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Blood collected on dry blood spots is fit for newborn screening of sickle cell disease (SCD) by different analytical systems
No full textSickle cell disease (SCD) is a severe hereditary hemoglobinopathy with the highest burden in sub-Saharan Africa. Timely diagnosis via newborn screening is critical to enabling low-cost, life-saving interventions, yet its implementation remains inconsistent worldwide. This study assessed the performance and analytical stability of dried blood spot (DBS) samples collected on Guthrie cards for quantifying hemoglobin S (Hb S), using three high-performance liquid chromatography (HPLC) platforms and one capillary electrophoresis system. Simulated neonatal samples at three Hb S concentrations (non-carrier, carrier, and affected) were analyzed at three timepoints (immediate, 1 week, and 2 weeks post-collection). Across all methods, Hb S quantification was highly reproducible, with inter-timepoint variation remaining within the predefined critical threshold for the vast majority of the measurements. While minor discrepancies were observed for fetal hemoglobin (Hb F), all methods correctly classified samples for SCD screening purposes. These findings confirm that Guthrie card-based DBS is a robust and practical matrix for Hb S detection, suitable for transport and delayed analysis—even across different analytical platforms. Limitations include the use of spiked rather than native SCD neonatal samples and ambient-temperature shipping. Nonetheless, the results support broader adoption of DBS in SCD screening programs, particularly in low-resource or decentralized settings, and highlight the need for further standardization of Hb F quantification
Effectiveness comparison of first-line CDK4/6 inhibitors in patients with hormone-positive HER2-negative advanced breast cancer according to tumor histology: a sub-analysis of the real-world, multicenter, Italian study PALMARES-2
No full textIntroduction: Invasive lobular breast cancer (ILC) is the second most common breast cancer subtype, with distinctive biological and epidemiologic features. Although phase III trials of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in hormone receptor-positive, HER2-negative advanced breast cancer (HR+/HER2-aBC) included patients with ILC, their real-world effectiveness in this population remains poorly characterized. Material and methods: In this sub-analysis of the multicenter, real-world PALMARES-2 study (NCT06805812), we assessed the predictive and prognostic value of lobular histology in HR+/HER2-aBC treated with first-line endocrine therapy (ET) plus CDK4/6i. The primary endpoint was real-world progression-free survival (rwPFS). Associations between histology and outcomes were adjusted for 15 covariates using multivariable Cox-regression and inverse probability of treatment weighting. Results: Among 1982 patients, 367 (18.5 %) had ILC and 1481 (74.7 %) non-special type (NST). Median follow-up was 29.8 and 31.2 months, respectively. ILC was associated with shorter rwPFS versus NST (adjusted hazard ratio [aHR]: 1.24, 95 %CI:1.04–1.47, P=0.017). Palbociclib efficacy was not affected by lobular histology (P for interaction = 0.553) while abemaciclib was less effective in ILC (P = 0.009). All three CDK4/6i achieved similar rwPFS in ILC (ribociclib vs palbociclib: aHR: 1.01, 95 %CI: 0.67–1.45, P = 0.949; abemaciclib vs palbociclib: aHR: 1.13, 95 %CI: 0.75–1.71, P = 0.551; abemaciclib vs ribociclib: aHR: 1.15, 95 %CI: 0.73–1.80, P = 0.549). Conclusions: Tumor histology affects the real-world effectiveness of first line ET plus CDK4/6i. In ILC, all three CDK4/6i performed similarly; therefore, treatment selection should prioritize tolerability, manageability, drug-drug interactions, and patient preferences
SOCIAL AND REPUTATIONAL DRIVERS OF SUNK-COST SENSITIVITY IN INDIVIDUAL AND COLLECTIVE DECISION-MAKING
No full textWhy do people stick with failing plans after investing resources? This dissertation argues that sunk-cost behavior is shaped more by social pressures than by cognitive bias. Across three preregistered, “waste-free” studies, I show that people persist to protect reputation and relationships—especially when others have invested or when commitment signals reliability. When social audiences or obligations disappear, escalation fades. Additional chapters show that voters reward decision-makers who stay committed and develop a framework explaining both cognitive and social costs of changing course. Together, the work explains when sunk costs bind—and when they don’t
BIORELEVANT RELEASE TESTING OF LONG-ACTING INJECTABLES INTENDED FOR PARENTERAL ADMINISTRATION
No full textIn vitro release testing is pivotal in supporting various stages of pharmaceutical development, from formulation design to routine quality control. Its implementation ensures the consistent quality, performance, and regulatory compliance of medicinal products. For orally administered small-molecule drugs, in vitro testing has been extensively studied to establish a quantitative relationship between the dissolution data and plasma drug concentration-time profiles (in vitro-in vivo correlation (IVIVC)). However, the applicability of IVIVC models is limited when interactions of complex drug product (complex in the characteristics of the drug substance, the formulation and/or the route of administration) with the physiological environment occur.
