University of Perugia

Background and objectives: Antibodies to proteolipid protein-1 (PLP1-IgG), a major central myelin protein also expressed in the peripheral nervous system (PNS) as the isoform DM20, have been previously identified mostly in patients with multiple sclerosis (MS), with unclear clinical implications. However, most studies relied on nonconformational immunoassays and included few patients with non-MS CNS autoimmune demyelinating disorders (ADDs). We aimed to investigate conformational PLP1-IgG in the whole ADD spectrum. Methods: We devised a new live cell-based assay (CBA) for PLP1-IgG and used it to test 2 cohorts (retrospective exploratory, n = 284; prospective validation, n = 824) of patients with ADDs and controls (n = 177). Patients were classified as MS, neuromyelitis optica spectrum disorders (NMOSDs), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and other ADDs. PLP1-IgG-positive samples were tested for IgG subclasses, DM20-IgG, and on rat brain tissue-based assay (TBA). Complement-dependent cytotoxicity (CDC) was assessed on a live CBA and antigen specificity and conformational binding through immunoadsorption/colocalization/fixation experiments. Results: PLP1-IgG were found in 0 of 177 controls and 42 of 1104 patients with ADDs mainly diagnosed as other ADDs (19/42) with frequent myelitis/encephalomyelitis (14/19) and coexisting PNS involvement (13/19). Four of 19 patients with other ADDs fulfilled the seronegative NMOSD criteria. PLP1-IgG were also found in patients with MOGAD (11/42), more frequently with PNS involvement (p = 0.01), and in patients with MS (12/42), more frequently with atypical features (p < 0.001). PLP1-IgG-positive MOGAD had higher EDSS scores (p < 0.001) and PLP1-IgG-positive MS had higher severity scores (MSSS, p < 0.001) compared with those PLP1-IgG-negative. Overall, PLP1-IgG were found in 24.1% of patients with CNS+PNS-ADD, 21.2% with atypical MS, 8.3% with MOGAD, 12.0% with seronegative NMOSD, and 1.4% with typical MS. Their frequency within each diagnostic subgroup was consistent between the exploratory and validation cohorts. PLP1-IgG a) colocalized with their target on CBA-TBA, where their binding was abolished after immunoadsorption and fixation-induced conformational epitope alteration; b) mostly pertained to the IgG1/IgG3 subclass (68.3%) and were able to induce CDC; and c) coreacted with DM20 in all 12 patients with PNS involvement tested. Discussion: Conformational PLP1-IgG predominantly identify patients with non-MS ADDs. They should be tested mainly in those with CNS + PNS ADD, coherently with DM20-IgG coreactivity. PLP1-IgG could also be investigated as disease modifiers and prognostic markers in MS and MOGAD. Preliminary evidence supports their pathogenic potential.

Familial Platelet Disorder with associated Myeloid Malignancy (FPDMM, FPD/AML, RUNX1‐FPD), caused by monoallelic deleterious germline RUNX1 variants, is characterized by bleeding diathesis and predisposition for hematologic malignancies, particularly myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Clinical data on FPDMM‐associated AML (FPDMM‐AML) are limited, complicating evidence‐based clinical decision‐making. Here, we present retrospective genetic and clinical data of the largest cohort of FPDMM patients reported to date. We describe 159 European patients (from 94 families) of whom 134 were evaluable for the development of malignant disease. Sixty developed a hematologic malignancy (44.8%), most frequently AML (36/134, 26.9%) or MDS (18/134, 13.4%). Somatic alterations of RUNX1 by gene mutation (48%) and chromosome 21 aberrations (14.3%) were the most common somatic genetic aberrations in FPDMM‐AML, followed by FLT3‐ITD mutations (24.1%). Somatic RUNX1 and FLT3‐ITD mutations were not detected in FPDMM‐associated MDS, suggesting important contributions to leukemic transformation. Remission‐induction chemotherapy resulted in complete remission in 80% of FPDMM‐AML patients with a 5‐year overall survival (OS) of 50.4%. Survival outcome was non‐inferior compared to a large cohort of newly diagnosed adult RUNX1‐mutated AML (5‐year OS 36.6%, p = 0.5), with relatively infrequent concurrent adverse risk somatic aberrations (ASXL1 mutation, monosomal karyotype, monosomy 5/del 5q) in FPDMM‐AML. Collectively, data support the notion that step‐wise leukemic evolution in FPDMM is associated with distinct genetic events and indicate that a substantial subset of FPDMM‐AML patients achieves prolonged survival with conventional AML treatment, including allogeneic stem cell transplant. These findings are anticipated to inform personalized clinical decision‐making in this rare disorder.

