Francesca Donnaloja

Background: Lipoprotein(a) [Lp(a)] is a causal risk factor for atherosclerotic cardiovascular disease, which remains unaddressed by current lipid-lowering therapies. Given its established role as a genetic independent cardiovascular risk factor, national and international guidelines recommend screening for Lp(a) levels, as elevated concentrations indicate a higher risk of cardiovascular events. Despite these implications and the availability of a simple standardized assay reimbursed by the Italian National Health Service, Lp(a) testing remains largely underused in the Italian clinical practice. The aim of this project was to identify barriers to Lp(a) testing in clinical practice and to develop targeted strategies to promote its incorporation into secondary cardiovascular prevention strategies in Italy, using an implementation science framework. Methods: This project adopted a multi-method approach, using the Behavior Change Wheel (BCW) framework to identify barriers to Lp(a) testing. Barriers identified in the literature were mapped using the Capability, Opportunity, Motivation– Behavior (COM-B) model, and further characterized through the Theoretical Domains Framework. Each identified barrier was subsequently discussed and rated for perceived impact during a multidisciplinary working group involving 12 stakeholders (cardiologists, internists, lipidologists and laboratory professionals). Building on these findings, several intervention strategies were developed in line with BCW guidance and prioritized by stakeholders during a second multidisciplinary working group to ensure overall feasibility . Results: Capability-related barriers, including limited knowledge of Lp(a) as a cardiovascular risk factor, and uncertainty about its role on patient management, were among the most influential. Opportunity barriers included the absence of approved Lp(a)-lowering treatments, and a lack of test standardization. Motivational barriers included a lack of evidence of clinical benefit of Lp(a) reduction and limited awareness of its role in patient management. To address the identified barriers, training initiatives, creation of working groups, sharing of practical tools, alignment between clinicians and laboratories, and patient support emerged as high-priority interventions. Conclusion: To promote Lp(a) testing in secondary cardiovascular prevention Italian clinical practice, this project identified behavioral barriers across all COM-B domains and designed actionable key strategies using a theory-driven approach. Future research should pilot these activities to overcome identified barriers and improve patient management.

Multicriteria Decision Analysis (MCDA) has gained increasing relevance in healthcare as an approach for evaluating options across multiple criteria. This study aims to provide an overview of MCDA applications in Italy, examining their decision contexts, the preference elicitation methods employed, and the stakeholder groups involved. A literature review was conducted across PubMed and Google Scholar (searches up to November 2025), supplemented by Italian studies identified in an international systematic review. For each study, data were collected on publication year, decision context, preference elicitation methods, and stakeholder involvement. Nineteen studies met the eligibility criteria, 16 of which were published after 2017. Most applications concerned priority-setting decisions related to coverage, reimbursement or funding of healthcare interventions, particularly the evaluation of drugs, therapeutic products, and other health technologies. Preference elicitation methods were predominantly compositional, with direct rating and the Analytic Hierarchy Process being the most frequently applied techniques; decompositional approaches were rarely used. Approximately half of the studies implemented a multi-stakeholder approach. Clinicians were the most frequently included group, followed by healthcare providers, while other stakeholder categories, including patients, were less commonly involved. The use of MCDA in Italy is progressively increasing and generally aligns with global trends. However, important opportunities for further development remain. These include extending MCDA applications to earlier stages of the technology lifecycle, adopting more rigorous and robust preference elicitation techniques, and strengthening its multi-stakeholder orientation, particularly by enhancing patient involvement, in order to improve the methodological quality and policy relevance of future MCDA applications in the Italian context.

Introduction Multiple sclerosis (MS) is a chronic neurodegenerative disease that leads to impaired cognitive function and accumulation of disability, with significant socioeconomic burden. Serious unmet need in the context of managing MS has given rise to ongoing research efforts, leading to the launch of new drugs planned for the near future, and subsequent concerns about the sustainability of healthcare systems. This study assessed the changes in the Italian MS market and their impact on the expenditures of the Italian National Healthcare Service between 2023 and 2028. Methods A horizon-scanning model was developed to estimate annual expenditure from 2023 to 2028. Annual expenditure for MS was calculated by combining the number of patients treated with each product (clinical inputs) and the yearly costs of therapy (economic inputs). Baseline inputs (2020–2022) were collected from IQVIA^® real-world data, while input estimation for the 5-year forecast was integrated with analog analyses and the insights of clinicians and former payers. Results The number of equivalent patients treated in 2028 in Italy was estimated at around 67,000, with an increase of 10% versus 2022. In terms of treatment pattern evolution, first-line treatments are expected to reduce their shares from 47% in 2022 to 27% in 2028, and Bruton tyrosine kinase inhibitors are expected to reach 23% of patient shares. Overall, expenditure for MS is estimated to decrease from €721 million in 2022 to €551 million in 2028, mainly due to losses of exclusivity and renegotiation of drug prices. Conclusion Despite the increase in the number of patients treated for MS and the launch of new molecules that will reach high market penetration, the model confirmed sustainability for the Italian National Healthcare Service.

Despite substantial progress in understanding the complex pathophysiology, hypertension remains a serious public health challenge affecting over 1.2 billion adults aged 30–79 years worldwide. Appropriate knowledge of the different pharmaceutical classes of antihypertensive agents and an understanding of the characteristics of individual molecules are essential to optimize clinical outcomes in patients with hypertension. We conducted a computer‐assisted web interviewing (CAWI) quantitative survey in Italy, Poland, and Turkey to investigate physicians’ prescriptions, knowledge, and perceptions of antihypertensive drugs with a focus on β‐blockers, to assess antihypertensive usage patterns and the reasons underlying prescription choices. The survey findings show that β‐blockers retain a pivotal role in the management of hypertension and are prescribed more often for patients with cardiovascular comorbidities than for patients with diabetic comorbidities. In all three countries, nebivolol is the only β‐blocker among the ones analyzed which is consistently prescribed to 20% or more of patients and is overall the most prescribed one for the population with comorbid diabetes. In terms of specific β‐blockers’ features, this study revealed knowledge gaps that underline the need for educational activities focused on the differences among β‐blockers, which are important in choosing the most suitable agent for individualized antihypertensive therapy.