These limitations are particularly evident for parenteral administration routes, such as subcutaneous and intradermal delivery, where the structural and compositional complexity of the injection site can markedly influence drug release, diffusion, and bioavailability. Consequently, there is a growing need of reliable dissolution methods that mimic key aspects of human physiology, both in terms of the composition and physicochemical properties of bodily fluids and hydrodynamics at the specific site of drug administration.
This PhD project aimed to advance the development of biorelevant in vitro testing strategies for complex drug delivery systems intended for parenteral administration, as well as for innovative oral formulations. The first part of the work focused on the subcutaneous tissue, evaluating current methodologies for assessing drug release following subcutaneous administration. Poly(lactide-co-glycolide) microspheres loaded with naltrexone or flurbiprofen were used as model delivery systems to investigate the impact of interstitial fluid and extracellular matrix components on release behavior under different hydrodynamic conditions. Biorelevant media were developed based on an extensive analysis of subcutaneous tissue characteristics, and human tissue samples were analyzed to clarify discrepancies in reported glycosaminoglycan content.
The second part of the project addressed intradermal administration by developing a synthetic model that reproduces the key mechanical properties of the dermis, enabling a more reproducible assessment of drug diffusion compared with conventional ex vivo approaches. Finally, the performance of orodispersible dosage forms containing β-galactosidase was investigated in simulated gastric conditions to evaluate the influence of variability in gastric fluid volumes on in vitro lactose hydrolysis.
Overall, this work contributes to a deeper understanding of the role of biorelevant testing in predicting drug release and performance for complex drug products, supporting more reliable formulation development and regulatory assessment
Reading between the nodes: making multidomain frailty networks clinically meaningful in heart failure
No full textGreater disease severity in adults with paediatric-onset versus adult-onset bronchiectasis: a multicentre EMBARC registry study
No full textBackground: Young adults with paediatric-onset bronchiectasis (POBE) represent a minority of bronchiectasis patients and are poorly characterised. We aimed to compare the characteristics and severity of adults with POBE to adult-onset bronchiectasis (AOBE). Methods: Data from four EMBARC (European Multicentre Bronchiectasis Audit and Research Collaboration) centres were analysed. POBE was defined as patient-reported symptom onset before the age of 18 years, while AOBE was defined as symptom onset at or after the age of 18 years. We compared POBE to AOBE and used multivariable models to identify factors associated with disease severity, including lung function, Pseudomonas aeruginosa infection, exacerbations and hospitalisations. Results: Among 1422 patients, 249 (17.5%) had POBE (mean onset age: 6.5 years) and 1173 had AOBE (mean onset age: 55.4 years). POBE patients were younger at enrolment (50.3 versus 66 years), had longer disease duration (43.3 versus 10.8 years), worse lung function (forced expiratory volume in 1 s (FEV1): 70.8% versus 84.2% predicted), greater radiological extent (Reiff score: 6.0 versus 4.4), higher bacterial infection rates (72.3% versus 54.6%) and more exacerbations (median: 2 versus 1 per year) compared to AOBE (p<0.001 across all comparisons). Symptom duration was independently associated with P. aeruginosa infection, hospitalisation, exacerbations and reduced FEV1 % pred. Congenital aetiologies, such as primary ciliary dyskinesia and primary immunodeficiencies, further contributed to disease severity. Conclusions: Adults with POBE exhibit greater disease severity than those with AOBE, likely due to prolonged symptom duration and congenital aetiologies. Conventional bronchiectasis severity scores may underestimate severity in young people with POBE. Optimised care, including structured transition to adult care, may mitigate progression in POBE patients
Direct current stimulation (DCS) modulates gene expression related to human diseases in the marine chordate Botryllus schlosseri
No full textObjective: Direct current stimulation (DCS) -i.e., the application of a static electric field to the brain through surface scalp electrodes- emerged as a novel therapy for neuropsychiatric disorders. In this study, DCS-induced changes in gene expression were assessed on Botryllus schlosseri, a ubiquitous simple colonial chordate living in temperate seas and sharing genetic remarkable similarities with mammals. Methods: Colonies underwent either sham or real DCS stimulation. Behavioral assessments, including the Siphon Stimulation Test and heart-rate measurements, were conducted before and at three intervals post-stimulation (3, 24, and 48 h). Gene expression was analyzed with sequencing reads via Trimmomatic®. Results: Analysis of heart rate frequency revealed post-treatment differences between the groups immediately after stimulation (p = 0.001), with the effect decreasing over time. Real DCS differentially expressed 164 genes at three h post-DCS, 123 at 24 h, and 199 at 48 h. Conclusions: Our study introduces a novel pre-clinical model for DCS application demonstrating for the first in vivo time an after-effect on gene expression related to inflammation, human development, and neurodegeneration. To the best of our knowledge, this is the first paper addressing DCS effects on gene expression in a living animal model
