Chronic myeloid leukemia (CML) in childhood represents only 3% of newly diagnosed pediatric leukemia. The diagnostic hallmark of CML is the Philadelphia (Ph) chromosome, which derives from the fusion ...of the ABL1-oncogene located on chromosome 9 to the breakpoint cluster region (BCR) gene on chromosome 22, resulting in a constitutively dysregulated ABL1 tyrosine kinase, either as 210 kDa or 190 kDa. Depending on the localization of the breakpoint site within the major BCR region, the majority of CML patients exhibit transcripts with either the b3a2 or b2a2 junction, or both. Several questions are still open with regard to childhood CML, especially concerning the biologic and clinical features of the disease, and the treatment of choice for pediatric patients with CML. Moreover, over the last few years, several tyrosine kinase inhibitors (TKIs) have been available for children and adolescents with CML, and current clinical practice investigates what the effective and optimal doses of TKIs are in these two categories of patients. The use of TKIs in pediatric patients with CML has also opened up questions on the following items: (1) the long-term effects of these drugs on children; (2) the management of pediatric CML forms resistant or intolerant to TKIs; (3) the monitoring of disease outcomes during treatment; (4) and the right timing to discontinue therapy. Despite the efficacy of TKIs also in the pediatric population, the potential late adverse effects, and the drug resistance, leave open the possibility of allogeneic hematopoietic stem cell transplantation as a treatment option in pediatric CML. Published data and personal experiences regarding these issues will be analyzed and discussed.
Gaucher disease (GD) has been increasingly recognized as a continuum of phenotypes with variable neurological and sensory involvement. No study has yet specifically explored the spectrum of ...neuropsychiatric and sensory abnormalities in GD patients through a multidisciplinary approach. Abnormalities involving the nervous system, including sensory abnormalities, cognitive disturbances, and psychiatric comorbidities, have been identified in GD1 and GD3 patients. In this prospective study, named SENOPRO, we performed neurological, neuroradiological, neuropsychological, ophthalmological, and hearing assessments in 22 GD patients: 19 GD1 and 3 GD3. First, we highlighted a high rate of parkinsonian motor and non-motor symptoms (including high rates of excessive daytime sleepiness), especially in GD1 patients harboring severe glucocerebrosidase variants. Secondly, neuropsychological evaluations revealed a high prevalence of cognitive impairment and psychiatric disturbances, both in patients initially classified as GD1 and GD3. Thirdly, hippocampal brain volume reduction was associated with impaired short- and long-term performance in an episodic memory test. Fourthly, audiometric assessment showed an impaired speech perception in noise in the majority of patients, indicative of an impaired central processing of hearing, associated with high rates of slight hearing loss both in GD1 and GD3 patients. Finally, relevant structural and functional abnormalities along the visual system were found both in GD1 and GD3 patients by means of visual evoked potentials and optical coherence tomography. Overall, our findings support the concept of GD as a spectrum of disease subtypes, and support the importance of in-depth periodic monitoring of cognitive and motor performances, mood, sleep patterns, and sensory abnormalities in all patients with GD, independently from the patient's initial classification.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The aim of this paper is to examine generic competition in the UK, with a special focus on the role of Health Technology Assessment (HTA) on generic market entry and diffusion. In the UK, where no ...direct price regulation on pharmaceuticals exists, HTA has a leading role for recommending the use of medicines providing a non-regulatory aspect that may influence the dynamics in the generic market. The paper focuses on the role of Technology Appraisals issued by the National Institute for Health and Care Excellence (NICE). We follow a two-step approach. First, we examine the probability of generic entry. Second, conditional on generic entry, we examine the determinants of generic market share. We use data from IQVIA British Pharmaceutical Index (BPI) for the primary care market for 60 products that lost patent between 2003 and 2012. Our results suggest that market size remains one of the main drivers of generic entry. After controlling for market size, intermolecular substitution and difficulty of manufacturing increase the likelihood of generic entry. After generic entry, our estimates suggest that generic market share is highly state dependent. Our findings also suggest that while NICE recommendations do influence generic uptake, there is only marginal evidence they affect generic entry.
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CEKLJ, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
AbstractNonstructural components typically are not designed for seismic loads, yet their behavior can affect the postearthquake building functionality significantly. Nonstructural damage occurs at ...low to moderate seismic intensities, heavily contributing to downtime and overall financial loss. Moreover, the failure of these elements can represent a potential life-safety threat for occupants and pedestrians. Due to increased awareness of these issues, in recent decades substantial research efforts have been dedicated to the study of nonstructural seismic behavior. Focusing on architectural elements (facades, partitions, and ceilings), this paper provides a state-of-the-art review of fragility functions. Seismic damage states were described and literature data were collected to build fragility domains for different nonstructural archetypes. Furthermore, references to innovative low-damage technologies are provided, and traditional (i.e., construction practice) systems were compared with low-damage components in terms of fragility. A fragility-based direct design approach is suggested based on the state-of-the-art review: nonstructural details could be designed, manufactured, or selected specifically to target desired tailored fragility curves representing targeted (multi)performance levels.
