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Glioblastoma (GBM) is a poor prognosis grade 4 glioma. After surgical resection, the standard therapy consists of concurrent radiotherapy (RT) and temozolomide (TMZ) followed by TMZ alone. Our previous data on melanoma patients showed that Dendritic Cell vaccination (DCvax) could increase the amount of intratumoral-activated cytotoxic T lymphocytes. This is a single-arm, monocentric, phase II trial in two steps according to Simon's design. The trial aims to evaluate progression-free survival (PFS) at three months and the safety of a DCvax integrated with standard therapy in resected GBM patients. DCvax administration begins after completion of RT-CTwith weekly administrations for 4 weeks, then is alternated monthly with TMZ cycles. The primary endpoints are PFS at three months and safety. One of the secondary objectives is to evaluate the immune response both and (DTH skin test). By December 2022, the first pre-planned step of the study was concluded with the enrollment, treatment and follow up of 9 evaluable patients. Two patients had progressed within three months after leukapheresis, but none had experienced DCvax-related G3-4 toxicities Five patients experienced a positive DTH test towards KLH and one of these also towards autologous tumor homogenate. The median PFS from leukapheresis was 11.3 months and 12.2 months from surgery. This combination therapy is well-tolerated, and the two endpoints required for the first step have been achieved. Therefore, the study will proceed to enroll the remaining 19 patients. (Eudract number: 2020-003755-15 https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-003755-15/IT).

Cranioplasty is the surgical technology employed to repair a traumatic head injury, cerebrovascular disease, oncology resection and congenital anomalies. Actually, different bone substitutes are used, either derived from biological products such as hydroxyapatite and demineralized bone matrix or synthetic ones such as sulfate or phosphate ceramics and polymer-based substitutes. Considering that the choice of the best material for cranioplasty is controversial, linked to the best operation procedure, the intent of this review was to report the outcome of research conducted on materials used for such applications, comparing the most used materials. The most interesting challenge is to preserve the mechanical properties while improving the bioactivity, porosity, biocompatibility, antibacterial properties, lowering thickness and costs. Among polymer materials, polymethylmethacrylate and polyetheretherketone are the most motivating, due to their biocompatibility, rigidity and toughness. Other biomaterials, with ecofriendly attributes, such as polycaprolactone and polylactic acid have been investigated, due to their microstructure that mimic the trabecular bone, encouraging vascularization and cell–cell communications. Taking into consideration that each material must be selected for specific clinical use, the main limitation remains the defects and the lack of vascularization, consequently porous synthetic substitutes could be an interesting way to support a faster and wider vascularization, with the aim to improve patient prognosis.

Background: Neurinomas are benign, usually encapsulated, tumors growing in peripheral nerve sheath with a high incidence in the cerebellopontine angle. Case Description: We report a case of vestibular neurinoma (VN) with a \"biphasic\" pattern of intratumoral hemorrhage presenting with cephalalgia along with progressive ipsilateral mild impairment of both VII and VIII cranial nerves. A thorough preoperative magnetic resonance imaging study better characterized the patchy pattern of the round shaped lesion, resulting in three different intensity signals, due to the peculiar characteristics of the tumoral mass and the recurrent bleedings, respectively. Postoperatively, histological examination confirmed the diagnosis of neurinoma. Conclusion: Hemorrhagic VN are rare tumors; from the first case described in 1974 only 43 more have been reported in the literature so far. Noteworthy, \"biphasic\" bleedings are even rarer. From an accurate review of the literature we collected and thus emphasized the radiological and clinical features of this rare entity. Eventually, we suggest that the early surgical removal of clots and tumor is essential to provide the best chance of neurological improvement.

