 48-week, multicenter, longitudinal cohort real-life study was conducted at 15headache centers across eight Italian regions between December 20, 2018 and July 31, 2020. We considered all consecutive patients with high-frequency episodic migraine (HFEM) or CM aged 18–65years. Each patient was treated with erenumab 70mg, administered monthly. The dose was switched to 140mg in nonresponders and in responders who had become nonresponders for at least 4weeks. Change in monthly migraine days (MMDs) or monthly headache days (MHDs) at Weeks 45–48 compared with baseline was the primary efficacy endpoint. Secondary endpoints encompassed variation in monthly analgesic intake, achievement of a ≥50%, ≥75%, or 100% reduction in migraine or headache days, and any change in the Visual Analogue Scale (VAS) and Headache Impact Test-6 scores (HIT-6) during the same time interval. Results: A total of 242 patients with migraine received at least one dose of erenumab 70mg and were considered for safety analysis, whereas 221 received a monthly erenumab dose for ≥48weeks and were included in the effectiveness and safety analysis set. All patients had previously been treated unsuccessfully with ≥3migraine-preventive medication classes. From baseline to Weeks 45–48, erenumab treatment reduced MMD by 4.3±5.3(mean±SD) in patients with HFEM, and MHD by 12.8±8.9 (mean±SD) in subjects with CM. VAS and HIT-6scores were decreased by 1.8±1.9 (mean±SD) and 12.3±11 (mean±SD) in HFEM, and by 3.0±2.2 (mean±SD) and 13.1±11.2 (mean±SD) in CM. Median monthly analgesic intake passed from 11.0 (interquartile range [IQR] 10.0–13.0) to 5 (IQR 2.0–8.0) in HFEM and from 20.0 (IQR 15.0–30.0) to 6.0 (IQR 3.8–10.0) in CM. The ≥50% responders were 56.1% (32/57) in HFEM and 75.6% (124/164) in CM; ≥75% responders were 31.6% (18/57) and 44.5% (73/164); and 100% responders were 8.8% (5/57) and 1.2% (2/164), respectively. At Week 48, 83.6% (137/164) of patients with CM had reverted to EM. Erenumab was safe and well tolerated. Responsiveness to erenumab was positively associated with cutaneous allodynia (OR: 5.44, 95% CI: 1.52–19.41; p=0.009) in HFEM. In patients with CM, ≥50% responsiveness was positively associated with male sex (OR: 2.99, 95% CI: 1.03–8.7; p=0.044) and baseline migraine frequency (OR: 1.12, 95% CI: 1.05–1.20; p=0.001) and negatively associated with psychiatric comorbidities (OR: 0.37, 95% CI: 0.15–0.87; p=0.023) and prior treatment failures (OR: 0.77, 95% CI: 0.64–0.92; p=0.004). Conclusions: Long-term (48-week) erenumab treatment provides sustained effectiveness, safety, and tolerability in real-life patients with HFEM or CM with ≥3 prior preventive treatment failures. The dose of 140mg was required in most patients along the study and should be taken into consideration as the starting dose. Allodynia (in HFEM), male sex, and baseline migraine frequency (in CM) might represent positive responsiveness predictors. Conversely, psychiatric comorbidities and multiple prior preventive treatment failures could be negative predictors in patients with CM.

Objectives: The COVID-19 pandemic and the consequent lockdown came as a storm disrupting people’s everyday life. This study aimed at observing whether the COVID-19 related lockdown influenced migraine frequency and disability in migraine patients on therapy with monoclonal antibodies inhibiting the CGRP pathway. Methods: In this longitudinal observational cohort study, 147 consecutive patients receiving monthly administration of erenumab or galcanezumab were enrolled in four Italian headache centers. All patients filled a questionnaire concerning working and household settings, recent flu symptoms or COVID-19 diagnosis, and family loss due to COVID-19 infection. Monthly migraine days (MMDs), monthly painkiller intake (MPI), and HIT-6 disability relative to the first month of lockdown imposition (T-lock) and the month before (T-free) were also collected. Results: From T-free to T-lock, the cohort displayed a reduction in MMDs (from 10.5 ± 7.6 to 9.8 ± 7.6, p =.024) and HIT-6 scores (from 59.3 ± 8.3 men reduced MPI more frequently than women (p =.005). Conclusions: Our study observed that the lockdown impact to 57.8 ± 8.8, p=.009), while MPI resulted unchanged (from 11.6 ± 11.5 to 11.1 ± 11.7; p =.114). MMDs, MPI, and HIT-6 variations from T-free to T-lock did not differ according to work settings or household. Patients beyond the first 3 months of therapy presented less often a reduction in MMDs (p =.006) and on everyday life did not affect the migraine load in patients receiving monoclonal antibodies inhibiting the CGRP pathway. Patients in the first months of therapy experienced a greater improvement according to drug pharmacokinetics, while women more frequently needed rescue medications, possibly indicating presenteeism or cephalalgophobia.

