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Palmitoylethanolamide (PEA) has been prescribed in neuropathic pain management for over 20 years. This study aims to summarize what has been published on the topic in the last 15 years and determine the appropriateness of the prescribing. It describes the pharmacological aspect of PEA, especially focusing on its pharmacodynamics and pharmacokinetics. Then, it deeply explores why PEA may be useful in the pharmacological management of both neuropathic and mixed pain. Finally, it examines some innovative patent, which aims to address obstacles encountered with conventional PEA formulations, for its pharmacodynamic characteristics. One of them (Equisetum-PEA) seems promising. It partially ameliorates the bioavailability and the targeted distribution. It seems to introduce novel advancements that can potentially enhance the therapeutic effectiveness of PEA in terms of its anti-inflammatory, antioxidant, and analgesic properties. The deep literature analysis aims to examine the potential advantages of PEA, in the context of several pathological conditions that may benefit from this molecule. It focuses on various published data regarding the clinical efficacy of PEA in managing neuropathic and mixed pain. Also, it tries to understand if it can modernize the field of therapy based on PEA, thus offering a better treatment option for individuals with chronic long-term inflammation, oxidative stress, and neuropathic or mixed pain with a neuropathic component. The study examines the possible impact of PEA on personalized medicine strategies and its potential for translation into clinical practice. It analyses the possibilities that PEA has in enhancing patient outcomes in a range of central nervous system and inflammatory conditions. A complete analysis of the therapeutic potentialities of this product was missing. This extensive narrative review makes a valuable contribution to the ongoing comprehension of PEA therapy. It establishes a foundation for further exploration in research and potential uses in clinical settings., Competing Interests: Declarations. Conflict of Interests: Giustino Varrassi declares relationships as a component of the speakers’ bureau, consultant and member of advisory boards of: Abbott International; Berlin-Chemie; Dompé Farmaceutici (Italy); Epitech Group (Italy); Grünenthal; Inomed (Italy); Menarini Africa and Middle East (Abu Dhabi); Menarini Asia–Pacific (Singapore); Menarini Central America (Guatemala); Menarini International; L. Molteni & C. Dei Fratelli Alitti (Italy); Shionogi, Takeda (Italy); Viatris (Italy); Zambon (Italy). His laboratory in the past has received research grants from CNR (Italy), Dompé Farmaceutici (Italy); Epitech Group (Italy); Fondazione Maugeri (Italy), Pfizer (Italy). Gabriele Finco declares relationships during the past 2 years as a conference speaker, member of advisory boards or consultant for the following pharmaceutical companies: Abiogen Pharma (Italy); Alfasigma (Italy); Angelini Industries (Italy); Bayer Italia (Italy); Grünenthal Italia (Italy); Lundbeck Italia (Italy); L. Molteni & C. Dei Fratelli Alitti (Italy); SPA (Italy); Sandoz (Italy); Viatris (Italy); Zambon (Italy). Domenico Tiso and Chiara Corno declare relationships with Urgo Foundation. Salvatore Sardo declares relationships as a conference speaker with Agave Group (Italy). Giustino Varrassi is the Co-Editor-in-Chief of the Journal “Pain and Therapy.” Antonella Paladini and Martina Rekatsina are members of the Editorial Board of the Journal “Pain and Therapy.” Giustino Varrassi, Antonella Paladini and Martina Rekatsina were not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Matteo Luigi Giuseppe Leoni, Marco Cascella, Vittorio Schweiger and Diego Maria Michele Fornasari have no conflict of interest to declare related to this research. Ethical Approval: This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors., (© 2024. The Author(s).)

The field of cyber risks is rapidly expanding, yet significant research remains to be conducted. Numerous taxonomy-based systems have been proposed in both the academic literature and industrial practice to classify cyber risk threats. However, the fragmentation of various approaches has resulted in a plethora of taxonomies, often incongruent with one another. In this study, we undertake a comprehensive review of these alternative taxonomies and offer a common framework for their classification based on their scope. Furthermore, we introduce desirable properties of a taxonomy, which enable comparisons of different taxonomies with the same scope. Finally, we discuss the managerial implications stemming from the utilization of each taxonomy class to support decision-making processes., (© 2024 The Author(s). Risk Analysis published by Wiley Periodicals LLC on behalf of Society for Risk Analysis.)

Metal halide perovskites have shown exceptionally slow hot-carrier cooling, which has been attributed to various physical mechanisms without reaching a consensus. Here, experiment and theory are combined to unveil the carrier cooling process in formamidinium (FA) and caesium (Cs) tin triiodide thin films. Through impulsive vibrational spectroscopy and molecular dynamics, much shorter phonon dephasing times of the hybrid perovskite, which accounts for the larger blueshift in the photoluminescence seen at high excitation density for FASnI 3 compared to CsSnI 3 is reported. Density functional theory investigations reveal that the largest contribution to the blueshift is accounted by a giant, dynamic band-filling effect in Sn-based perovskites, which in turn can explain the cooling disparity with the Pb-based counterparts. Several years after the first experimental observations, here a deeper understanding of the cooling mechanism of these materials is provided. Design principles for hot-carrier materials, which may be useful for future implementations of hot-carrier solar cells are further provided., (© 2024 The Author(s). Advanced Materials published by Wiley‐VCH GmbH.)

