Search

Modern wind turbines are the largest rotating machines ever built, with blade lengths exceeding 100 m. Previous studies demonstrated how the flow around the tip airfoils of such large machines reaches local flow Mach numbers (Ma), at which the incompressibility assumption might be violated, and, even in normal operating conditions, local supersonic flow could appear. In the present study, a numerical analysis of the FFA-W3-211 wind turbine tip airfoil is performed. The results are obtained by means of the application of numerical tools: (1) XFOIL with the Prandtl–Glauert compressible correction and (2) computational fluid dynamic (CFD) simulations, where an unsteady Reynolds-averaged Navier–Stokes (URANS) model is used. A preliminary validation of the latter CFD model is performed to demonstrate that the URANS approach is a viable method for predicting the aerodynamic performances in compressible and transonic flow that provides additional and more reliable information compared to the classical compressibility corrections. From this study, three key findings can be highlighted. Primarily, the main transonic features of the FFA-W3-211 wind turbine tip airfoil have been assessed, selecting specific test cases of particular industrial interest. Then, the threshold between subsonic and supersonic flow is provided, considering also an increase of the Reynolds number (Re) from a characteristic value used in the wind tunnel experiments to the one realistic for large rotors. A strong dependence on this quantity is observed, revealing that, for the same Mach number, also the Reynolds number plays a crucial role in promoting the occurrence of transonic flow. Finally, the possible presence or absence of shock waves was investigated. The results indicate that the appearance of transonic flow is a necessary but not a sufficient condition to lead to shock formation.

Donatella Delle Cave,1,* Maria Mangini,2,* Chiara Tramontano,3,* Luca De Stefano,3 Marco Corona,1 Ilaria Rea,3 Anna Chiara De Luca,2 Enza Lonardo1 1National Research Council, Institute of Genetics and Biophysics, Naples, 80131, Italy; 2National Research Council, Institute for Experimental Endocrinology and Oncology “G. Salvatore”, Second Unit, Naples, 80131, Italy; 3National Research Council, Institute of Applied Sciences and Intelligent Systems, Unit of Naples, Naples, 80131, Italy*These authors contributed equally to this workCorrespondence: Ilaria Rea; Anna Chiara De Luca, Email ilaria.rea@na.isasi.cnr.it; annachiara.deluca@cnr.itBackground: Metastasis-initiating cells are key players in progression, resistance, and relapse of colorectal cancer (CRC), by leveraging the regulatory relationship between Transforming Growth Factor-beta (TGF-β) signaling and anti-L1 cell adhesion molecule (L1CAM).Methods: This study introduces a novel strategy for CRC targeted therapy and imaging based on the use of a hybrid nanosystem made of gold nanoparticles-covered porous biosilica further modified with the (L1CAM) antibody.Results: The nanosystem intracellularly delivers galunisertib (LY), a TGF-β inhibitor, aiming to inhibit epithelial-mesenchymal transition (EMT), a process pivotal for metastasis. Anti-L1CAM antibody-functionalized nanoparticles (NPs) target tumor-initiating cells expressing L1CAM, inhibiting cancer growth. The number of antibody molecules conjugated to the single NP is precisely quantified, revealing a high surface coverage that facilitates the tumor targeting. The therapeutic efficacy of the nanosystem is investigated in organoid-like cultures of CRC cells and in vivo mouse models, showing a significant reduction in tumor growth. The spatial distribution of NPs within CRC tumors from mice is investigated using a label-free optical approach based on Raman micro-spectroscopy.Conclusion: This research highlights the multifunctional capabilities of engineered biosilica NPs, which offer new insights in targeted CRC therapy and imaging, improving patient outcomes and paving the way for personalized therapies.Keywords: targeted drug delivery, Raman imaging, antibody quantification, biosilica nanoparticle, in vivo treatment, colorectal cancer