Graphical abstract, Highlights • Sulfolane was evaluated in mice, rat, and guinea pig 28-day toxicity studies. • The rat was more sensitive compared to mice and guinea pigs. • Rats generally had the highest plasma concentrations at 24 h after the last dose., Sulfolane is a solvent used in industrial refining with identified environmental exposure in drinking water. Due to potential large species differences, the National Toxicology Program (NTP) conducted 28-day toxicity studies in male and female Hsd:Sprague Dawley® SD® rats, B6C3F1/N mice, and Hartley guinea pigs. A wide dose range of 0, 1, 10, 30, 100, 300, and 800 mg/kg was administered via gavage. Histopathology, clinical pathology, and organ weights were evaluated after 28 days of exposure. In addition, plasma concentrations of sulfolane were evaluated 2 and 24 h after the last dose. Increased mortality was observed in the highest dose group of guinea pigs and mice while decreased body weight was observed in rats compared to controls. Histopathological lesions were observed in the kidney (male rat), stomach (male mice), esophagus (male and female guinea pigs), and nose (male guinea pigs). Plasma concentrations were generally higher in rats and guinea pigs compared to mice with evidence of saturated clearance at higher doses. Male rats appear to be the most sensitive with hyaline droplet accumulation occurring at all doses, although the human relevance of this finding is questionable.

[Image: see text] Melanoma is a highly aggressive cancer with poor prognosis. Although more than 80% of melanomas harbor an activating mutation in genes within the MAPK pathway, which are mutually exclusive, usefulness of therapies targeting MAPK pathway are impeded by innate and/or acquired resistance in most patients. In this study, using melanoma cells, we report the efficacy of a recently developed pyrazolo[3,4-d]pyrimidine derived c-Src inhibitor 10a and identify a molecular signature which is predictive of 10a chemosensitivity. We show that the expression of TMED7, PLOD2, XRCC5, and NSUN5 are candidate biomarkers for 10a sensitivity. Although an undifferentiated/mesenchymal/invasive status of melanoma cells is associated with resistance to 10a, we show here for the first time that melanoma cells can be sensitized to 10a via treatment with valproic acid, a histone deacetylase inhibitor.

Peres, F., Fallacara, E., Manzoni, L., Castelli, M., Popovič, A., Rodrigues, M., & Estevens, P. (2021). Time series clustering of online gambling activities for addicted users’ detection. Applied Sciences (Switzerland), 11(5), [2397]. https://doi.org/10.3390/app11052397 Ever since the worldwide demand for gambling services started to spread, its expansion has continued steadily. To wit, online gambling is a major industry in every European country, generating billions of Euros in revenue for commercial actors and governments alike. Despite such evidently beneficial effects, online gambling is ultimately a vast social experiment with potentially disastrous social and personal consequences that could result in an overall deterioration of social and familial relationships. Despite the relevance of this problem in society, there is a lack of tools for characterizing the behavior of online gamblers based on the data that are collected daily by betting platforms. This paper uses a time series clustering algorithm that can help decision-makers in identifying behaviors associated with potential pathological gamblers. In particular, experimental results obtained by analyzing sports event bets and black jack data demonstrate the suitability of the proposed method in detecting critical (i.e., pathological) players. This algorithm is the first component of a system developed in collaboration with the Portuguese authority for the control of betting activities. publishersversion published

Filoviruses (Family Filoviridae genera Ebolavirus and Marburgvirus) are negative-stranded RNA viruses that cause severe health effects in humans and non-human primates, including death. Except in outbreak settings, vaccines and other medical countermeasures against Ebola virus (EBOV) will require testing under the FDA Animal Rule. Multiple vaccine candidates have been evaluated using cynomolgus monkeys (CM) exposed to EBOV Kikwit strain. To the best of our knowledge, however, animal model development data supporting the use of CM in vaccine research have not been submitted to the FDA. This study describes a large CM database (122 CM, 62 female and 60 male, age 2 to 9 years) and demonstrates the consistency of the CM model through time to death models and descriptive statistics. CMs were exposed to EBOV doses of 0.1 to 100,000 PFU in 33 studies conducted at three Animal Biosafety Level 4 facilities, by three exposure routes. Time to death was modeled using Cox proportional hazards models with a frailty term that incorporated study-to-study variability. Despite significant differences attributed to exposure variables, all CMs exposed to the 100 to 1,000 pfu doses commonly used in vaccine studies died or met euthanasia criteria within 21 days of exposure, median 7 days, 93% between 5 and 12 days of exposure. Moderate clinical signs were observed 4 to 5 days after exposure and preceded death or euthanasia by approximately one day. Viremia was detected within a few days of infection. Hematology indices were indicative of viremia and the propensity for hemorrhage with progression of Ebola viremia. Changes associated with coagulation parameters and platelets were consistent with coagulation disruption. Changes in leukocyte profiles were indicative of an acute inflammatory response. Increased liver enzymes were observed shortly after exposure. Taken together, these factors suggest that the cynomolgus monkey is a reliable animal model for human disease.

