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ABSTRACTBackgroundSelf-administration of subcutaneous interferon beta-1a (sc IFN β-1a) can be achieved with the RebiSmart® electromechanical autoinjector. This study investigated adherence to, and duration of persistence with, the newest version of the device (v1.6) among 2644 people receiving sc IFN β-1a for multiple sclerosis (MS).Research design and methodsThis retrospective, observational study utilized data from RebiSmart® devices, recorded on the MSdialog database, between January 2014 and November 2019. Adherence and persistence were evaluated over a 3-year period and assessed in relation to age, sex, injection type, and injection depth.ResultsThe population of RebiSmart® users (N = 2644) comprised of 1826 (69.1%) females and mean age was 39 (range 16–83) years. Adherence to RebiSmart® use and data transfer to the MSdialog database was consistently high (mean 91.7%; range 86.8–92.6%), including across all variables (81.6–100%). Mean (±SD) persistence during the study period was 1.35 ± 1.06 years, with a maximum recorded persistence of 5.1 years. In multivariate analysis, the longest durations of persistence were observed among older individuals and males (p < 0.0001 and p = 0.0078, respectively).ConclusionsPeople living with MS were highly adherent to use of the RebiSmart® device, with higher persistence generally observed for older and/or male individuals.

The current paper aims to enrich the current understanding of the link between the choice of residential location, the propensity to cycle to work and the propensity to cycle for non-commuting purposes. To highlight the relationship among these choice dimensions we used a composite econometric model that allows for the joint modelling of multiple outcomes. Residential location and cycling propensities are modelled as a function of socio-demographic and level-of-service variables. The inclusion of common error terms allows us to control for self-selection and unobserved effects that can simultaneously influence the underlying propensities. The data for this study is drawn from a survey conducted in the metropolitan areas of Cagliari and Sassari (Sardinia, Italy) in 2016 among a sample of local employees. The sample comprises 2,128 observations. Our results indicate that a significant portion of unobserved variance between the residential location choice and the propensity to cycle for non-commuting reasons exists, suggesting the presence of a self-selection effect.

The goal of this study is to understand and explore how facilitators to cycling are perceived by different segments of individuals, in view of assessing how to best promote the use of the bicycle in urban areas bicycle-unfriendly. The data for this study is drawn from a survey conducted in the metropolitan area of Cagliari, a starter cycling city in Italy, in 2014-2016 among a sample of local employees. The sample comprises 1,481 observations. All participants were asked to rate, by means of a 5-point Likert Scale, the importance of eight different specified factors that would encourage them to start cycling or to cycle more often. These factors, which are the dependent variables of our study, are modelled jointly using a multivariate ordered probit framework. Our results clearly indicates that how people perceive the implementation of policy measures aimed to encourage more frequent cycling depends on their socio-demographic characteristics. Hence, a holistic approach with a variety of activities is needed, as improvements in cycling infrastructure may not be enough.

TheACEI/D (rs4341),ACTN3c.1729C>T (rs1815739),COL5A1C>T (rs2722) andMCT1c.1470A>T (rs1049434) polymorphisms (and their interaction) are associated with muscle injury in football players.The ACED allele, the ACTN3C allele, the COL5A1C allele, and the MCT1T allele seem to protect football players from developing muscle injuries.The Total Genotype Score was associated with the incidence of muscle injuries in Italian top-level footballers, and this result needs replication in a larger independent cohort.

Mountain cultural landscapes of southern Europe have been affected during the 20th century by significant land use changes, due to depopulation and abandonment of traditional agro-silvo-pastoral practices. In addition, the cessation of traditional forest management led to a homogenization of forest structures and to the loss of habitats. Italy is one of the European countries most affected by the consequences of depopulation of mountain areas. Moscheta is located in the Italian Apennines, in Tuscany, and its economy has been based for centuries on forests (for timber, firewood, charcoal, and chestnuts to produce flour) and livestock. The aim of the paper is to analyze the land use changes occurred in a typical forest mountain landscape of southern Europe in the last 191 years, and to describe the characteristics and the results of the Forest Landscape Restoration project recently implemented. The methodology is based on GIS-based spatial analyses comparing the landscape of 1832, 2013 and 2023. In the period 1832–2013, 45% of the total surface was affected by forestation (average rate of 1.9 ha/year) mainly due to the abandonment of pastures and wooded pastures, but also to direct conifer afforestation. Chestnut groves were abandoned as they were no more economically interesting. From the 2010s, a Forest Landscape Restoration (FLR) project was implemented considering the economical, technical and future management feasibility. It focused on recovering the monumental chestnut groves and the wooded pastures, but also on interventions to increase the touristic attractiveness (paths management, Historical Landscape Museum creation, traditional buildings for chestnut drying restoration). The area was also inscribed in 2016 in the National list of Historical Rural Landscape established by the Italian Ministry of Agriculture. The analyses of the 2013–2023 landscape changes demonstrated that 4 ha of historical chestnut groves and 6.5 ha of wooded pastures have been recently restored, bringing their total surface to 17 ha and to 67 ha, respectively. In addition, results demonstrate that forestation completely stopped in the last 10 years. Other interventions are planned for the future: maintenance of chestnut groves, rehabilitation of other wooded pastures, re-introduction of the traditional practice of pollarding on ten beech trees. This study represents the first assessment of the FLR carried out in Moscheta, and demonstrates that the restoration of open spaces and of cultural forests is possible and could have a big impact on mountain cultural landscapes, contributing to the preservation and enhancement of ecosystem services and of touristic attractiveness, with potential direct benefits on the local economy.