Abstract Background To investigate the frequency of difficult-to-treat (D2T) rheumatoid arthritis (RA) in patients early escalated to biologic/targeted synthetic disease modifying anti-rheumatic drugs (b/tsDMARDs) after failure of treat-to-target with methotrexate (MTX). Methods From a prospective cohort of early RA, all patients with their first access in the years 2005–2018, and eventually starting a b/tsDMARD before the end of 2022, were included and followed-up until April 2024. Study outcomes included drug survival on each consecutive b/tsDMARDs, development of D2T (according to the EULAR definition and subsequent modifications), and its predictors. Results Of a total cohort of 722 early RA patients treated with initial MTX and followed-up for at least 3 years from diagnosis, 155 (21.5%) had started a b/tsDMARD after a median of 19 months. In more than 70% of the cases, RA was uncontrolled despite optimal doses of MTX of ≥ 15 mg/day. The retention rates of the first and the second b/tsDMARD were approximatively 70% after 1 year but dropped to 40% after 5 years. After a median (IQR) follow up of 72.6 (34.5-134.2) months, 45 patients (29%) fulfilled the EULAR D2T criteria. At multivariable analysis, higher number of swollen joints and worse pain scores were confirmed as predictors of D2T. Furthermore, in this early RA cohort, shorter disease duration at the start of treatment with b/tsDMARDs, together with negativity for autoantibodies, were also independent predictors of D2T. Conclusions Early implementation of treatment after failure of treat-to-target with MTX may not prevent the development of D2T in RA. Patients showing early refractoriness to conventional drugs and those lacking autoantibodies are at higher risk of multiple treatment failures.

Attention deficit is one of the most prominent and disabling symptoms in Fragile X syndrome (FXS). Hypersensitivity to sensory stimuli contributes to attention difficulties by overwhelming and/or distracting affected individuals, which disrupts activities of daily living at home and learning at school. We find that auditory or visual distractors selectively impair visual discrimination performance in humans and mice with FXS but not in typically developing controls. In both species, males and females were examined. Vasoactive intestinal polypeptide (VIP) neurons were significantly modulated by incorrect responses in the poststimulus period during early distractor trials in WT mice, consistent with their known role as error signals. Strikingly, however, VIP cells from Fmr1 -/- mice showed little modulation in error trials, and this correlated with their poor performance on the distractor task. Thus, VIP interneurons and their reduced modulatory influence on pyramidal cells could be a potential therapeutic target for attentional difficulties in FXS.SIGNIFICANCE STATEMENT Sensory hypersensitivity, impulsivity, and persistent inattention are among the most consistent clinical features of FXS, all of which impede daily functioning and create barriers to learning. However, the neural mechanisms underlying sensory over-reactivity remain elusive. To overcome a significant challenge in translational FXS research we demonstrate a compelling alignment of sensory over-reactivity in both humans with FXS and Fmr1 -/- mice (the principal animal model of FXS) using a novel analogous distractor task. Two-photon microscopy in mice revealed that lack of modulation by VIP cells contributes to susceptibility to distractors. Implementing research efforts we describe here can help identify dysfunctional neural mechanisms associated not only with sensory issues but broader impairments, including those in learning and cognition.

Abstract Recent failures translating preclinical behavioral treatment effects to positive clinical trial results in humans with Fragile X Syndrome (FXS) support refocusing attention on biological pathways and associated measures, such as electroencephalography (EEG), with strong translational potential and small molecule target engagement. This study utilized guided machine learning to test promising translational EEG measures (resting power and auditory chirp oscillatory variables) in a large heterogeneous sample of individuals with FXS to identify best performing EEG variables for reliably separating individuals with FXS, and genetically-mediated subgroups within FXS, from typically developing controls. Best performing variables included resting relative frontal theta power, all combined posterior-head resting power bands, posterior peak alpha frequency (PAF), combined PAF across all measured regions, combined theta, alpha, and gamma power during the chirp, and all combined chirp oscillatory variables. Sub-group analyses for resting EEG best discriminated non-mosaic FXS males via frontal theta resting relative power (AUC = 0.8759), even with data reduced to a 20-channel clinical montage (AUC = 0.9062). In the chirp task, FXS females and non-mosaic males were nearly perfectly discriminated by combined theta, alpha, and gamma power (AUC = 0.9444) and a combination of all variables (AUC = 0.9610), respectively. Results support use of resting and auditory oscillatory tasks to reliably identify neural deficit in FXS, and to identify specific translational targets for genetically-mediated sub-groups, supporting potential points for stratification.