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Janus kinases (JAKs) are a family of non-receptor tyrosine kinases, composed by four members, JAK1, JAK2, JAK3 and TYK2. JAKs are involved in different inflammatory and autoimmune diseases, as well as in malignancies, through the activation of the JAK/STAT signalling pathway. Furthermore, the V617F mutation in JAK2 was identified in patients affected by myeloproliferative neoplasms. This knowledge prompted researchers from academia and pharmaceutical companies to investigate this field in order to discover small molecule JAK inhibitors. These efforts recently afforded to the market approval of four JAK inhibitors. Despite the fact that all these drugs are pyrrolo[2,3-d]pyrimidine derivatives, many compounds endowed with different heterocyclic scaffolds have been reported in the literature as selective or multi-JAK inhibitors, and a number of them is currently being evaluated in clinical trials. In this review we will report many representative compounds that have been published in articles or patents in the last five years (period 2013-2017). The inhibitors will be classified on the basis of their chemical structure, focusing, when possible, on their structure activity relationships, selectivity and biological activity. For every class of derivatives, compounds disclosed before 2013 that have entered clinical trials will also be briefly reported, to underline the importance of a particular chemical scaffold in the search for new inhibitors.

The goal of this study is to understand how very elderly patients (VEP) after ischemic stroke are currently treated in a Stroke Unit (SU) Hub in Italy. We designed a retrospective monocentric study on patients admitted in the SU of "AO San Camillo Forlanini" over an 8-year period.Data were collected among patients with acute ischemic stroke admitted to SU between January 2012 and December 2019. Patients were divided into three sub-groups: Adults (18-65 years); Elderly (66-85 years); and VEP (85 years). Vascular risk factors and clinical variables as predictors of short-term clinical outcome were compared among age groups.A total of 1979 patients were enrolled, 254 were VEP (12.8%). The proportion of VEP showed no significant modifications during the 8-year period (11.9% in 2012-2015 and 13.7% in 2016-2019; p=0.93). The proportion of women, hypertension and atrial fibrillation was significantly higher in VEP compared to other age groups (p0.001). The rate of VEP being treated with rt-PA increased from 2012-2015 to 2016-2019 (from 12.8% to 25.5%, p0.001). Endovascular thrombectomy was rarely performed in VEP (1.5% of VEP). Rt-PA treatment was associated with favorable outcome for all three age groups (p0.05).We showed that VEP present different vascular risk factor profiles, clinical features, and prognostic elements for short-term stroke outcome. Future studies will reveal whether we will observe an increasing trend in the use of rt-PA and endovascular thrombectomy and whether it will result in improved functional outcome for VEP.

The paper describes the necessary transition from the consolidated practices of contemporary residential architecture to innovative sustainable design and construction practices, which can be pursued by applying the principles of digital fabrication to the construction industry. The contribution is divided into two parts: the first investigates the theoretical-critical assumptions of research and the second part describes a design experience that led to the creation of a housing prototype with an irregular geometry made up of CLT panels. The paper will explain the need to overcome the current phase of experimentation using digital fabrication technologies applied to small pavilions with complex shapes or high budget, to move to their application on residential building. The application of these technologies to residential architecture is desirable both for the diffusion and for the relevance of the change it would produce.

The paper concerns the theme of topological interlocking blocks for architecture and the relationship between flat stereotomic assemblies and curved morphologies. After a brief history of the subject, theoretical foundations and speculative research are presented. The research includes several built full-scale prototypes and architectural elements. The last part of the chapter describes the didactic experiences concerning the theme, during the third year Architectural Design Studio held by the authors, at Politecnico di Bari, Italy.

Objective To assess whether erenumab influences cerebral vasomotor reactivity and flow-mediated dilation in migraine patients. Methods Consecutive migraineurs prescribed erenumab at our Headache Centre and age and sex-matching controls were invited to participate in this observational longitudinal study. Patients were evaluated for cerebral vasomotor reactivity to hypercapnia (breath-holding index) in middle and posterior cerebral arteries and for brachial corrected flow mediated dilation at baseline (T0), after 2 weeks from the first erenumab injection (T2) and after 2 weeks from the fourth Erenumab injection (T18). Patients displaying a reduction of at least 50% in monthly migraine days after completing the fourth month of therapy were classified as responders. Results Sixty patients and 25 controls agreed to participate. Middle and posterior cerebral artery mean flow velocities, breath-holding index and flow-mediated dilation did not differ at T0 and from T0 to T2 in patients and controls. In patients, we neither observed a variation of the explored variables from T0 to T18 nor an interaction between evaluation times (T0–T2 or T0–T18) and chronic condition at T0, responder state or erenumab fourth dose. Conclusions Our findings demonstrate that erenumab preserves cerebral vasomotor reactivity and flow-mediated dilation in migraineurs without aura.