Recently walking and cycling, known as active mobility, have attracted the attention of both citizens and policymakers. Many new pedestrian areas and cycle paths have been created or extended in various cities across Europe and monetary incentives have been offered to support and encourage citizens to use active mobility. Starting from this context, the aim of the current paper is to evaluate the impact that interventions of re-functionalization of the street space have in boosting cycling mobility in the city of Cagliari (Italy). Employing data collected in three distinct cross-sectional surveys (2014, 2019 and 2020), we constructed a logit model that simulates individuals’ probability to cycle/not cycle for one purpose or another. Model results indicate a general increase in the probability to cycle over time and that individuals living in those areas where cycling facilities are provided were more likely to use the bicycle than the rest of the city’s residents. Furthermore, our findings show that measures developed to improve cycling infrastructure should be implemented jointly with interventions of urban regeneration, that modify the environment in terms of both safety and livability. Finally, our results stress the importance of the longitudinal assessment of policies and strategies.

Trained immunity (TI) is a proinflammatory program induced in monocyte/macrophages upon sensing of specific pathogens and is characterized by immunometabolic and epigenetic changes that enhance cytokine production. Maladaptive activation of TI (ie, in the absence of infection) may result in detrimental inflammation and development of disease; however, the exact role and extent of inappropriate activation of TI in the pathogenesis of human diseases is undetermined. In this study, we uncovered the oncogene-induced, maladaptive induction of TI in the pathogenesis of a human inflammatory myeloid neoplasm (Erdheim-Chester disease, [ECD]), characterized by the BRAFV600E oncogenic mutation in monocyte/macrophages and excess cytokine production. Mechanistically, myeloid cells expressing BRAFV600E exhibit all molecular features of TI: activation of the AKT/mammalian target of rapamycin signaling axis; increased glycolysis, glutaminolysis, and cholesterol synthesis; epigenetic changes on promoters of genes encoding cytokines; and enhanced cytokine production leading to hyperinflammatory responses. In patients with ECD, effective therapeutic strategies combat this maladaptive TI phenotype; in addition, pharmacologic inhibition of immunometabolic changes underlying TI (ie, glycolysis) effectively dampens cytokine production by myeloid cells. This study revealed the deleterious potential of inappropriate activation of TI in the pathogenesis of human inflammatory myeloid neoplasms and the opportunity for inhibition of TI in conditions characterized by maladaptive myeloid-driven inflammation.

Trained immunity (TI) is a proinflammatory program induced in monocyte/macrophages upon sensing of specific pathogens and is characterized by immunometabolic and epigenetic changes that enhance cytokine production. Maladaptive activation of TI (ie, in the absence of infection) may result in detrimental inflammation and development of disease; however, the exact role and extent of inappropriate activation of TI in the pathogenesis of human diseases is undetermined. In this study, we uncovered the oncogene-induced, maladaptive induction of TI in the pathogenesis of a human inflammatory myeloid neoplasm (Erdheim-Chester disease, [ECD]), characterized by the BRAFV600E oncogenic mutation in monocyte/macrophages and excess cytokine production. Mechanistically, myeloid cells expressing BRAFV600E exhibit all molecular features of TI: activation of the AKT/mammalian target of rapamycin signaling axis; increased glycolysis, glutaminolysis, and cholesterol synthesis; epigenetic changes on promoters of genes encoding cytokines; and enhanced cytokine production leading to hyperinflammatory responses. In patients with ECD, effective therapeutic strategies combat this maladaptive TI phenotype; in addition, pharmacologic inhibition of immunometabolic changes underlying TI (ie, glycolysis) effectively dampens cytokine production by myeloid cells. This study revealed the deleterious potential of inappropriate activation of TI in the pathogenesis of human inflammatory myeloid neoplasms and the opportunity for inhibition of TI in conditions characterized by maladaptive myeloid-driven inflammation.