Background and aims: No consensus exists on how aggressively to treat relapsing–remitting multiple sclerosis (RRMS) nor on the timing of the treatment. The objective of this study was to evaluate disability trajectories in RRMS patients treated with an early intensive treatment (EIT) or with a moderate-efficacy treatment followed by escalation to higher-efficacy disease modifying therapy (ESC). Methods: RRMS patients with ⩾5-year follow-up and ⩾3 visits after disease modifying therapy (DMT) start were selected from the Italian MS Registry. EIT group included patients who received as first DMT fingolimod, natalizumab, mitoxantrone, alemtuzumab, ocrelizumab, cladribine. ESC group patients received the high efficacy DMT after ⩾1 year of glatiramer acetate, interferons, azathioprine, teriflunomide or dimethylfumarate treatment. Patients were 1:1 propensity score (PS) matched for characteristics at the first DMT. The disability trajectories were evaluated by applying a longitudinal model for repeated measures. The effect of early versus late start of high-efficacy DMT was assessed by the mean annual Expanded Disability Status Scale (EDSS) changes compared with baseline values (delta-EDSS) in EIT and ESC groups. Results: The study cohort included 2702 RRMS patients. The PS matching procedure produced 363 pairs, followed for a median (interquartile range) of 8.5 (6.5–11.7) years. Mean annual delta-EDSS values were all significantly (p < 0.02) higher in the ESC group compared with the EIT group. In particular, the mean delta-EDSS differences between the two groups tended to increase from 0.1 (0.01–0.19, p = 0.03) at 1 year to 0.30 (0.07–0.53, p = 0.009) at 5 years and to 0.67 (0.31–1.03, p = 0.0003) at 10 years. Conclusion: Our results indicate that EIT strategy is more effective than ESC strategy in controlling disability progression over time.

Late onset multiple sclerosis (LOMS) represents between 0.6 and 12% of all MS patients. However, little is known on the incidence of LOMS in the general population. Therefore, we aimed to study the annual incidence of LOMS in a population-based cohort. The study was conducted in the province of Catania, Italy. Case ascertainment was conducted retrospectively including all patients aged ≥ 50 years at onset and with the onset between 2005 and 2020. Incidence rates (IR) have been calculated for all the study period, according to sex, age classes and for subperiods. Incidence rate ratios (IRR) have been computed to compare incidence rates. During the study period, 183 patients with LOMS were identified (113 women; 61.8%). The mean age at onset was 55.8 ± 5.4 years and the main phenotype was Relapsing Remitting MS ( n  = 123; 67.2%). The average annual crude IR was 2.87/100,000 person-years (95% Confidence Intervals, CI 2.31–3.13). IR increased from 2.54/100,000 in 2005–2010 to 3.32/100,000 in 2016–2020, especially in in the age group 60–69 (IRR 3.48; 95%CI 1.41–9.76; p-value 0.002). In conclusion, an increased IR over the time was observed in the age-group 60–69, possibly reflecting an increased age at onset of MS.

According to the leading literature, the valid enforcement of property rights is a key ingredient for economic development. However, their enforcement can be problematic in international relations, which can be a valid approximation of an anarchic or state of nature environment. In such a context, we do not have a third party that may sanction any illegal behaviour, since the existing international organizations may lack the necessary power to force countries to behave in a specific way. A large variety of papers have attempted to provide a self-enforcing solution to a conflict among players by defining a bargaining range, which may prevent the emergence of a war. Hence, players renounce the fight and leave peacefully, enforcing de facto property rights. In contrast, we propose a model in which contestants decide to solve their dispute by forming a union. The latter can be interpreted in a broad sense, also encompassing the possibility that they form a new political entity. We highlight the welfare implications of that solution and define the non-empty set of parameters, which support such a decision in the long run. Intuitively, from a dual perspective, the model also discloses the circumstances that may lead players to deviate from the union path and split. Therefore, our paper contributes to the literature about the formation and breakdown of countries, although our primary concern is to present a model with an innovative solution to conflicts. Moreover, our work stresses the importance of the enforcement of property rights to guarantee the peaceful development of relations among countries.

As of today, 20 disease-modifying drugs (DMDs) have been approved for the treatment of relapsing multiple sclerosis (MS) and, based on their efficacy, they can be grouped into moderate-efficacy DMDs and high-efficacy DMDs. The choice of the drug mostly relies on the judgment and experience of neurologists and the evaluation of the therapeutic response can only be obtained by monitoring the clinical and magnetic resonance imaging (MRI) status during follow up. In an era where therapies are focused on personalization, this study aims to develop a modeling infrastructure to predict the evolution of relapsing MS and the response to treatments. We built a computational modeling infrastructure named Universal Immune System Simulator (UISS), which can simulate the main features and dynamics of the immune system activities. We extended UISS to simulate all the underlying MS pathogenesis and its interaction with the host immune system. This simulator is a multi-scale, multi-organ, agent-based simulator with an attached module capable of simulating the dynamics of specific biological pathways at the molecular level. We simulated six MS patients with different relapsing–remitting courses. These patients were characterized based on their age, sex, presence of oligoclonal bands, therapy, and MRI lesion load at the onset. The simulator framework is made freely available and can be used following the links provided in the availability section. Even though the model can be further personalized employing immunological parameters and genetic information, we generated a few simulation scenarios for each patient based on the available data. Among these simulations, it was possible to find the scenarios that realistically matched the real clinical and MRI history. Moreover, for two patients, the simulator anticipated the timing of subsequent relapses, which occurred, suggesting that UISS may have the potential to assist MS specialists in predicting the course of the disease and the response to treatment.