Virtual reality is a candidate to become the preferred interface for architectural design review, but the effectiveness and usability of such systems is still an issue. We put together a multidisciplinary team to implement a test methodology and system to compare VR with 2D interaction, with a coherent test platform using Rhinoceros as industry-standard CAD software. A direct and valid comparison of the two setups is made possible by using the same software for both conditions. We designed and modeled three similar CAD models of a 2 two-story villa (1 for the training and 2 for the test) and we implanted 13 artificial errors, simulating common CAD issues. Users were asked to find the errors in a 10 minutes fixed-time session for each setup respectively. We completed our test with 10 students from the design and architecture faculty, with proven experience of the 2D version of the CAD. We did not find any significant differences between the two modalities in cognitive workload, but the user preference was clearly towards VR. The presented work may provide interesting insights for future human-centered studies and to improve future VR architectural applications.

Objectives To evaluate the effects of the reorganisation of an intensive care unit for COVID-19 patients in the context of the SARS-CoV-2 pandemic on wellbeing perceived by nurses. Methods An observational cross-sectional study was conducted to evaluate wellbeing perceived by nurses who during the study were on duty in the COVID-19 intensive care unit. The “Covid-19-Nurse Well-being at Work (NWB) scale” questionnaire consisting of 72 items divided into 13 sections, was validated and used to collect data. Results The level of wellbeing perceived by the nurses was very good (4.77; SD 0.83). Differences in the of level of perceived wellbeing were found for “years of experience” and the various levels of competence. We found a positive correlation between “female gender” and “nurses’ togetherness and collaboration”, a negative correlation between “male gender” and “satisfactory practical organisation of work, and a negative correlation between “work experience” and the overall “level of wellbeing at work. Conclusions The reorganisation had positive effects in terms of wellbeing perceived by the nurses. The factors that contributed mostly to the perception of wellbeing were in the area of “support”, “communication, and “socializing with colleagues”. It is appropriate to consider “gender differences”, “work experience” and “levels of competence” when implementing this type of reorganisation to respond to a pandemic or a health emergency.

Background Increased exposure to perfluoroalkyl substances (PFAS) potentially affects infant and childhood health through immunosuppression. Given rapidly evolving research on PFAS, it is important to comprehensively examine the impact of PFAS exposure among the pediatric population as new research becomes available due to potential fragility of the developing immune system. Objectives This review assessed the effects of PFAS fetal, infant and childhood exposures upon the development of immune function during early life stages. Methods Researchers completed a literature review, searching PubMed for human studies published since 2010 for PFAS and health outcomes among infants and children. Included articles incorporated key search terms in the title or abstract; non-research reports and non-English papers were excluded. The search identified 518 studies for possible inclusion. Following hands-on review, 34 were determined relevant. Subsequent analyses found 8 additional relevant articles, totaling 42 studies. Results Major immune-related sequelae from PFAS exposures on infant and child health outcomes documented in recent literature include: • Strong indication of immunosuppression, with diminished childhood antibody response to vaccination, particularly with PFOA, PFOS and PFHxS exposures. • Some indication of increased risks of childhood infectious diseases/infections, particularly from PFOS exposures. • Limited indication of an effect of PFAS exposure on allergic reactions/allergen specific IgE antibodies. • Limited indication of an effect of PFAS exposure on atopic dermatitis (AD). • Limited indication of an effect of PFAS exposure on asthma and lung function. Conclusion This review summarizes recent findings of PFAS effects on infant and childhood immune health. Evidence of immunosuppression, diminished vaccine efficacy, and increased risk of infections, allergies, asthma and AD were described following in utero, infant, and early childhood PFAS exposures. Further investigation is warranted to characterize PFAS exposure pathways and potential modes of action in relation to PFAS effects on the developing immune system. Incontrovertible proof of PFAS immunotoxic effects could optimally be obtained by a large prospective study cohort of mothers and children from infancy through school-age. Regular assessments of circulating antibodies and response to infant and childhood vaccines during growth years could prove invaluable., Highlights • This review summarizes findings of PFAS effects on infant and child immune health. • In utero, infant, and early childhood PFAS exposures were examined. • Strong evidence of PFAS exposure on diminished childhood antibody vaccination response. • Moderate evidence of PFAS exposure on increased risk of childhood infectious diseases. • Limited evidence of PFAS exposure on allergic reactions, atopic dermatitis, asthma., PFAS, perfluoroalkyl substances, infant and child health, immune function, allergy, infection, asthma