This work investigates nanostructured Ho 0.5 Ca 0.5 MnO 3 , considered a model system of the Ln 0.5 Ca 0.5 MnO 3 series of manganites with perovskite structures featuring small lanthanide (Ln) ions half-substituted by Ca ions. Here, we propose a modified hybrid sol-gel-solid-state approach to produce multiple samples with a single batch, obtaining very high crystalline quality and ensuring the same chemical composition, with an average particle size in the range 39-135 nm modulated on-demand by a controlled calcination process. Our findings evidence that, provided the crystalline structure is preserved, the charge-ordering transition can be observed even at the nanoscale. Additionally, this research explores the presence of glassy phenomena, which are commonly seen in this class of materials, to enhance our understanding beyond simplistic qualitative observations. Comprehensive characterization using DC and AC magnetometry, along with relaxation and aging measurements, reveals that the complex dynamics typical of glassy phenomena emerge only at the nanoscale and are not visible in the bulk counterpart. Nevertheless, the analysis confirms that even the sample with the smallest nanoparticles cannot be intrinsically classified as canonical spin glass., Competing Interests: The authors declare no conflict of interest.

By combining Er III and Yb III ions with 3,6-dithiophene-anilate (Th 2 An) and scorpionate hydrotris(pyrazol-1-yl)borate (HBpz 3 - ) ligands new luminescent dinuclear complexes are obtained. The two materials formulated as [((HB(pz) 3 ) 2 Yb) 2 (μ-th 2 An)]·4DCM·1.3H 2 O 1Yb and [((HB(pz) 3 ) 2 Er) 2 (μ-th 2 An)]·4DCM·1.8H 2 O 1Er, respectively, have been structurally characterized by SC-XRD and PXRD studies. This study presents a comprehensive investigation of the photophysical properties of the Th 2 An ligand for the first time. Our findings reveal the crucial role of the thiophene anilate as an effective optical antenna, which sensitizes near-infrared (NIR)-emitting lanthanide ions, specifically Er III and Yb III . The significant impact of vibrational quenching on the Ln III NIR emission efficiency has been also highlighted.

The management of immune-mediated nephropathies in the elderly presents unique challenges due to age-related physiological changes, comorbidities, and frailty. This review addresses the clinical workup, diagnostic evaluation, and treatment strategies for this rapidly growing patient population. We highlight the inadequacies of current classification systems and the lack of evidence-based guidelines tailored to individuals ≥75 years. The review discusses the specific considerations in diagnosing and treating common conditions such as minimal change disease, focal and segmental glomerulosclerosis, membranous nephropathy, ANCA-associated vasculitis, infection-related and post-infectious glomerulonephritis, and anti-GBM disease. Managing these diseases requires a nuanced approach due to age-related changes in the immune system and the presence of multiple comorbidities. Immunosuppressive therapy, including corticosteroids, rituximab, and cyclophosphamide, remains a cornerstone of treatment, but the choice and dosage of drugs must be carefully balanced to avoid severe side effects. Comorbidity management, regular monitoring of kidney function, and a patient-centered approach are crucial for improving outcomes and quality of life. A multidisciplinary team can provide comprehensive care, addressing all aspects of the patient's health. Supportive care, the role of kidney biopsy, and the balance between immunosuppressive therapy and the risk of complications are emphasized. Collaborative, individualized care approaches are recommended to improve outcomes and quality of life for elderly patients with immune-mediated kidney diseases. Future research should focus on including older patients in clinical trials to establish robust, age-specific guidelines.

Seabather's eruption (SBE) is an acute dermatitis characterized clinically by erythematous papules located almost exclusively under a bathing suit. SBE is caused by contact on the skin by the jellyfish, Linuche unguiculata (L. unguiculata). To report our clinical experience of SBE, with a description of the presentation of the first SBE cases from the Mediterranean Sea. In the period 1987-2023, we observed seven patients with SBE; four males and three females, with an age ranging from 16 to 56 years (mean age: 37.2 years). All patients contracted SBE in the Mediterranean Sea, which was characterized by a typical clinical picture of erythematous papules located almost exclusively under the bra or underpants, accompanied by severe pruritus. In all patients, SBE showed a typical clinical presentation and it was possible to exclude other diagnoses, such as swimmer's itch, folliculitis, acne/acneiform eruptions, and follicular larva migrans. No cases of SBE have been previously reported from patients swimming in the Mediterranean Sea. L. unguiculata may have reached the Mediterranean Sea from the Atlantic Ocean, however, it is also possible that SBE in our patients was caused by different microorganisms other than L. unguiculata, supporting the hypothesis, as previously suggested, that SBE can be caused by microorganisms other than L. unguiculata.

Purpose: To measure the displacement of retinal vascular plexi and choriocapillaris after pars plana vitrectomy for idiopathic macular hole, using optical coherence tomography angiography, and correlate it with clinical data., Methods: Retrospective series with a 6-month follow-up. Records included Best Corrected Visual Acuity, M-charts, structural optical coherence tomography, and optical coherence tomography angiography. Coronal displacement was calculated comparing consecutive images across the 6.4 mm × 6.4 mm field and concentric circular regions of 0.5, 1.5, and 3.0 mm radii . Each circular region was further divided in four quadrants indicated as follows: SuperoTemporal; SuperNasal; InferoTemporal; InferoNasal., Results: The study comprised 33 patients (11 men and 22 women) with 68.9 ± 10.2 years mean age, similar among sexes. Macular hole closed in 31/33 (93.9%) of cases and Best Corrected Visual Acuity improved from mean 20/62 (0.50 ± 0.62 logarithm of Minimum Angle of Resolution) to 20/47 (0.23 ± 0.63 logarithm of Minimum Angle of Resolution; P = 0.0064). Vertical and horizontal metamorphopsia decreased from 0.98 ± 0.68 to 0.51 ± 0.59° ( P = 0.0028) and 0.84 ± 0.63 to 0.29 ± 0.45° ( P < 0.001), respectively. The average retinal displacement was 81.2 ± 44.1 µ m for the superficial plexus and 79.4 ± 45.7 µ m for the deep one, both greater than the choriocapillaris displacement (60.9 ± 20.2 µ m; P < 0.05). The temporal and superior quadrants displaced more than the others ( P < 0.05). Macular hole size correlated to retinal displacement within the central 0.5-mm radius area at all layers ( P < 0.05 in all cases)., Conclusion: Macular hole closure is associated with significant retinal displacement of all retinal layers and choriocapillaris remodeling. Surgical peeling removes the constraining effect of the internal limiting membrane and promotes a multilayered displacement that fills the retinal defect, likely due to a change in the equilibrium of forces between the contractile retinal structures: the larger superficial retinal vessels and the retinal nerve fiber layer., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Opthalmic Communications Society, Inc.)