We developed an innovative millifluidic organ-on-a-chip device, named MINERVA 2.0, that is optically accessible and suitable to serial connection. In the present work, we evaluated MINERVA 2.0 as millifluidic gut epithelium-on-a-chip by using computational modeling and biological assessment. We also tested MINERVA 2.0 in a serially connected configuration prodromal to address the complexity of multiorgan interaction. Once cultured under perfusion in our device, human gut immortalized Caco-2 epithelial cells were able to survive at least up to 7 days and form a three-dimensional layer with detectable tight junctions (occludin and zonulin-1 positive). Functional layer development was supported by measurable trans-epithelial resistance and FITC-dextran permeability regulation, together with mucin-2 expression. The dynamic culturing led to a specific transcriptomic profile, assessed by RNASeq, with a total of 524 dysregulated transcripts (191 upregulated and 333 downregulated) between static and dynamic condition. Overall, the collected results suggest that our gut-on-a-chip millifluidic model displays key gut epithelium features and, thanks to its modular design, may be the basis to build a customizable multiorgan-on-a-chip platform.

Mechanical stimuli from the extracellular environment affect cell morphology and functionality. Recently, we reported that mesenchymal stem cells (MSCs) grown in a custom-made 3D microscaffold, the Nichoid, are able to express higher levels of stemness markers. In fact, the Nichoid is an interesting device for autologous MSC expansion in clinical translation and would appear to regulate gene activity by altering intracellular force transmission. To corroborate this hypothesis, we investigated mechanotransduction-related nuclear mechanisms, and we also treated spread cells with a drug that destroys the actin cytoskeleton. We observed a roundish nuclear shape in MSCs cultured in the Nichoid and correlated the nuclear curvature with the import of transcription factors. We observed a more homogeneous euchromatin distribution in cells cultured in the Nichoid with respect to the Flat sample, corresponding to a standard glass coverslip. These results suggest a different gene regulation, which we confirmed by an RNA-seq analysis that revealed the dysregulation of 1843 genes. We also observed a low structured lamina mesh, which, according to the implemented molecular dynamic simulations, indicates reduced damping activity, thus supporting the hypothesis of low intracellular force transmission. Also, our investigations regarding lamin expression and spatial organization support the hypothesis that the gene dysregulation induced by the Nichoid is mainly related to a reduction in force transmission. In conclusion, our findings revealing the Nichoid's effects on MSC behavior is a step forward in the control of stem cells via mechanical manipulation, thus paving the way to new strategies for MSC translation to clinical applications.

Bioprinting is a key technique to fabricate cell-laden volumetric constructs with controlled geometry. It can be used not only to replicate the architecture of a target organ but also to produce shapes that allow for the mimicry, in vitro, of specific desired features. Among the various materials suitable to be processed with this technique, sodium alginate is currently considered one of the most appealing because of its versatility. To date, the most widespread strategies to print alginate-based bioinks exploit external gelation as a primary process, by directly extruding the hydrogel-precursor solution into a crosslinking bath or within a sacrificial crosslinking hydrogel, where the gelation takes place. In this work, we describe the print optimization and the processing of Hep3Gel: an internally crosslinked alginate and ECM-based bioink for the production of volumetric hepatic tissue models. We adopted an unconventional strategy, by moving from the reproduction of the geometry and the architecture of liver tissue to the use of bioprinting to fabricate structures that can promote a high degree of oxygenation, as is the case with hepatic tissue. To this end, the design of structures was optimized by employing computational methods. The printability of the bioink was then studied and optimized through a combination of different a priori and a posteriori analyses. We produced 14-layered constructs, thus highlighting the possibility to exploit internal gelation alone to directly print self-standing structures with finely controlled viscoelastic properties. Constructs loaded with HepG2 cells were successfully printed and cultured in static conditions for up to 12 d, underlining the suitability of Hep3Gel to support mid/long-term cultures.

Alzheimer’s disease (AD) represents one of the most common and debilitating neurodegenerative disorders. By the end of 2040, AD patients might reach 11.2 million in the USA, around 70% higher than 2022, with severe consequences on the society. As now, we still need research to find effective methods to treat AD. Most studies focused on the tau and amyloid hypothesis, but many other factors are likely involved in the pathophysiology of AD. In this review, we summarize scientific evidence dealing with the mechanotransduction players in AD to highlight the most relevant mechano-responsive elements that play a role in AD pathophysiology. We focused on the AD-related role of extracellular matrix (ECM), nuclear lamina, nuclear transport and synaptic activity. The literature supports that ECM alteration causes the lamin A increment in the AD patients, leading to the formation of nuclear blebs and invaginations. Nuclear blebs have consequences on the nuclear pore complexes, impairing nucleo-cytoplasmic transport. This may result in tau hyperphosphorylation and its consequent self-aggregation in tangles, which impairs the neurotransmitters transport. It all exacerbates in synaptic transmission impairment, leading to the characteristic AD patient’s memory loss. Here we related for the first time all the evidence associating the mechanotransduction pathway with neurons. In addition, we highlighted the entire pathway influencing neurodegenerative diseases, paving the way for new research perspectives in the context of AD and related pathologies.