Emulsion-Solvent diffusion in a double-chip microfluidic platform for scalable production of Lipid@PLGA nanoparticles delivering siRNA therapeutics
No full textScalable nanoparticle manufacturing remains a key bottleneck in the clinical translation of RNA-based nanomedicines. In this study, we demonstrate the successful adaptation of a conventional emulsion-solvent diffusion protocol into an automated microfluidic workflow, illustrating its potential for streamlined and scalable nanoparticle production. Using the SunshineTM microfluidic platform (Unchained Labs), we systematically optimized formulation and process parameters to produce siRNA-loaded hybrid lipid-polymer nanoparticles, featuring a poly(lactic-co-glycolic acid) (PLGA) core and a dipalmitoylphosphatidylcholine shell (mDPPC@PLGA hNPs). Optimised mDPPC@PLGA hNPs exhibited key technological features, matching or exceeding the quality of their benchtop equivalents (bDPPC@PLGA hNPs). Using poly(vinyl alcohol) (PVA) as a stabilizer, monodisperse mDPPC@PLGA hNPs with controlled size (<170 nm) and consistent zeta potential (-30 mV) were achieved with production yields ≥ 40 %. The ability of mDPPC@PLGA hNPs to effectively entrap and slowly release a siRNA targeting nuclear factor NF-κB (siNFκB) was successfully demonstrated. Structural characterization through thermodynamic and SAXS analyses confirmed that the microfluidic produced hNPs retained comparable internal architecture to their benchtop counterparts. Most notably, siNFκB-loaded mDPPC@PLGA hNPs resulted in effective in vitro downregulation of NFκB in lipopolysaccharide-stimulated A549 lung epithelial cells. Collectively, these results establish a novel and robust approach for the scalable fabrication of functional, siRNA-loaded hybrid nanoparticles via emulsion-solvent diffusion, leveraging a commercially available, automated microfluidic system with a serial chip configuration
SOFT ADAPTIVE NANOCOMPOSITES BASED ONMETALLIC CLUSTER ASSEMBLED NETWORKS FORUNCONVENTIONAL DATA PROCESSING
No full textThe continuous increase in distributed sensors and soft autonomous systems
is pushing toward the development of electronic devices capable of
performing local data processing while being directly integrable into soft
and deformable platforms. In this framework, unconventional computing
approaches toghether with materials development provide a viable
strategy to integrate sensing and computation within the same physical
system, overcoming the limitations of traditional silicon-based architectures
in terms of mechanical mismatch and system integration. Here, gold
cluster-assembled films (MCAF) were produced on rigid and soft substrates
by Supersonic Cluster Beam Deposition and investigated as physical
platforms for unconventional data processing. The electrical
characterization of the metallic networks on rigid substrates revealed
nonlinear transport and resistive switching (RS) dynamics correlated to their
structural organization and to substrate-dependent forming processes. The
implantation of MCAF into PDMS enabled the realization of soft RS devices
responsive to electrical, mechanical, and environmental stimuli.
Multielectrode configurations were exploited to build environmentally
sensitive reconfigurable logic gates, while deposition on paper substrates
demonstrated the integration of sensing and bistable electrical response
on a flexible and sustainable platform
Predicting congenital hypothyroidism in newborns with complex risk profiles by using thyroid-stimulating hormone variations across serial dried blood spots
No full textObjectives Newborn screening for congenital hypothyroidism (CH) relies on thyroid-stimulating hormone (TSH) levels from dried blood spots (DBS). We investigated whether incorporating TSH variation across serial DBS could improve prediction of CH in term and preterm infants with complex risk profiles. Methods Among 207,895 newborns screened, 272 (0.13 %) were diagnosed with CH. TSH variations across 3 serial DBS were analyzed in 6,146 healthy infants (2.96 %). Predictive algorithms were developed using linear mixed-effects models in 1,968 term and 1,387 preterm infants with >= 2 and >= 3 DBS, respectively. Average DBS collection times were 58, 260, and 478 h for term and 63, 350, and 664 h for preterm infants. TSH was measured by GSP neonatal hTSH assay (Revvity). Results Daily TSH variation was influenced by the initial DBS1 value. For DBS1 >5.2 and <1.7 mUI/L, increase and decrease, respectively, in TSH level on DBS2 is detectable, and this particularly occurs in preterm infants. In preterms, CH could be excluded when TSH remained <5 mUI/L on DBS1, <6 mUI/L on DBS2, <4 mUI/L on DBS3, and with daily variation <12 % from DBS1 to DBS3 (sensitivity 100 %; specificity 77.85 %). Term infants with TSH <11 mUI/L on DBS1, <4.5 mUI/L on DBS2, and daily variation <13 % from DBS1 to DBS2 may be ruled out for CH (sensitivity 96.5 %; specificity 66.6 %). Conclusions Distinct predictive algorithms for term and preterm newborns, incorporating TSH variations as daily percentage changes, may improve CH rule out in children with complex risk profiles