Understanding the intricate interactions of molecular dyes with nucleic acids is pivotal for advancing medical and biochemical applications. In this work, we present a comprehensive study of the interplay between a novel series of bis-acridine orange (BAO) dyes and double-stranded DNA (dsDNA). These BAO dyes were intentionally designed as two acridine orange units connected by neutral linkers featuring a 2,5-disubstituted thiophene moiety. Comparative analysis of BAO compounds with the widely utilized DNA-binding dye EvaGreen (EG) was carried out for fibroblast staining and qPCR analysis. The results show that BAO dyes outperform EG by supporting PCR amplification over a broader concentration range (0.5-5.0 μM). Furthermore, they exhibit an exceptional capability to generate consistent DNA melting curves regardless of DNA concentration fluctuations. Molecular dynamics simulations showed that BAO dyes when interacting with dsDNA unfold from the stacked conformation to the elongated one. The difference in the energy between the conformations is shown to be concomitant with fluorescence enhancement. This study enriches our understanding of the intricate interplay between innovative BAO dyes and dsDNA, fostering their applications in medical and biochemical research, particularly in qPCR methodologies and bioimaging techniques.

Superconductivity in infinite layer nickelates Nd&#95;{1-x}Sr&#95;{x}NiO&#95;{2} has so far been achieved only in thin films, raising questions on the role of substrates and interfaces. Given the challenges associated with their synthesis it is imperative to identify their intrinsic properties. We use resonant inelastic x-ray scattering to investigate the influence of the SrTiO&#95;{3} capping layer on the excitations of Nd&#95;{1-x}Sr&#95;{x}NiO&#95;{2} (x=0 and 0.2). Spin excitations are observed in parent and 20% doped Nd&#95;{1-x}Sr&#95;{x}NiO&#95;{2} regardless of capping, proving that magnetism is intrinsic to infinite-layer nickelates and appears in a significant fraction of their phase diagram. In parent and superconducting Nd&#95;{1-x}Sr&#95;{x}NiO&#95;{2}, the spin excitations are slightly hardened in capped samples compared to the noncapped ones. Additionally, a weaker Ni-Nd charge transfer peak at ∼0.6  eV suggests that the hybridization between Ni 3d and Nd 5d orbitals is reduced in capped samples. From our data, capping induces only minimal differences in Nd&#95;{1-x}Sr&#95;{x}NiO&#95;{2} and we phenomenologically discuss these differences based on the reconstruction of the SrTiO&#95;{3}-NdNiO&#95;{2} interface and other mechanisms such as crystalline disorder.

Burst-like activation of postural muscles has been previously described and plays a crucial role in elucidating the strategies for postural control adopted by the central nervous system (CNS). A spatio-temporal descriptor of surface electromyographic (sEMG) bursts (STB) is proposed and applied to statistically quantify the burst-like activity of the right and left (R-L) lumbar erector spinae muscle of nine seated violinists playing for two hours. The STB signal is the number of pixels of the high density sEMG (HDsEMG) maps simultaneously showing sEMG amplitude above a given threshold. Burst activity was present in all nine subjects. Four of them met four stringent criteria allowing analysis of frequency, duration, and synchronization between the R-L bursts after 0, 15, 30, 60, 120 min of playing. Mean square coherence between STBs of the two muscles was > 0.75 within ⁓1 Hz bandwidth between 2.2 Hz and 4.5 Hz depending on subject. Non-parametric statistics was applied to compare, in time and space, the R-L features of the bursts. The mean STB width was significantly associated primarily to side and secondarily to time and ranged from 100 to 250 ms. The right STB signals led the left (p < 0.02) by 0 - 160 ms.The inverted pendulum composed by the upper body of a seated violinist is controlled in an intermittent way. The erector spinae of the selected subjects were active, on average, for less than 50% of the time. These findings demonstrate a CNS strategy of intermittent back muscle activation presumably aimed to reducing fatigue during hours of playing in seated violinists., (© 2024. The Author(s).)

Background: Acute central nervous system (CNS) complications are common and well described among pediatric patients undergoing haematopoietic cell transplantation (HCT). However, their long-term outcomes are not known. The aim of this study is to describe the incidence, characteristics, and risk factors of long-term epilepsy in pediatric patients with acute CNS complications of HCT., Methods: This retrospective study included pediatric patients who developed acute CNS complications from autologous or allogeneic HCT between 2000 and 2022. Clinical, therapeutic and prognostic data including long-term outcomes were analyzed. A diagnosis of epilepsy was provided if unprovoked seizures occurred during follow-up., Results: Ninety-four patients (63 males, 31 females, median age 10 years, range 1-21 years) were included. The most common acute CNS complications were posterior reversible encephalopathy syndrome (n = 43, 46 %) and infections (n = 15, 16 %). Sixty-five patients (69 %) had acute symptomatic seizures, with 14 (16 %) having one or more episodes of status epilepticus (SE). Nine patients (9.6 %) were diagnosed with long-term focal epilepsy during the follow-up (5-year cumulative incidence from the acute complication, 13.3 %). Acute symptomatic SE during neurological complications of HCT was associated with an increased risk of long-term epilepsy (OR=14, 95 % CI 2.87-68.97)., Conclusions: A higher occurrence of epilepsy has been observed in our cohort compared to the general population. Acute symptomatic SE during HCT was associated with a higher risk of long-term epilepsy. Pediatric patients with CNS complications during HCT could benefit from specific neurological follow-up. Further studies are needed to characterize mechanisms of epileptogenesis in pediatric patients undergoing HCT., Competing Interests: Declaration of competing interest The Authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2024 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