•An exploratory analysis is conducted between cyclists and non-cyclists.•Hypothetical scenarios for changing modal share in favour of cycling are defined.•The findings confirm that hard measures are necessary for encouraging cycling.

The low gene manipulation efficiency of human hematopoietic stem and progenitor cells (HSPC) remains a major hurdle for sustainable and broad clinical application of innovative therapies for a wide range of disorders. Given that all current and emerging gene transfer and editing technologies are bound to expose HSPC to exogenous nucleic acids and most often also to viral vectors, we reason that host antiviral factors and nucleic acid sensors play a pivotal role in the efficacy of HSPC genetic manipulation. Here, we review recent progress in our understanding of vector–host interactions and innate immunity in HSPC upon gene engineering and discuss how dissecting this crosstalk can guide the development of more stealth and efficient gene therapy approaches in the future.

•We examine the relationship between psycho-attitudinal factors and cycling frequency.•Psycho-attitudinal variables positively influence propensity to cycle.•Link between different socio-demographic variables, built environment characteristics and bike usage.•Improvement of cycling infrastructure might not be sufficient to encourage bike use.

•A two-wave panel survey is implemented among a sample of students.•Daily travel behaviour was monitored by collecting data through a smartphone app.•Between the two phases, a personalised travel plan was provided to car drivers.•30% of car drivers followed the indications of the personalized plan.

•The study aims to evaluate the level of accessibility offered by bicycling to the beaches before and after the implementation of a regional bike tourism network system.•A GIS-based procedure was employed and the method comprised of three main steps: (1) data collection and preparation, (2) GIS analysis, and (3) assessment of results.•The results demonstrate that, following the implementation of the regional cycle network Sardinia, various zones in the metropolitan area of Cagliari significantly increased their level of accessibility to the beaches, while others did not.•The adopted methodology has proven to be a valid tool for assessing cycling accessibility for different infrastructure scenarios.

There is ample consensus that, besides objective characteristics, psycho-attitudinal factors play a key role in influencing people’s mode choice. Hybrid choice models use these theoretical frameworks so as to include latent constructs for capturing the impact of subjective factors on mode choice. But recent work in transportation research raised the question about the ability of hybrid choice models to derive policy implications that aim to change travel behavior, given the focus on cross-sectional data. To address this problem we designed a survey for collecting longitudinal data (socio-economic and psycho-attitudinal) to evaluate, on the one hand, the long-term effects on travel mode choice of the implementation of a new light rail line in the metropolitan area of Cagliari (Italy), on the other to detect any changes in the psycho-attitudinal factors and socio-economic characteristics after implementation of those measures. In particular, the objective of the study is to analyze whether these changes in individual characteristics are able to affect mode choice from a modeling perspective, through the specification and estimation of hybrid models. Our results show that latent variables were not significantly different over waves, showing that the impact of the psychological construct remained stable over time, even after the introduction of the new light rail. Additionally, we found some evidence that the variables that explain the latent variables could change over time.

The demand for urban mobility has seen a marked increase over the last few decades. The expansion of road networks, the increase in distance traveled and in the number of trips made has created car-dependent cities. One solution for achieving the switch from private car to public transport is the introduction of a new public transport line that improves the accessibility and frequency of service. However, an important behavioral process underpins travel choices and often a change in choice context is not sufficient to evoke behavior change. Voluntary travel behavior change (VTBC) programs were developed for heightening individuals’ awareness of the consequences of their travel choices and of the benefits to be reaped from using sustainable alternatives, through information provision and communication strategies. The objective of the present paper is to analyze the effect on travel mode choice of introducing a new light railway line into the choice set (hard measure) when implementing a VTBC program on a large scale, but with a high degree of personalization (soft measure). Although numerous studies have demonstrated the need to implement a (hard) measure that acts on the choice context, in combination with a (soft) measure that acts in a personalized way on demand, as far as the authors are aware, few have put this into practice. The first results have shown that a combination of hard and soft measures is more effective in evoking travel behavior change and personalized travel plans produce better results than generalized soft measures.