Importance Integration of molecular biomarker information into systemic therapy has become standard practice in breast cancer care. However, its implementation in guiding radiotherapy (RT) is slower. Although postoperative RT is recommended for most patients after breast-conserving surgery and, depending on risk factors, following mastectomy, emerging evidence has indicated that patients with low scores on gene expression signatures or selected clinical-pathological features may have very low local recurrence rates. This narrative review explored the potential of biomarker-directed personalized RT approaches, which may optimize treatment strategies and be associated with improved patient outcomes and experiences. Observations Distinctions between prognostic and predictive biomarkers were highlighted, emphasizing the importance of analytical and clinical validity in biomarker-based studies. Findings from studies investigating the prognostic and predictive value of various genomic signatures and immunohistochemical markers for guiding breast RT were presented. These included the Adjuvant Radiotherapy Intensification Classifier and the Profile for the Omission of Local Adjuvant Radiation, which have shown potential in predicting RT benefits. The genomic-adjusted radiation dose and role of tumor-infiltrating lymphocytes were also discussed. Ongoing clinical trials exploring the use of biomarkers in ductal carcinoma in situ and invasive breast cancer to refine RT decision-making were illustrated. Conclusions and Relevance The results of this narrative review suggest that evidence-based shared decision-making is crucial to optimize treatment according to the individual’s predicted benefits and risks along with their personal preferences. Incorporation of biomarker-directed approaches in RT for breast cancer may hold promise for personalized treatment, potentially facilitating omission of RT for patients at low risk of recurrence, while identifying those who may benefit from intensified therapy. This personalized RT approach may be associated with improved clinical outcomes and quality of life and facilitate decision-making for people with breast cancer. However, there remains a need for robust clinical and analytical validation of biomarkers to ensure reliability and clinical utility for RT optimization.

Lithium‐ion batteries (LIBs) are one of the most advanced electrochemical energy storage technologies. However, the increasing demand for LIBs, coupled with problems related to availability and lack of manufacturing centers, has led to lithium market inflation. At this point, sodium‐ion batteries (SIB) represent an economically and environmentally attractive alternative for LIBs. Prussian Blue cathodes (PB) have been extensively studied as cost‐effective materials with volumetric variations that allow the accommodation of sodium ions in the structure. Herein, we present a quasi‐solid Na‐ion cell based on PB cathode and green gel polymer electrolyte (GPE). Nanometric and micrometric PB powders are synthesized and characterized using a wide variety of structural, compositional and electrochemical techniques. The effect of the PB particle size in combination with different electrolytes is investigated. Enhanced cell safety is obtained using a GPE prepared by following a novel green method that avoids using toxic organic solvents. All the tested cells report remarkable electrochemical performance, being the nanometric‐PB/ GPE/ Na cell configuration the one with the highest specific capacity and almost no capacity loss after 100 cycles, outperforming analogous cells assembled with liquid electrolyte. This electrochemical stability is triggered by a robust electrode‐electrolyte interphase.

Background The benefits and risks of extending anticoagulant treatment beyond the first 3 to 6 months in patients with venous thromboembolism (VTE) in clinical practice are not well understood. Methods ETNA-VTE Europe is a prospective, noninterventional, post-authorization study in unselected patients with VTE treated with edoxaban in eight European countries for up to 18 months. Recurrent VTE, major bleeding, and all-cause death were the primary study outcomes. Results The median age of the 2,644 patients was 65 years; 46.6% were female, and 22.8% had a history of VTE. The median treatment duration was 50.6 weeks (interquartile range: 23.4–77.7). VTE recurrence occurred in 100 patients (3.8% at an annual rate of 2.7%/year); 37 patients (1.4%) were on edoxaban at the time of the event, with a corresponding annualized rate of 1.6%/year. Major bleeding was experienced by 37 patients (1.4%) during edoxaban treatment, corresponding to an annualized rate of 1.5%/year. Overall, 95 patients died (3.6%; annualized rate 2.6%/year), with the majority for reasons other than VTE- and cardiovascular (CV)-related causes. Out of 15 deaths (1.9%; annualized rate 2.1%/year) that occurred during edoxaban treatment, 1 was related to VTE and 11 related to CV (annualized rate 0.0%/year and 0.5%/year). Conclusions ETNA-VTE Europe provides evidence for the real-world effectiveness of edoxaban treatment (up to 18 months) based on a low rate of VTE recurrence, all-cause death, and major bleeding, and is aligned with the results of the randomized clinical trial reassuring the use of edoxaban in the treatment of VTE in routine clinical practice.