A new series of muscarinic acetylcholine receptor (mAChR) ligands obtained by inserting different substituents in position 2 of the potent 6,6-diphenyl-1,4-dioxane antagonists 4 and 5 was designed and synthesized to investigate the influence of steric bulk on the mAChR affinity. Specifically, the insertion of a 2-methyl group, affording compounds 6 and 9, resulted as the most favorable modification in terms of affinity for all muscarinic subtypes. As supported by computational studies performed on the hM 1 receptor, this substituent may contribute to stabilize the ligand within the binding site by favoring the formation of stable interactions between the cationic head of the ligand and the residue D105. The increase of steric bulk, obtained by replacing the methyl group with an ethyl (7 and 10) and especially a phenyl substituent (8 and 11), caused a marked decrease of mAChR affinity, demonstrating the crucial role played by the steric bulk of the 2-substituent in the mAChR interaction. The most intriguing result was obtained with the tertiary amine 9, which, surprisingly, showed two different pK i values for all mAChRs, with preferential subpicomolar affinities for the M 1 , M 3 , and M 4 subtypes. Interestingly, biphasic curves were also observed with both the eutomer (S)-(-)-9 and the distomer (R)-( + )-9., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

Elites played a pivotal role in the formation of post-Roman Europe on both macro- and microlevels during the Early Medieval period. History and archaeology have long focused on their description and identification based on written sources or through their archaeological record. We provide a different perspective on this topic by integrating paleogenomic, archaeological, and isotopic data to gain insights into the role of one such elite group in a Langobard period community near Collegno, Italy dated to the 6-8th centuries CE. Our analysis of 28 newly sequenced genomes together with 24 previously published ones combined with isotope (Sr, C, N) measurements revealed that this community was established by and organized around a network of biologically and socially related individuals likely composed of multiple elite families that over time developed into a single extended pedigree. The community also included individuals with diverse genetic ancestries, maintaining its diversity by integrating newcomers and groups in later stages of its existence. This study highlights how shifts in political power and migration impacted the formation and development of a small rural community within a key region of the former Western Roman Empire after its dissolution and the emergence of a new kingdom. Furthermore, it suggests that Early Medieval elites had the capacity to incorporate individuals from varied backgrounds and that these elites were the result of (political) agency rather than belonging to biologically homogeneous groups., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: It is difficult to quantify the impact of the COVID-19 pandemic on mental health as many community surveys have limited quality, rely on screening tests to measure mental health conditions and distress, and often use convenience samples. Moreover, robust surveys come mainly from high-income countries., Aim: To measure the prevalence of depressive disorders with onset during the pandemic in a community of a Lower-Middle-income country (LMIC)-Tunisia., Methods: Clinical semi-structured face-to-face interviews were carried out during the pandemic (September-December 2021) by medical doctors among a representative sample of the general population in the governorate of La Manouba, Tunisia. Psychiatric diagnoses were established according to DSM-IV., Results: The prevalence of Major Depressive Disorder (MDD) started or recurred after the pandemic was 5.66%. The factors associated with MDD were loss of job and considerably diminished income due to the pandemic (OR = 2.1, 95% CI [1.5, 2.9]) and the perception of having the family's financial situation below the Tunisian average (OR = 2.3, 95% CI [1.7, 3.2]). Female sex, marital status as separated/divorced, and having a COVID-19 infection were associated with MDD only in the overall sample and urban areas, but not in rural areas. Age and having loved ones who passed away due to COVID-19 were not associated with MDD., Conclusion: In Tunisia, the pandemic seems to have increased the risk of depression in people experiencing a precarious financial situation, also due to the pre-existing economic crisis. Specific local level factors, such as not establishing a rigid lockdown for an extended period, may have protected young people and allowed for better mourning in families suffering the loss of a loved one.

Immune thrombotic thrombocytopenic purpura (iTTP) is a rare and potentially life-threatening disorder. Treatment advances have lowered morbidity rates, but past acute events can still cause long-term consequences, reducing health-related quality of life (HRQoL) and determining cognitive impairment, anxiety, and depression. We aimed to investigate these aspects and the role of caplacizumab and rituximab: 39 patients were evaluated using the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36), the FACIT-Fatigue, the Hospital Anxiety and Depression Scale, and the Functional Assessment in Cancer Therapy-Cognitive Function questionnaires. The median age at study inclusion was 50 years (IQR 38-60), and the median follow-up from diagnosis was 97 months (IQR 14-182); 82% of patients were female, and 36% had one or more recurrences. Caplacizumab was administered in 16 patients (41%), as well as rituximab. ITTP patients reported lower physical and mental HRQoL scores than the general population. No differences in physical or mental domains were observed between patients treated or not with caplacizumab, while those who received rituximab reported lower scores in mental health. Neurological impairment at diagnosis correlated with worse fatigue. The majority of patients (72%) reported anxiety or depression (82%). ITTP had a significant impact on the long-term cognitive function, fatigue, depression, and anxiety levels of patients, with a negative effect on their HRQoL. Our findings underscore the need to pay special attention to patients' long-term physical and mental health, regardless of the medical treatments received., (© 2024. The Author(s).)