Background and aims: Erenumab proved to be safe and well tolerated in a 5-year continuation of a 1-year double-blind, placebo-controlled study. Aim: to assess >48-week erenumab tolerability and safety in a real-world setting. Methods: In this long term (>48-week), multicenter (n = 15), longitudinal cohort real life study, we monitored all the adverse events emerged in consecutive adult patients with high-frequency episodic migraine (HFEM) or chronic migraine (CM) treated with monthly erenumab 70 mg or 140 mg from 20 December 2018 to 15 December 2020. Results: 442 patients (HFEM: 115;CM: 327) were treated with erenumab for >48 weeks: 209 (47.3%) patients were treated for 49–60 weeks, 132 (29.9%) for 61–72 weeks;73 (16.5%) for 73–84 weeks;21 (4.7%) for 85–100 weeks. Overall, >1 treatment emergent adverse event (TEAE) was reported by 136 (30.8%) [HFEM: 43 (37.4%);CM: 93 (28.4%)]. Most common TEAE were constipation (n = 66;14.9%), injection site erythema (n = 15;3.4%), and influenza (n = 7;1.6%). Serious adverse events (SAE) were reported by 8 patients (1.8%) and led to treatment discontinuation: severe constipation (n = 3), abdominal pain (n = 1), NSTEMI (n = 3), Covid-19 infection (n = 1). Only severe constipation was considered treatment-related SAE (0.45%). Conclusions: Conclusion: Erenumab is safe and well tolerated also in long-term treatment (>48 weeks) in real life.

The chapter explains the studies the New Fundamentals Research Group is carrying out on the digital update of stereotomy. Between the various experiments, the chapter focuses on the group or prototypes designed by the geometry of the hyperbolic paraboloid, both at the macro (architectural organism) and micro scale (architectural elements). Several full-scale prototypes have been designed and built, using specific parametric codes, to define the geometrical morphogenesis properties of the built structural morphologies. Consequent theoretical reflections are fully explained.

The aim of the article is to describe the historical background and the birth of a relatively new discipline consisting in the digital evolution of classical stereotomy. “Stereotomy 1.0” comprises the early development of the discipline primarily related to stonecutting. The new discipline, “Stereotomy 2.0” goes beyond this early concept to embrace contemporary design paradigms and materials. It is described in an “Unfinished Manifesto”, which describes its fundamental theoretical principles, understood as a new didactic comprehensive approach for the schools of architecture and a new design process useful for contemporary architectural design. Each point of the Manifesto is described in a short paragraph and shows the most important theoretical nodes of the renewed discipline. The various points are then exemplified by the experimental projects presented in the final part of the article.

Over the last years, hyaluronic acid (HA) injectable dermal fillers (DFs) have become the most popular agents for soft tissue contouring and volumizing. HA fillers are characterized by most of the properties that an ideal DF should have, due to HA unique chemical-physical properties, biocompatibility, biodegradability, and versatility. Therefore, HA DFs have revolutionized the filler market with a high number of products, which differ in terms of HA source, cross-linkage (agent and degree), HA concentration, hardness, cohesivity, consistency, inclusion or lack of anesthetic, indication, and longevity of correction. The article first provides a general introduction to DF world, and an overview of the different materials is available for fillers. Second, it describes the characteristics and the peculiarities of HA fillers, their differences from the other available materials, and therefore the reasons at the base of their success. Moreover, an update regarding the main Food and Drug Administration (FDA) approved fillers is presented.

Glioblastoma Multiforme (GBM) is the most common of malignant gliomas in adults with an exiguous life expectancy. Standard treatments are not curative and the resistance to both chemotherapy and conventional radiotherapy (RT) plans is the main cause of GBM care failures. Proton therapy (PT) shows a ballistic precision and a higher dose conformity than conventional RT. In this study we investigated the radiosensitive effects of a new targeted compound, SRC inhibitor, named Si306, in combination with PT on the U87 glioblastoma cell line. Clonogenic survival assay, dose modifying factor calculation and linear-quadratic model were performed to evaluate radiosensitizing effects mediated by combination of the Si306 with PT. Gene expression profiling by microarray was also conducted after PT treatments alone or combined, to identify gene signatures as biomarkers of response to treatments. Our results indicate that the Si306 compound exhibits a radiosensitizing action on the U87 cells causing a synergic cytotoxic effect with PT. In addition, microarray data confirm the SRC role as the main Si306 target and highlights new genes modulated by the combined action of Si306 and PT. We suggest, the Si306 as a new candidate to treat GBM in combination with PT, overcoming resistance to conventional treatments.