The low-energy ¹⁹ F(p, $\alpha$ α ) ¹⁶ O reaction has significant implications for nuclear astrophysics. The ¹⁹ F(p, $\alpha$ α ) ¹⁶ O reaction occurs via three channels: (p, $\alpha _0$ α 0 ), (p, $\alpha _\pi$ α π ), and (p, $\alpha _\gamma$ α γ ). At lower temperatures, below 0.15 GK, the (p, $\alpha _0$ α 0 ) channel is the dominant contributor of the reaction. The ¹⁹ F(p, $\alpha _{0}$ α 0 ) ¹⁶ O reaction cross section in the energy range of 400–900 keV was studied in this work. Recent data in the literature reveals a roughly 1.4 increase compared to prior findings reported in the NACRE (Nuclear Astrophysics Compilation of REactions) compilation. Therefore, we present new additional result of the study published in EPJA [22] employing a silicon strip detector array (LHASA - Large High-resolution Array of Silicon for Astrophysics). The anguar distributions, the reaction cross sections and the astrophysical S-factors of the (p, $\alpha _0$ α 0 ) channel were obtained through this experiment. Our findings resolve the discrepancies that exist between the two previously available data sets in the literature.

Patients with ischemic stroke (IS) or TIA face an elevated cardiovascular risk, warranting intensive lipid-lowering therapy. Despite recommendations, adherence to guidelines is suboptimal, leading to frequent undertreatment. This study aims to evaluate the statin use after IS and TIA. LIPYDS is a multicenter, observational, retrospective study including ≥ 18-year-old patients discharged after IS/TIA from 19 Italian centers in 2021. Multivariable logistic regression analysis was used to determine (1) the association between statin prescription (Any-statin versus No-statin), type (High-Intensity-statin versus Other-statin [Moderate/Low-Intensity]) with stroke etiology (TOAST), (2) clinical variables independently associated with statin prescription in the entire cohort and within TOAST categories. We included 3,740 patients (median age 75 [IQR 64–82]; median LDL-C 104 [IQR 79–131]). At discharge, 1,971 (52.7%) received a High-intensity-statin, 800 (21.4%) Other-statin, 969 (25.9%) No-statin therapy. Among patients not on statin therapy before the event (N = 2686 [71.8%]), 50.1% initiated High-intensity-statin (78.2% of those with Large-Artery-Atherosclerosis, 60.8% Small-Vessel-Disease, 34.7% Cardioembolic, 47.4% Undetermined etiology); in 33% the decision to abstain from initiating statin therapy persisted. Large-Artery-Atherosclerosis showed the strongest association with Any-statin (aOR 3.07 [95%CI 2.39−3.95], p < 0.001) and High-intensity-statin (aOR 4.51 [95%CI 3.39−6.00], p < 0.001), while Cardioembolic stroke showed an inverse association (respectively, aOR 0.36 [95%CI 0.31−0.43], p < 0.001 and aOR 0.52 [95%CI 0.44−0.62], p < 0.001). Stepwise regression highlighted LDL-C and previous statin therapy as consistent predictors of statin at discharge. Older patients and women were less likely to be on a high-intensity formulation. Statins, especially at high-intensity, are under-prescribed after IS and TIA, with older patients, women and those with non-atherosclerotic strokes being the most affected.

Background and Aims Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterised by progressive biliary inflammation and fibrosis, leading to liver cirrhosis and cholangiocarcinoma. GPBAR1 (TGR5) is a G protein‐coupled receptor for secondary bile acids. In this study, we have examined the therapeutic potential of BAR501, a selective GPBAR1 agonist in a PSC model. Methods Single‐cell analysis of healthy human liver samples and gene expression analysis of PSC liver samples were conducted. In vitro studies on a human cholangiocyte cell line (NHC), U937 and human hepatic stellate cells (hSteCs) were performed. Additionally, Abcb4 −/− mice were treated with BAR501 for 12–24 weeks. Results Single‐cell analysis demonstrated that GPBAR1 is expressed by macrophages, NK cells, sinusoidal cells and to a lesser extent by cholangiocytes. Total liver expression of GPBAR1 increases in PSC patients compared to that in healthy controls and positively correlates with markers for monocytes and NK cells and cytokeratin 19. In vitro treatment of NHCs with BAR501 reversed the acquisition of a pro‐inflammatory phenotype and the downregulation of GPBAR1 expression promoted by LPS in an NF‐κB‐dependent manner. Treating Abcb4 −/− mice reduced bile duct inflammation and liver fibrosis and prevented the downregulation of GPBAR1 expression. Treating mice with BAR501 also modulated the bile acid pool composition and reduced the dysbiosis‐associated gut permeability, and intestinal and systemic inflammation. Ex vivo experiments using conditioned media from BAR501‐treated cholangiocytes mitigated the activation of macrophages. Conclusions Our study provides evidence for the therapeutic potential of selective GPBAR1 agonists in intestinal inflammation–associated cholestasis, warranting the evaluation of BAR501 in PSC patients.