Data on iron overload status and change thresholds that can predict mortality in patients with transfusion-dependent β-thalassemia (TDT) are limited. This was a retrospective cohort study of 912 TDT patients followed for up to 10 years at treatment centers in Italy (median age 32 years, 51.6% female). The crude mortality rate was 2.9%. Following best-predictive threshold identification through receiver operating characteristic curve analyses, data from multivariate Cox-regression models showed that patients with Period Average Serum Ferritin (SF) > 2145 vs ≤ 2145 ng/mL were 7.1-fold (P < 0.001) or with Absolute Change SF > 1330 vs ≤ 1330 ng/mL increase were 21.5-fold (P < 0.001) more likely to die from any cause. Patients with Period Average Liver Iron Concentration (LIC) > 8 vs ≤ 8 mg/g were 20.2-fold (P < 0.001) or with Absolute Change LIC > 1.4 vs ≤ 1.4 mg/g increase were 27.6-fold (P < 0.001) more likely to die from any cause. Patients with Index (first) cardiac T2* (cT2*) < 27 vs ≥ 27 ms were 8.6-fold (P < 0.001) more likely to die from any cause. Similarly, results at varying thresholds were identified for death from cardiovascular disease. These findings should support decisions on iron chelation therapy by establishing treatment targets, including safe iron levels and clinically meaningful changes over time., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

We conducted a retrospective cohort study on 663 transfusion-dependent β-thalassemia patients receiving the same iron chelation monotherapy with deferoxamine, deferiprone, or deferasirox for up to 10 years (median age 31.8 years, 49.9 % females). Patients on all three iron chelators had a steady and significant decline in serum ferritin over the 10 years (median deferoxamine: -170.7 ng/mL, P = 0.049, deferiprone: -236.7 ng/mL, P = 0.001; deferasirox: -323.7 ng/mL, P < 0.001) yet had no significant change in liver iron concentration or cardiac T2*; while noting that patients generally had low hepatic and cardiac iron levels at study start. Median absolute, relative, and normalized changes were generally comparable between the three iron chelators. Patients receiving deferasirox had the highest morbidity and mortality-free survival probability among the three chelators, although the difference was only statistically significant when compared with deferoxamine (P = 0.037). On multivariate Cox regression analysis, there was no significant association between iron chelator type and the composite outcome of morbidity or mortality. In a real-world setting, there is comparable long-term iron chelation effectiveness between the three available iron chelators for patients with mild-to-moderate iron overload., Competing Interests: Declaration of competing interest KMM reports consultancy fees from Novartis, Celgene Corp (Bristol Myers Squibb), Agios Pharmaceuticals, CRISPR Therapeutics, Vifor Pharma, and Pharmacosmos; and research funding from Agios Pharmaceuticals and Pharmacosmos. SB reports being on the advisory board of Vertex Pharmaceuticals and Bristol Myers Squibb and receiving speaker honoraria from Bristol Myers Squibb and Chiesi. RO reports being on the advisory board of Chiesi and Bristol Myers Squibb and consultancy fees from Vertex Pharmaceuticals and Bristol Myers Squibb. GBF reports consultancy fees from Bristol Myers Squibb, Agios Pharmaceuticals, FORMA Therapeutics, Vertex Pharmaceuticals. RL reports receiving speaker honoraria from Bristol Myers Squibb. AP reports receiving speaker honoraria from Bristol Myers Squibb. FL reports being on the advisory board of Vertex Pharmaceuticals and Bristol Myers Squibb. GLF reports receiving speaker honoraria and being on the advisory board Vertex Pharmaceuticals, Bristol Myers Squibb, Hemanext and Garuda Pharmaceuticals. The remaining authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This review summarizes the results of a series of studies performed by our group with the aim to define the expression levels of thymosin β 4 and thymosin β 10 over time, starting from fetal development to different ages after birth, in different human organs and tissues. The first section describes the proteomics investigations performed on whole saliva from preterm newborns and gingival crevicular fluid, which revealed to us the importance of these acidic peptides and their multiple functions. These findings inspired us to start an in-depth investigation mainly based on immunochemistry to establish the distribution of thymosin β 4 and thymosin β 10 in different organs from adults and fetuses at different ages (after autopsy), and therefore to obtain suggestions on the functions of β-thymosins in health and disease. The functions of β-thymosins emerging from these studies, for instance, those performed during carcinogenesis, add significant details that could help to resolve the nowadays so-called "β-thymosin enigma", i.e., the potential molecular role played by these two pleiotropic peptides during human development.

In humans, the transient receptor potential vanilloid 1 ( TRPV1 ) gene is activated by exogenous (e.g., high temperatures, irritating compounds such as capsaicin) and endogenous (e.g., endocannabinoids, inflammatory factors, fatty acid metabolites, low pH) stimuli. It has been shown to be involved in several processes including nociception, thermosensation, and energy homeostasis. In this study, we investigated the association between TRPV1 gene variants, sensory perception (to capsaicin and PROP), and body composition (BMI and bioimpedance variables) in human populations. By comparing sequences deposited in worldwide databases, we identified two haplotype blocks (herein referred to as H1 and H2) that show strong stabilizing selection signals (MAF approaching 0.50, Tajima's D > +4.5) only in individuals with sub-Saharan African ancestry. We therefore studied the genetic variants of these two regions in 46 volunteers of sub-Saharan descent and 45 Italian volunteers (both sexes). Linear regression analyses showed significant associations between TRPV1 diplotypes and body composition, but not with capsaicin perception. Specifically, in African women carrying the H1-b and H2-b haplotypes, a higher percentage of fat mass and lower extracellular fluid retention was observed, whereas no significant association was found in men. Our results suggest the possible action of sex-driven balancing selection at the non-coding sequences of the TRPV1 gene, with adaptive effects on water balance and lipid deposition.