The present contribution proposes three projects and relative speculative reflections, elaborated by the writers, concerning the important theme of the wooden roof construction, showing the results of the three competitions organized by the Terres de Hetre® consortium, entitled: “L’architecture au service de construction en bois de hetre des vosges”. The three projects, object of the paper (awarded with the third placement during the first edition and with the second placement during the third edition), describe an effort to demonstrate new applications, characteristics, shapes and unexpected unexpressed potentials of this traditional material for a new contemporary design; they are architectures that have the common characteristic of being all a great challenge to the intrinsic limits of the wooden material: in all the outcomes results the research of geometric complexity and the limit of the static-mechanical resistance of the elements is evident. The architectural forms are developed starting from a series of geometric and topological variations on the theme of the wood-frame roof: the first with powerful overhangs on the model of the gull-wing structure, the second on the tree-shape model and the third on the shell-ruled–surface model.

Objective: To assess the impact of electronic health record (EHR) on healthcare quality, we hence carried out a systematic review and meta-analysis of published studies on this topic. Methods: PubMed, Web of Knowledge, Scopus and Cochrane Library databases were searched to identify studies that investigated the association between the EHR implementation and process or outcome indicators. Two reviewers screened identified citations and extracted data according to the PRISMA guidelines. Meta-analysis was performed using the random effects model for each indicator. Heterogeneity was quantified using the Cochran Q test and I2 statistics, and publication bias was assessed using the Egger’s test. Results: Of the 23 398 citations identified, 47 articles were included in the analysis. Meta-analysis showed an association between EHR use and a reduced documentation time with a difference in mean of −22.4% [95% confidence interval (CI) = −38.8 to −6.0%; P < 0.007]. EHR resulted also associated with a higher guideline adherence with a risk ratio (RR) of 1.33 (95% CI = 1.01 to 1.76; P = 0.049) and a lower number of medication errors with an overall RR of 0.46 (95% CI = 0.38 to 0.55; P < 0.001), and adverse drug effects (ADEs) with an overall RR of 0.66 (95% CI = 0.44 to 0.99; P = 0.045). No association with mortality was evident ( P = 0.936). High heterogeneity among the studies was evident. Publication bias was not evident. Conclusions: EHR system, when properly implemented, can improve the quality of healthcare, increasing time efficiency and guideline adherence and reducing medication errors and ADEs. Strategies for EHR implementation should be therefore recommended and promoted.

The aim of this study was the preclinical development of a set of pyrazolo[3,4-d]pyrimidine structure-based small molecules ATP-competitive SRC inhibitors for the therapy of glioblastoma (GBM), a rare but extremely aggressive and infiltrative glial tumor with a very limited response to therapies. Ongoing preclinical and clinical studies of tyrosine kinase inhibitors (TKIs) for the therapy of GBM identified SRC family inhibitors as a significant and effective therapeutic strategy (i.e. dasatinib, bosutinib, PP2). In vitro Screening: From the wide in-house synthesized pyrazolo[3,4-d]pyrimidines’ library, nine compounds have been selected to be formulated and tested in in vitro and in vivo GBM pharmacological models. Among all the examined formulations, the prodrug approach has been applied to the candidate drugs, introducing the N-methylpiperazine moiety by a carbamate-based linker (in vivo enzymatically hydrolysable). Drugs and corresponding prodrugs have been screened on the basis of their SRC Ki and in vitro ADME properties. GBM U87 cell assays showed IC50 in the sub-micromolar range (1.5 - 15.0 µM) for almost all compounds and improved cellular uptake of the prodrugs in respect to the corresponding drugs. PK and Toxicity: After that, the most promising compound has been selected for further in vitro assays and in vivo tests. In vivo pharmacokinetics and pharmacodynamics have been evaluated for the compound by various formulations, routes of administration and dosages. In all cases investigated, the compound has been proved to reach the brain. As expected, prodrug plasmatic MRT and AUC confirmed the realization of an extended release formulation that allows a higher overall exposure to the drug. In addition, considering an estimated oral bioavailability of 40.4% and a 11-fold higher Cmax in respect to i.v. and i.p. administration, the oral route can be identified as the most advantageous for the compound for GBM treatment. Moreover, an acute toxicity study revealed that the LD50 for i.v. toxicity is more than 100 mg/kg with a good tolerability. In vivo Efficacy Tests: The selected compound and its prodrug were orally administered in GBM orthotopic mouse model and results indicated a median survival rate 10% greater for prodrug-treated mice in respect to drug-treated mice and 35% greater in respect to control group. The combination effect of the compound and radiotherapy was also investigated in subcutaneous U87 xenografted mice model and resulted in a reduction of the tumor growth close to 80% in respect to the control growth. Conclusions: Taking into account all the data collected regarding their pharmacological properties, pyrazolo[3,4-d]pyrimidines SRC inhibitors class of compounds deserve further investigation to show its potential to become a new therapy for GBM. Citation Format: Arianna Mancini, Anna Lucia Fallacara, Claudio Zamperini, Giulia Iovenitti, Alessio Molinari, Enrico Rango, Adriano Angelucci, Silvia Schenone, Maurizio Botta. Preclinical development of novel pyrazolo[3,4-d]pyrimidines structure-based TKIs for the treatment of glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2201.