In statistical analysis, Cochran's formula plays a crucial role in disentangling the relationships between marginal and conditional regression coefficients. However, its results and implications are valid only within the linear case. Despite this, due to its simplicity and interpretability, practitioners often continue to use Cochran's formula also outside linear models. With reference to binary outcome models, we derived the approximated expression of the marginal regression coefficient when marginalization is performed over a continuous covariate and show that it mimics Cochran's formula under certain simplifying assumptions. We initially postulate a logistic link function and then show how it can be generalized. We then explore the implications of this formula in the context of sensitivity analysis and causal mediation analysis, thereby enlarging the number of circumstances where explicit parametric formulations can be used to evaluate causal direct and indirect effects, otherwise computed via numerical integration. Simulations show that our proposed estimators perform equally well as others based on numerical methods and that the additional interpretability of the explicit formulas does not compromise their precision.

In this work, we present an efficient Brønsted acid‐catalysed intramolecular hydroamination reaction of homopropargyl N‐tosyl amides to produce synthetically useful substituted γ‐lactams through the corresponding alkynyl phenyl selenide intermediates. Our focus on optimising the cyclisation protocol under flow conditions has led to a significant enhancement in efficiency, thereby reducing the time and resources required for the process. DFT calculations of the reaction mechanism for the catalytic transformation of a model alkynyl phenyl selenide were also conducted.

Background:Dental anxiety and odontophobia significantly impact patient care and oral health. These conditions stem from factors such as direct conditioning, vicarious learning, and psychological predispositions, often leading to somatic symptoms and severe avoidance behaviors. Hypnosis has emerged as an effective approach for managing dental anxiety, providing benefits such as reduced fear and pain perception, improved patient collaboration, and enhanced healing. Materials and Methods:This systematic review followed PRISMA guidelines and analyzed studies retrieved from PubMed, Scopus, and Cochrane databases between 2019 and 2024. Randomized controlled trials, crosssectional studies, and comparative analyses examining hypnosis for dental anxiety and phobia were included. The Newcastle-Ottawa Scale assessed study quality and risk of bias. Data extraction focused on study design, outcomes, and patient demographics. Results:The search identified 75 papers, of which 56 were screened after removing duplicates. Following inclusion criteria, eight studies were analyzed. The risk of bias varied, with one high-quality study, two medium, and five low-quality studies. Evidence demonstrated hypnosis reduced anxiety, improved patient cooperation, and supported better oral health outcomes by addressing anticipatory anxiety and avoidance behaviors. Conclusion: Hypnosis, combined with techniques like hypnotic communication and iatrosedation, offers a nonpharmacological strategy to manage dental anxiety and phobia. These approaches establish trust, redefine negative past experiences, and personalize patient care, leading to improved dental experiences and psycho-oral health. Implementing these methods in dental practice can enhance patient well-being and treatment outcomes.

Background. Mucositis and peri-implant disease are pathological conditions found following bacterial colonization on the peri-implant soft tissues and on the implant fixture during implant-prosthetic rehabilitation, from single edentulism to full-arch rehabilitation. The therapeutic approaches to the two pathological conditions use surgical and non-surgical therapeutic protocols, with the aim of eliminating the bacterial biofilm from the implant surface, through the use of mechanical, chemical or photodynamic agents. The aim was to evaluate the effect of the electric field generated by the Ximplant machine on the bacterial load and on the biofilm grown on the dental implants. Materials and methods. Twenty-eight dental implants were contaminated with the saliva of a donor, and subsequently fifteen implants were treated with the electric field generating machine while twelve were not treated. The bacterial biofilm was then measured by resazurin assay, both on treated and untreated implants. Results. The results revealed a difference between treated and untreated implants in terms of biofilm activity,as assessed by color change using the resazurin assay. Treated implants (n = 15) showed no color change across all observation time points (2 hours, 1 day, 2 days, 3 days), indicating an absence of bacterial activity or residual biofilm. Conversely, all untreated implants (n = 12) exhibited a consistentcolor change starting at 2 hours, suggesting persistent biofilm activity. A sterile implant used as a negative control (n = 1) showed no color change throughout the experiment, confirming the absenceof contamination. Conclusion.The study showed preliminary success of the electrofield in reducing microbial populations and destroying clinical biofilm, compared to a sterile implant as a control

Separation of the two mirror images of a chiral molecule, the enantiomers, is a historically complicated problem of major relevance for biological systems. Since chiral molecules are optically active, it has been speculated that strong coupling to circularly polarized fields may be used as a general procedure to unlock enantiospecific reactions. In this work, we focus on how chiral cavities can be used to drive asymmetry in the photochemistry of chiral molecular systems. We first show that strong coupling to circularly polarized fields leads to enantiospecific Rabi splittings, an effect that displays a collective behavior in line with other strong coupling phenomena. Additionally, entanglement with circularly polarized light generates an asymmetry in the enantiomer population of the polaritons, leading to a condensation of the excitation on a preferred molecular configuration. These results confirm that chiral cavities represent a tantalizing opportunity to drive asymmetric photochemistry in enantiomeric mixtures.