Background and Purpose: Cladribine tablets, a purine analogue antimetabolite, offer a unique treatment regimen, involving short courses at the start of the first and second year, with no further treatment needed in years 3 and 4. However, comprehensive evidence regarding patient outcomes beyond the initial 24 months of cladribine treatment is limited., Methods: This retrospective, multicenter study enrolled 204 patients with multiple sclerosis who had completed the 2-year course of cladribine treatment. The primary outcomes were therapeutic choices and clinical disease activity assessed by annualized relapse rate after the 2-year treatment course., Results: A total of 204 patients were enrolled; most patients (75.4%) did not initiate new treatments in the 12 months postcladribine. The study found a significant reduction in annualized relapse rate at the 12-month follow-up after cladribine completion compared to the year prior to starting therapy (0.07 ± 0.25 vs. 0.82 ± 0.80, p < 0.001). Furthermore, patients with relapses during cladribine treatment were more likely to start new therapies, whereas older patients were less likely. The safety profile of cladribine was favorable, with lymphopenia being the primary registered adverse event., Conclusions: This study provides insights into therapeutic choices and disease activity following cladribine treatment. It highlights cladribine's effectiveness in reducing relapse rates and disability progression, reaffirming its favorable safety profile. Real-world data, aligned with previous reports, draw attention to ocrelizumab and natalizumab as common choices after cladribine. However, larger, prospective studies for validation and a more comprehensive understanding of cladribine's long-term impact are necessary., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Objectives: The aim of this study was to evaluate the effectiveness and safety profile of filgotinib, a JAK1 preferential inhibitor, in rheumatoid arthritis (RA) patients included in Italian GISEA (Group for the Study of Early Arthritis) registry., Methods: Data from RA patients treated with filgotinib, recorded in the GISEA registry, were analysed. Disease activity scores and patient-reported outcomes (PROs) were assessed at baseline, as well as during 12-month follow-up. A difficult-to-treat (D2T) RA patient was defined according with EULAR criteria. Retention rate of filgotinib was estimated by the Kaplan-Meier method and factors influencing drug discontinuation were estimated by Cox regression models., Results: 246 RA patients (female 89%, 57.6±12.2 years old) started filgotinib, mostly as second (22%) or further (43.9%) b/tsDMARDs line of treatment. At 3 and 12 months, 18.8% and 27.5% of patients achieved Clinical Diseases Activity Index based remission and 30.1% and 37.7% obtained a visual analogue scale of pain ≤20 (all p<0.01 vs. baseline). Filgotinib survival rate was 84.5% at the 6-month and 75.8% at 12-month follow-up, and was comparable either in monotherapy or combination therapy, and irrespective of glucocorticoid intake. b/tsDMARD naive patients had the lowest hazard ratio (HR) of filgotinib discontinuation (HR 0.29, 95%CI 0.14-0.64), while D2T-RA the highest (HR 1.82, 95%CI 1.01-3.3). Eight patients (3.3%) discontinued filgotinib due to adverse events., Conclusions: In an Italian real-life setting, filgotinib is confirmed to be safe and with a good effectiveness profile both in monotherapy and without glucocorticoids.

The composition and thickness of the passive film formed on the surface of an austenitic Ni-free DIN 1.4456 stainless steel (18% Cr, 18% Mn, and 2% Mo) used in orthodontics were investigated by X-ray photoelectron spectroscopy following contact with three complex artificial saliva solutions containing different organic components. It was found that the synergistic action of low pH and the presence of sodium citrate and lactic acid in the Darvell formulation resulted in thin passive films strongly enriched in chromium phosphates and oxyhydroxides and depleted in iron oxide. The differences in the surface chemistry of the passive film formed upon contact with the different artificial saliva formulations can be related to the more intense alloy dissolution in the active/passive transition, as shown by the polarization curves. Citrates or lactic acid can complex iron and promote alloy dissolution. The corrosion rates diminish with time, and after 16 h, they are found to be about 0.5 μm/year for all saliva formulations examined.

Pleistocene environments are among the most studied issues in paleoecology and human evolution research in eastern Africa. Many data have been recorded from archaeological sites located at low and medium elevations (≤ 1500 m), whereas few contexts are known at 2000 m and above. Here, we present a substantial isotopic study from Melka Kunture, a complex of prehistoric sites located at 2000-2200 m above sea level in the central Ethiopian highlands. We analyzed the stable carbon and oxygen isotopic composition of 308 faunal tooth enamel samples from sites dated between 2.02 and 0.6 Ma to investigate the animal diets and habitats. The carbon isotopic results indicate that the analyzed taxa had C 4 -dominated and mixed C 3 -C 4 diets with no significant diachronic changes in feeding behavior with time. This is consistent with faunal and phytolith analyses, which suggested environments characterized by open grasslands (with both C 3 and C 4 grasses), patches of bushes and thickets, and aquatic vegetation. However, palynological data previously documented mountain forests, woodlands, and high-elevation grasslands. Additionally, the carbon isotopic comparison with other eastern African localities shows that differences in elevation did not influence animal feeding strategies and habitat partitioning, even though plant species vary according to altitudinal gradients. In contrast, the oxygen isotopic comparison suggests significant differences consistent with the altitude effect. Our approach allows us to detect diverse aspects of animal behavior, habitat, and vegetation that should be considered when reconstructing past environments., (© 2024. The Author(s).)