Purpose Glioblastoma multiforme (GBM) is the most aggressive types of central nervous system tumors. The aim of the project is to validate an innovative molecule developed by Lead Discovery Siena [LDS] showing inhibitory activity against Src kinases to be associated with proton therapy treatments. Materials Human glioblastoma cells (U87) were treated at INFN-LNS in Catania with 2 and 10 Gy of proton beams at dose rate of 10 Gy/min in the middle of the extended modulated Bragg peak and in combination with different concentrations of the LDS molecule (10 and 20 μM). The fraction of surviving cells (SF) was evaluated with the clonogenicity test 15 days after irradiation. Results The data in the figure show the synergistic effect of the combined treatment with LDS. Conclusions In vitro studies confirmed the efficacy of the hadron therapy treatment in combination with the molecule. The next step is to translate these studies on the mouse model thanks to the existence of an Animal Facility created by the synergy between the following institution: the LNS-INFN, the University of Catania – Capir Center, IBFM-CNR and H. Cannizzaro, with the departments of Nuclear Medicine and Medical Physics. The facility will be able to provide unique research activities in the European panorama: hadron therapy treatments, dose distribution studies using the Monte Carlo GEANT4 method, molecular imaging using microPET/ CT tomography with different radiotracers and image processing implementation for therapy response quantification.

The goal of this project is to conduct the first geographically distributed, low-frequency skywave propagation measurements during a solar eclipse. There is a lack of knowledge about how radio waves below frequencies of 500 kHz are affected by a total eclipse and a lack of experimental data reflecting these low-frequency radio wave transmissions at geographically diverse locations during an eclipse. A low-frequency band receiver system for people across the United States to assemble and use is designed, allowing for a crowd-sourced collection of measurements of relative signal strength of the WWVB and Dixon low-frequency station signals during the eclipse over North America on August 21, 2017.

A comprehensive 2-year oral chronic toxicity/carcinogenicity study was conducted with smokeless tobacco using modern toxicological test methods and well-accepted standards. The study included a 1-year interim subgroup to assess toxicity at that intermediate time point. Test groups consisted of a tobacco blend (B) used in snus, and an aqueous tobacco extract of that tobacco blend (E) administered at 0.2, 2, or 5 mg nicotine/kg body weight/day via dosed feed to male and female Wistar Han rats. The dosages were selected to simulate potential exposure in humans ingesting smokeless tobacco or an aqueous extract of smokeless tobacco (the latter intended to simulate a snus extract, to enable bridging these data to snus epidemiology data). The following endpoints were evaluated: clinical observations, body weights, feed consumption (FC), ophthalmic exams, toxicokinetics, clinical pathology, gross pathology, and histopathology. During the 2-year study, clear treatment-related, dose-responsive effects included: (1) increases in plasma nicotine and cotinine (indicating that animals were appropriately exposed to levels relevant to human exposure) and (2) decreases in body weights with some alterations in FC. At the 2-year time point, two tumor types (in the highest B doses) displayed statistically significantly increased incidence trends vs. controls: (1) uterine carcinoma in females and (2) epididymal mesothelioma in males. Three tumor types displayed statistically significantly decreased incidence trends: (1) mammary gland adenomas in females, (2) skin basal cell carcinomas in females, and (3) thyroid follicular cell adenomas in males. These increases (and decreases) in tumor trends were interpreted as not being treatment-related because: (1) there were no preneoplastic or related non-neoplastic histopathological findings in the treated rats at the 1-year or 2-year time points to suggest that any of these neoplastic findings were treatment-related and (2) the tumor morphologies and incidences were generally within the expected range of historical controls for Wistar Han rats. Findings from this study indicate that chronic exposure of male and female Wistar Han rats to either a tobacco blend used in snus, or a tobacco extract of that blend does not lead to increased toxicity or carcinogenicity, based on the specified outcomes measured.

Sudden hearing loss (SHL) is a highly disabling affliction that can severely affect the subject’s social and relational life. Although the etiology of the complaint is still debated, it is thought that microcirculation disturbances conditioned by an endothelial dysfunction might be the main pathogenetic mechanism. Adhesion molecules favoring interaction between leukocytes and endothelial cells are early markers of endothelial damage. In the present report, we describe a case of SHL that derived evident benefit from a single session of LDL/fibrinogen apheresis, with complete hearing recovery. In this patient, in addition to reducing LDL cholesterol and fibrinogen, the circulating adhesion molecules (sE-selectin, sVCAM-1 and sICAM-1), previously present in higher than normal concentrations, were reduced by the treatment.