Rare cases of immune thrombocytopenia (ITP) occurring after SARS-CoV-2 mRNA vaccines have recently reached public attention. It has been reported in patients with previous ITP or other autoimmune ...diseases and in individuals with an apparent negative past medical history. The management and the outcome of these cases are still not well investigated and reported in the medical literature. A 23-year-old female with a past medical history of ITP, in stable complete remission for 3 years and on mycophenolate treatment received SARS-CoV-2 mRNA vaccine. She presented severe ITP recurrence with hemorrhagic symptoms after the second vaccine dose. A combined treatment with high-dose immunoglobulin and prednisone was successfully administered with a full recovery of platelet count. The patient remains in ITP remission and on mycophenolate therapy, five months later. At our Center, none of the other 76 adult “fragile patients” with ITP on immunosuppressive treatment who had received the SARS-CoV-2 mRNA vaccine, developed such a severe thrombocytopenic recurrence. Follow-up of large cohorts of patients receiving mRNA vaccine will answer the question as to whether it increases the risk of autoimmune conditions. So far, the benefits of the vaccination largely outweigh the risk of infection in these patients.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract OBJECTIVES Results of epidemiological studies of lipid profiles in individuals with Down Syndrome (DS) in different settings showed discordant results but laboratory norms for this ...population has been lacking. The aim of our study is to evaluate lipid profiles in a large population of Italian children with DS. METHODS Lipid profiles of 357 patients with diagnosis of DS were recorded. RESULTS: Multiple linear regression was employed to estimate models for each lipid fraction as a function of sex and age in patients with DS. CONCLUSIONS The main contribution of this paper is to provide data about lipid profile on a large cohort of people with Down syndrome. Long-term surveillance will be crucial to establish if this specific lipid profile may translate into increased morbidity and mortality from cardiovascular diseases (CVD)
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Innovative damage-mitigation technologies have been recently developed to improve the seismic performance of structural and non-structural elements. The combination of these solutions can lead to a ...high-performance and cost-efficient building system, capable of sustaining earthquakes with limited damage and reduced socio-economic losses. This article investigates the convenience of implementing damage-control solutions through a cost/performance-based evaluation of multi-story-reinforced concrete buildings, comprising alternative combinations of traditional vs low-damage technologies for both structural skeletons (frames, walls) and non-structural elements (heavy/light facades, heavy/light partitions, suspended ceilings). The significant benefits of the innovative systems are investigated through loss assessment studies, implemented using a practical approach based on numerical pushover analyses and the capacity spectrum method. The parametric analyses confirm that the integrated low-damage structural/non-structural system can lead to significant savings, in these specific cases, in the range of 150-300 euro/m2 during the 50-year building-life and downtime reductions at ultimate limit state in the order of 2-7 months.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
•Seismic safety and environmental sustainability need to be considered simultaneously.•A probabilistic risk assessment is proposed to support building investment decisions.•Integrated seismic and ...energy economic losses are used as design decision variable.•Traditional vs low-damage seismic-resisting technologies are investigated.•Design solutions are assessed and compared in terms of reliability and risk values.
Structural safety and environmental sustainability are major factors in investment decisions for building systems, but are rarely considered simultaneously. Recent research efforts have redressed this by developing assessment methodologies and technical solutions for integrated energy efficiency and seismic performance. These studies are typically limited to existing buildings and retrofit interventions at global building scale, whereas an effective framework could and should be part of the design process of either new or existing buildings at both building and component scales. This paper proposes a probabilistic-based assessment framework to assess the building performance in terms of integrated economic losses and support the selection of resilience-enhanced solutions. The proposed methodology is validated through its application to reinforced concrete case-study buildings consisting of traditional vs low-damage earthquake-resistant technologies coupled with energy efficiency strategies. Seismic and energy risk assessment analyses are performed accounting for both modelling uncertainties and earthquake/weather variability. Probabilistic distributions of the integrated economic losses are finally derived to compare the design solutions in terms of risk and reliability. The research outcomes demonstrate the effectiveness of the probabilistic approach for decision-making in building projects. Specifically, it is found that the economic losses can be highly underestimated (greater than40 %) in the single domains (energy or seismic); greater savings and return on investment can be achieved when the seismic safety is involved in the design process; probabilistic distributions and reliability/risk values can represent an effective tool to assess and compare design solutions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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