The bamboo-coral Isidella elongata is a key habitat-forming species in the deep Mediterranean Sea. This alcyonacean is listed as an indicator of Vulnerable Marine Ecosystems (VMEs) and as Critically Endangered due to bottom trawling impacts. In this work, a modeling approach was used to predict and map the habitat suitability of I. elongata in the Mediterranean Sea under current environmental conditions. Occurrence data were modeled as a function of environmental parameters. Using climate change scenarios and fishing effort data, the risk of climate change and fisheries impacts on habitat suitability were estimated, and climate refugia were identified. A drastic loss of habitat is predicted, and climate change scenarios suggest a loss of 60% of suitable habitats by 2100. In the central Mediterranean, climate refugia overlapped with active fishing grounds. This study represents the first attempt to identify hot spots for the protection of soft bottom Vulnerable Marine Ecosystems for the entire Mediterranean Sea, and highlights areas most at risk from trawling. This work is relevant to the objectives of the EU Marine Strategy Framework and Maritime Spatial Planning Directives, the Biodiversity Strategy for 2030 regarding priority areas for conservation., (© 2024. The Author(s).)

Patients with chronic myeloid leukemia (CML) treated with nilotinib or ponatinib may experience arterial occlusive events (AOEs). It is currently recommended to thoroughly assess cardiovascular risk factors before treating CML. We identified 455 consecutive CML adult patients, 335 treated with nilotinib and 120 with ponatinib; 380 patients without previous cardiovascular diseases or diabetes were stratified according to the Systematic Coronary Risk Evaluation (SCORE2) and SCORE2-Older Persons (SCORE2-OP). This updated algorithm from the European Society of Cardiology (ESC) estimates a 10-year risk of fatal and non-fatal cardiovascular diseases. It is based on sex, age, smoking habits, systolic blood pressure, non-high-density lipoprotein cholesterol, and European geographical region of cardiovascular risk. The SCORE2/SCORE2-OP algorithm translated more patients (50.2%) to the high-very high cardiovascular risk category than the previous SCORE (25.3%). Patients with a high to very high SCORE2/SCORE2-OP risk showed a significantly higher incidence rate of AOEs (69.2% vs. 46.5%, p < 0.001). The older SCORE was less specific in estimating AOEs in patients classified as low-intermediate risk (69.8 vs. 54.2%). In multivariate analysis, no associations were found between AOEs and gender, age, and type or dose of tyrosine kinase inhibitor. Only the SCORE2/SCORE2-OP risk was confirmed as a significant predictive factor (p = 0.028; hazard ratio = 2.2; 95% confidence interval = 1.1-4.5). Patients with AOEs required, in most cases, imaging diagnostic tests, additional drugs, and sometimes invasive procedures, increasing access to visits and hospital management. This real-life study suggested that the SCORE2 and SCORE2-OP charts could help identify cardiovascular fragility in CML patients providing them with more attention and a proper TKI selection., (© 2023. The Author(s).)

Background: COVID-19 vaccines have been recommended to people with multiple sclerosis (pwMS) and, to ensure durable immunity, a third booster dose has been administered in several countries. Data about potential risks associated with the third booster dose in pwMS, such as vaccine-triggered disease exacerbations, are still scarce., Objective: To investigate whether the administration of a third booster dose of mRNA COVID-19 vaccines was associated with an increased risk of short-term disease reactivation in a large cohort of pwMS., Methods: We retrospectively selected 1265 pwMS who received a third booster dose of an mRNA COVID-19 vaccine. Demographic and clinical data were collected, including the presence, number and characteristics of relapses in the 60 days prior to and after the third booster dose., Results: In the selected cohort, the relapse rate in the two months after administration of the third booster dose of mRNA COVID-19 vaccines did not increase when compared with the prior two months. Indeed, the percentage of pwMS experiencing relapses in the 60 days following the administration of the third booster dose was 2.1%, similar to the percentage recorded in 60 days prior to vaccination, which was 1.9%., Conclusions: The third booster dose of mRNA COVID-19 vaccines appeared to be safe for pwMS., (© 2023. The Author(s).)

Purpose: To study visual function, retinal layer thickness changes, and tangential displacement after pars plana vitrectomy for epiretinal membrane., Methods: Retrospective series of patients undergoing pars plana vitrectomy for epiretinal membrane, with 6-month follow-up including best-corrected visual acuity, optical coherence tomography, M-charts, epiretinal membrane grading, and infrared fundus photograph at time 0 (T0, preop) at months 1 (T1), 3 (T3), and 6 (T6) postop (±1 week). Retinal layer thickness and tangential ( en face ) retinal displacement between successive times for the entire retinal surface and the central horizontal and vertical meridian were also measured. En face displacement was calculated as optical flow of consecutive images., Results: Average best-corrected visual acuity improved from 0.28 ± 0.08 logarithm of Minimum Angle of Resolution at T0 to 0.16 ± 0.25 at T6 ( P = 0.05), best-corrected visual acuity improvement correlated with best corrected visual acuity (BCVA) at T0 ( P < 0.001). Vertical metamorphopsia decreased from 1.33° ± 0.70° at T0 to 0.82° ± 0.69° at T6 ( P < 0.05). Foveal thickness reduced from 453 ± 53 µ m at T0 to 359 ± 31 µ m at T6 ( P < 0.05) and reduction correlated with best-corrected visual acuity improvement ( P < 0.05). Foveal layers decreased ( P < 0.05) in all cases. The mean en face deformation was 155.82 ± 50.17 µ m and mostly occurred in the first month: T0-T1 displacement was 83.59 ± 30.28 µ m, T1-T3 was 36.28 ± 14.45 µ m, while T3-T6 was 39.11 ± 22.79 µ m ( P < 0.001) on average. Perifoveal and parafoveal deformation correlated with optical coherence tomography foveal thickness reduction at all time intervals (1, 3, and 6 months: P < 0.01)., Conclusion: Epiretinal membrane peeling affects all retinal layer thickness and results in new force balance across the entire retina and tangential displacement. Both en face and in-depth changes correlate with visual function., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Opthalmic Communications Society, Inc.)