Quiescent human hematopoietic stem cells (HSCs) are ideal targets for gene therapy applications due to their preserved stemness and repopulation capacities; however, they have not been exploited extensively because of their resistance to genetic manipulation. We report here the development of a lentiviral transduction protocol that overcomes this resistance in long-term repopulating quiescent HSCs, allowing their efficient genetic manipulation. Mechanistically, lentiviral vector transduction of quiescent HSC was found to be restricted at the level of vector entry and by limited pyrimidine pools. These restrictions were overcome by the combined addition of cyclosporin H (CsH) and deoxynucleosides during lentiviral vector transduction. Clinically relevant transduction levels were paired with higher polyclonal engraftment of long-term repopulating HSC as compared with standard ex vivocultured controls. These findings identify the cell-intrinsic barriers that restrict the transduction of quiescent HSC and provide a means to overcome them, paving the way for the genetic engineering of unstimulated HSC.

The ACTN3gene may influence performance in team sports, in which sprint action and high-speed movements, regulated by the anaerobic energy system, are crucial to the ultimate success of a match. The aim of this study was to determine the association between the ACTN3R577X (rs1815739) polymorphism and elite team sport athletic status in Italian male athletes. We compared the genotype and allele frequency of the ACTN3R577X polymorphism between team sport athletes (n= 75), endurance athletes (n= 40), sprint/power athletes (n= 64), and non-athletic healthy controls (n= 192) from Italy. Genomic DNA was collected using a buccal swab. Extraction was performed according to the manufacturer’s directions provided with a commercially available kit (Qiagen S.r.l., Milan, Italy). Team sport athletes showed a lower frequency of the 577RR genotype compared to the 577XX genotype than sprint/power athletes (p= 0.044). However, the ACTN3R577X polymorphism was not associated with team sport athletic status compared to endurance athletes and non-athletic controls. Our results agree with a recent large-scale study involving athletes from Spain, Poland, and Russia. The ACTN3R577X polymorphism was not associated with team sport athletic status compared to endurance athletes and non-athletic controls.

The aim of this study was to investigate the association between MCT1 rs1049434 polymorphism and indirect muscle injuries in elite football players. One hundred and seventy-three male elite Italian football players (age = 19.2 ± 5.3 years) were recruited from a first-league football club participating at the Official National Italian Football Championship (Serie A, Primavera, Allievi, Giovanissimi). The cohort was genotyped for the MCT1 rs1049434 polymorphism, and muscle injuries data were collected during the period of 2009–2014 (five football seasons). Genomic DNA was extracted using a buccal swab, and genotyping was performed using PCR method. Structural-mechanical injuries and functional muscle disorder were included in the acute indirect muscle injury group. Participants with the MCT1 AA (AA = 1.57 ± 3.07, n= 69) genotype exhibit significantly higher injury incidents compared to participants with the TT genotype (TT = 0.09 ± 0.25, n= 22, P= 0.04). The MCT1 rs1049434 polymorphism is associated with the incidence of muscle injuries in elite football players. We anticipate that the knowledge of athletes’ genetic predisposition to sports-related injuries might aid in individualizing training programs.

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Innate immune factors may restrict hematopoietic stem cell (HSC) genetic engineering and contribute to broad individual variability in gene therapy outcomes. Here, we show that HSCs harbor an early, constitutively active innate immune block to lentiviral transduction that can be efficiently overcome by cyclosporine H (CsH). CsH potently enhances gene transfer and editing in human long-term repopulating HSCs by inhibiting interferon-induced transmembrane protein 3 (IFITM3), which potently restricts VSV glycoprotein-mediated vector entry. Importantly, individual variability in endogenous IFITM3 levels correlated with permissiveness of HSCs to lentiviral transduction, suggesting that CsH treatment will be useful for improving ex vivogene therapy and standardizing HSC transduction across patients. Overall, our work unravels the involvement of innate pathogen recognition molecules in immune blocks to gene correction in primary human HSCs and highlights how these roadblocks can be overcome to develop innovative cell and gene therapies.

We hypothesized that the role of stroke volume (SV) in the metaboreflex-induced cardiac output (CO) increase was blunted when the metaboreflex was stimulated by exercise muscle ischemia (EMI) compared with post-exercise muscle ischemia (PEMI), because during EMI heart rate (HR) increases and limits diastolic filling. Twelve healthy volunteers were recruited and their hemodynamic responses to the metaboreflex evoked by EMI, PEMI, and by a control dynamic exercise were assessed. The main finding was that the blood pressure increment was very similar in the EMI and PEMI settings. In both conditions the main mechanism used to raise blood pressure was a CO elevation. However, during the EMI test CO was increased as a result of HR elevation whereas during the PEMI test CO was increased as a result of an increase in SV. These results were explainable on the basis of the different HR behavior between the two settings, which in turn led to different diastolic time and myocardial performance.