The production of type 1 (interferon or IFN-gamma) and type 2 (interleukin or IL-4 and IL-10) cytokines by mitogen-stimulated peripheral blood mononuclear cells (PBMCs) obtained from asymptomatic human immunodeficiency virus-seropositive (HIV+) patients untreated with any antiviral, antibacterial or antimycotic drugs, and from healthy individuals, was evaluated by quantitative ELISA. Patients who were HIV+ were characterized by the absence of abnormal cytokine production. The level of each cytokine differed among individuals in the same group with intersubject variations greater for HIV+ patients than for healthy individuals. The longitudinal evaluation of IFN-gamma, IL-4 and IL-10 production showed intrasubject variations which were particularly marked in HIV+ patients. Accordingly, HIV+ patients and, to a lesser extent, healthy individuals were characterized by a wide spectrum of possible profiles, which were confined to type 0 phenotype. In HIV+ patients no correlation was found between each cytokine level and the number of CD4+ T cells, not even in those with a falling CD4+ T-cell count and clinical symptoms.

Normal sleep is associated to physiological nocturnal rises in Interleukin 1 beta (IL 1 beta) secretion. The 24 h pattern of IL 1 beta, beta-Endorphin (beta-EPH), ACTH and cortisol (F) production was evaluated in four male healthy volunteers. Two subjects were unable to sleep, due to the stress of the experiment; in these cases, no detectable plasma IL 1 beta secretion, both diurnal and nocturnal, was present, beta-EPH plasma levels were significantly higher (p < 0.01) than in the subjects who slept regularly and, in one case, increased F plasma levels were also reported. A strong negative correlation between IL 1 beta and beta-EPH plasma levels was present in all the cases. In conclusion, stress-induced sleep alterations might deeply affect both diurnal and nocturnal IL 1 beta plasma secretion, probably due to the hypothalamus-pituitary-adrenal axis (HPAA) activation, and beta-EPH might be the reliable marker of the stress-induced HPAA activation level.

The aim of this study was to analyze and compare the results obtained in otosclerosis patient undergoing stapedotomy and partial stapedectomy.Retrospective review of surgical series. The guidelines of the American Academy of Otolaryngology-Head and Neck Surgery for the evaluation of results of treatment of conductive hearing loss were used.Pure tone average (0.5 to 3 kHz) air-bone gap was 6.1 dB in the partial stapedectomy and 6 dB in the stapedotomy group. The air-bone gap (ABG) closure rate did not differ between the 2 groups, except at 4 kHz, where stapedotomy group showed greater closure (P 0.003). Mean postoperative ABG gain was significantly (P0.05) higher in the stapedotomy group at 2, 3, and 4 kHz. Mean postoperative air-conduction gain did not differ significantly. Mean postoperative bone conduction (BC) change (1, 2, and 4 kHz) was 3.68 dB in partial stapedectomy and -0.02 dB in stapedotomy group, the difference being significant (P 0.007). Differences in BC change between the 2 groups were significant at each frequency.Similar good results can be obtained in experienced hands using either partial stapedectomy or stapedotomy technique. ABG closure rates were analogous in the 2 techniques as well as the complication rate. Although stapedotomy obtain better results at high frequencies, partial stapedectomy is associated with increased BC threshold at all frequencies.

Hashimoto's thyroiditis, the most common form of autoimmune thyroid disease, is characterised by lymphocytic infiltration of the thyroid gland, gradual destruction of the organ and production of thyroid specific auto antibodies (antithyroid peroxidase and antithyroglobulin antibodies). There are evidences that cast doubt on the pathogenetic role of these antibodies in thyroid autoimmunity. It is very likely that cellular destruction is mediated by other cellular mechanisms, such as auto reactive T-lymphocytes, natural killer and cytokines. However, other studies performed in animal models have led to the conclusion that organ specific autoimmune thyroiditis should be regarded as a polygenic disease with a penetrance that is strongly influenced by environmental factors. According to our recent results, patients affected by autoimmune thyroiditis exhibited a decreased percentage of NK and CD25 + bearing cells significantly in comparison to normal controls. Altogether these data indicated that in the patients with autoimmune thyroid disease a certain degree of peripheral immune deficiency was present.

Tumor Necrosis Factor-alpha/cachectin (TNF-alpha/cachectin), Lipopolysaccharide (LPS), ACTH, beta-Endorphin (beta-EPH), and Cortisol (F) levels were determined in 33 Headache patients: 22 patients were affected with Migraine (M) and 11 patients with Chronic Type Tension Headache (CTTH). TNF-alpha/cachectin serum level was detected in 15 out of 22 migraneous patients and in no CTTH patients. Plasma LPS was observed in 11 out of 15 TNF-alpha/cachectin positive migraneous patients (73%) and in 3 out of 11 CTTH patients (27%). A negative correlation was observed between TNF-alpha/cachectin values and either ACTH or beta-EPH. In the group of migraneous patients the presence of serum TNF-alpha/cachectin showed a sensibility of .6 and a specificity of 1. The endocrine and immunological implications concerning these data are discussed.