Objective: To compare the prevalence of postpartum depression (PPD) symptoms between high-income countries (HIC) and low- and middle-income countries (LMIC) during the COVID-19 pandemic., Methods: The PubMed, Embase, Virtual Health Library, Scopus, Web of Science, PsycINFO, and CINAHL databases were searched until October 2022 for studies that collected data during the pandemic. The metaprop command was used in the Stata statistical software version 12.0 to run a random-effects meta-analysis., Results: A total of 15 studies with 4,788 postpartum women were included. The overall prevalence of PPD symptoms was 31% (95%CI 21.85-40.99). The pooled prevalence of PPD symptoms among women from HIC (30.5% [95%CI 16.95-46.02]) did not differ significantly from that of women from LMIC (31.5% [95%CI 19.26-45.15]). However, studies that analyzed women up to 1 month after childbirth reported a lower prevalence of PPD symptoms (17.5% [95%CI 9.85-26.62]) compared to those that observed them up to 1 year after childbirth (38.3% [95%CI 33.96-42.83])., Conclusions: The prevalence of PPD symptoms was high across countries, regardless of human development index. This condition must be regularly tracked worldwide to assess, discuss, and recommend more assertive steps that may be implemented to address it based on the particular characteristics of each country., Competing Interests: This work was funded by Libbs Pharmaceuticals (LITT2104). The funders had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. The authors report no conflicts of interest.

Objectives: We aimed to investigate the effectiveness of tumour necrosis factor inhibitors (TNFi), anti-interleukin-17 or interleukin-12/23 monoclonal antibodies (anti-IL) on comorbidities in a cohort of patients with spondyloarthritis (SpA), using an average treatment effect (ATE) analysis., Methods: SpA patients from the multicentre Italian GISEA Registry were divided into groups according to pharmacological exposure: no treatment (G0), TNFi (G1) and non-responders to TNFi switched to anti-IL (G2). In each group, we recorded the prevalence and incidence of infectious, cardiopulmonary, endocrinological, gastrointestinal, oncologic, renal and neurologic comorbidities. Each comorbidity was then fitted for ATE and baseline features were evaluated for importance., Results: The main findings of this study comprising 4458 SpA patients relate to cancer, other gastrointestinal diseases (OGID) and fibromyalgia. ATE showed no increased risk of solid cancer in G1 (0.42 95% CI 0.20-0.85) and G2 (0.26 95% CI 0.08-0.71) vs. G0, with significantly higher incidence in G0 (14.07/1000 patient-years, p=0.0001). Conversely, a significantly higher risk of OGID and fibromyalgia was found in G1 (1.56 95% CI 1.06-2.33; 1.69 95% CI 1.05-2.68, respectively) and G2 (1.91 95% CI 1.05-3.24; 2.13 95% CI 1.14-3.41, respectively) vs. G0. No treatment risk reduction was observed in haematological malignancies, cardiovascular events and endocrinological comorbidities., Conclusions: Overall, our study confirms the safety of TNFi and anti-IL in SpA patients, albeit with some caveats pertaining to solid cancers, OGID and fibromyalgia. Furthermore, taking into consideration causality with observational data may yield more reliable and relevant clinical information.

Phenotypic screenings are usually combined with deconvolution techniques to characterize the mechanism of action for the retrieved hits. These studies can be supported by various computational analyses, although docking simulations are rarely employed. The present study aims to assess if multiple docking calculations can prove successful in target prediction. In detail, the docking simulations submitted to the MEDIATE initiative are utilized to predict the viral targets involved in the hits retrieved by a recently published cytopathic screening. Multiple docking results are combined by the EFO approach to develop target-specific consensus models. The combination of multiple docking simulations enhances the performances of the developed consensus models (average increases in EF1% value of 40% and 25% when combining three and two docking runs, respectively). These models are able to propose reliable targets for about half of the retrieved hits (31 out of 59). Thus, the study emphasizes that docking simulations might be effective in target identification and provide a convincing validation for the collaborative strategies that inspire the MEDIATE initiative. Disappointingly, cross-target and cross-program correlations suggest that common scoring functions are not specific enough for the simulated target.

Background: Hemoglobinopathies, among which thalassemic syndromes (transfusion-dependent and non-transfusion dependent thalassemias) and sickle cell disease (SCD), are the most widespread monogenic diseases worldwide. Hemoglobinopathies are endemic and spread-out all-over Italy, as result of internal and external migration flows. Nowadays, the increase therapeutic options associated to the general aging of patients with hemoglobinopathies related to the improvement in clinical management, contribute to the abnormalities in kidney function going from blood and urine test alterations to chronic kidney disease and end stage renal disease., Methods: Here, we carried out a revision of the literature as panel of recognized experts in hemoglobinopathies with the consultancy and the revision of two nephrologists on kidney alteration and kidney disease in patients with TDT, NTDT and SCD. This is part of the action of the Italian society for the study of thalassemia and hemoglobinopties (SITE). The purpose of this "good practice (GP)" is to provide recommendations for follow-up and therapy for the management of kidney alterations in patients with TDT, NTDT and SCD. The literature review covers the period 1.1.2016 to 31.12.2022. In consideration of the rarity of these diseases, the analysis was extended from 5 to 7 years. Moreover, in the absence of relevant scientific papers in the identified time frame, we referred to pivotal or population studies, when available. Finally, in the absence of evidence-based data from prospective and randomized trials, the authors had to refer to expert opinion (expert consensus) for many topics., Results: We generated question and answer boxes to offer a friendly consultation, using color code strategy and focused answers., Conclusions: The present GP will help in improving the clinical management, and the quality of care of patients with hemoglobinopathies.