According to standard economic theory, human beings are expected to work more and better when benefits in the form of lower costs or higher reward increase. Principal–agent theory applied to the theory of the firm relies on this relationship and states that employees should be paid according to how well they perform their tasks. In this framework, monitoring devices are introduced to control employees’ performance and determine salaries. In this paper we construct a principal–agent model to describe the relationship between citizens/voters and elected representatives in which monitoring devices are introduced to control the performance of the latter. We demonstrate that tighter controls may produce better performance but also may produce a reduction in the intrinsic motivations of elected representatives, resulting in a reduction of their work effort. These results are interpreted in the light of the motivation crowding theory.

Objectives:Thrombocytopenia is a hallmark for patients with cirrhosis and it is perceived as a risk factor for bleeding events. However, the relationship between platelet count and bleeding is still unclear.Methods:We investigated the relationship between platelet count and major or clinical relevant nonmajor bleedings during a follow-up of ∼4 years.Results:A total of 280 cirrhotic patients with different degrees of liver disease (67% males; age 64±37 years; 47% Child-Pugh B and C) were followed up for a median of 1,129 (interquartile range: 800-1,498) days yielding 953.12 patient-year of observation. The annual rate of any significant bleeding was 5.45%/year (3.57%/year and 1.89%/year for major and minor bleeding, respectively). Fifty-two (18.6%) patients experienced a major (n=34) or minor (n=18) bleeding event, predominantly from gastrointestinal origin. Platelet counts progressively decreased with the worsening of liver disease and were similar in patients with or without major or minor bleeding: a platelet count ≤50 × 103 /μl was detected in 3 (6%) patients with and in 20 (9%) patients without any bleeding event. Conversely, prothrombin time-international normalized ratio was slightly higher in patients with overall or major bleeding. On Cox proportional hazard analysis, only a previous gastrointestinal bleeding (hazard ratio (HR): 1.96; 95% confidence interval: 1.11-3.47; P=0.020) and encephalopathy (HR: 2.05; 95% confidence interval: 1.16-3.62; P=0.013) independently predicted overall bleeding events.Conclusions:Platelet count does not predict unprovoked major or minor bleeding in cirrhotic patients.

Polar marine environments host a complex assemblage of cold-adapted auto- and heterotrophic microorganisms that affect water biogeochemistry and ecosystem functions. However, due to logistical difficulties, remote regions like those in close proximity to glaciers have received little attention, resulting in a paucity of microbiological data. To fill these gaps and obtain novel insights into microbial structure and function in Arctic regions, a survey of microbial communities in an area close to the Blomstrandbreen glacier in Kongsfjorden (Svalbard Archipelago; Arctic Ocean) was carried out during an early summer period. An Unmanned Autonomous Vehicle designed to safely obtain seawater samples from offshore-glacier transects (PROTEUS, Portable RObotic Technology for Unmanned Surveys) was equipped with an automatic remotely-controlled water multi-sampler so that it could sample just beneath the glacier, where access from the sea is difficult and dangerous. The samples were analysed by image analysis for the abundance of total prokaryotes, viable and respiring cells, their morphological traits and biomass; by flow cytometry for autotrophic and prokaryotic cells (with high and low nucleic acid contents) as well as virus-like particle counts; by BIOLOG ECOPLATES for potential community metabolism; and by fluorimetry for potential enzymatic activity rates on organic polymers. Contextually, the main physical and chemical (temperature, salinity, pH, dissolved oxygen and nutrients) parameters were detected. Altogether, besides the PROTEUS vehicle’s suitability for collecting samples from otherwise inaccessible sites, the multivariate analysis of the overall dataset allowed the identification of three main sub-regions differently affected by the haline gradient (close to the glacier) or terrigenous inputs coming from the coast. A complex microbiological scenario was depicted by different patterns of microbial abundance and metabolism among the transects, suggesting that ice melting and Atlantic water inflow differently supported microbial growth.