Growing scientific evidence suggests a link between the expression of toll-like receptor 4 (TLR4) and cervical cancer carcinogenesis. Specifically, a close relation between TLR4 expression and FIGO stage, lymph node metastases, and tumor size has been reported in cervical cancer. In the present study, we aimed to evaluate the relationship between TLR4 expression levels and human papillomavirus (HPV) infection and/or high-risk (hr) HPV integration status in patients with a histological diagnosis of high-grade squamous intraepithelial lesion (H-SIL), and squamous cell carcinoma (SCC) of the uterine cervix. Sixty biopsies of cervical neoplasia, comprising H-SIL (n = 20) and SCC (n = 40), were evaluated for TLR4 expression by immunohistochemistry. All samples were positive for high-risk HPV as confirmed by in situ hybridization (ISH) and broad-spectrum PCR followed by Sanger sequencing analysis. The intensity of TLR4 staining was higher in tissues negative for intraepithelial lesion or malignancy (NILM) than in H-SIL, and further reduced in SCC. Moreover, statistically significant differences have been observed in the percentage of TLR4 expression between NILM and H-SIL and between H-SIL and SCC, with higher percentages of expression in H-SIL than in SCC. Our results showed a significant downregulation of TLR4 in HPV-related H-SIL and SCC, compared to NILM. These data support the hypothesis that TLR4 expression is suppressed in HPV-driven oncogenesis.

Abstract This viewpoint summarizes findings from analyses of large personal patient databases of myeloproliferative neoplasms (MPNs) to assess the impact of thrombosis on mortality, disease progression, and second cancers (SC). Despite advances, the current incidence of arterial and venous thrombosis remains a challenge. These events appear to signal a more aggressive disease course, as evidenced by their association with myelofibrosis progression and mortality using multistate models and time-dependent multivariable analysis. Inflammatory biomarkers, such as the neutrophil-to-lymphocyte ratio (NLR), are associated with the aggressiveness of polycythemia vera (PV) and essential thrombocythemia (ET), linking thrombosis to SC risk. This suggests a common inflammatory pathway likely influencing cardiovascular disease and cancer incidence. Notably, this is observed more frequently in younger patients, likely due to prolonged exposure to MPN and environmental inflammatory triggers. These data underscore the need for new studies to validate these associations, delineate the sequence of events, and identify therapeutic targets to mitigate thrombotic events and potentially improve overall patient outcomes in MPN.

Diferentes manejos de desfolhação podem resultar em desempenhos variáveis nas leguminosas forrageiras. Diante disto, o objetivo deste estudo foi avaliar as variações no acúmulo de forragem e valor nutritivo de quatro cultivares de Arachis pintoi Krapov. & W. C. Greg. (Alqueire-1, Amarillo, Belmonte e BRS Mandobi) em dois intervalos de corte (28 e 35 dias) e duas alturas de corte (5 e 10 cm). Determinou-se o acúmulo de matéria seca (MS) de forragem, composição morfológica, valor nutritivo, digestibilidade in vitro da matéria orgânica da forragem e massa de plantas invasoras. O cultivar Belmonte apresentou maior acúmulo de MS de forragem, com média de 5,9 Mg MS ha-1 estação-1 nos diferentes manejos adotados. Belmonte apresentou maior acúmulo médio de MS de folíolos em relação aos demais cultivares, com o menor acúmulo médio de MS de folíolos obtida pelo cultivar Amarillo. O cultivar Belmonte também apresentou maior concentração de proteína bruta (277 g kg-1 MS) e de digestibilidade in vitro da matéria orgânica (717 g kg-1 MS) em relação aos cultivares Alqueire-1 e Amarillo e concentrações de fibra em detergente neutro (366 g kg-1 MS) intermediárias comparativamente aos demais cultivares. O manejo com altura de corte de 5 cm confere maior acúmulo de MS de forragem ao A. pintoi. Plantas invasoras são mais evidentes em dosséis manejados sob altura de corte de 5 cm. Os manejos adotados não afetam a composição química e a digestibilidade in vitro da matéria orgânica dos cultivares. O cultivar Belmonte apresenta características produtivas e nutritivas que lhe caracterizam como o amendoim forrageiro com maior potencial para uso.

The transdermal drug delivery (TDD) route has gathered considerable attention for its potential to improve therapeutic efficacy while minimizing systemic side effects. Among transdermal technologies, microneedle (MN) devices have proven to be a promising approach that combines the advantages of traditional needle injections and non-invasive topical applications. This review provides a comprehensive analysis of progress in transdermal drug delivery systems (TDDS) via MN from 2000 to 2023, integrating bibliometric analysis and patent landscape to present a multi-faceted perspective on the evolution of this technology. The study identifies key trends, challenges, and opportunities in the research, implementation, and commercialization of MN tools through a systematic examination of scientific literature and an extensive investigation of global patent databases. The study of bibliometric trends reveals the leading experts, organizations, companies, and countries contributing to this field, collaboration networks, and the thematic evolution of research topics. The patent analysis offers insights into innovative trajectories, key players, and geographical distribution of intellectual property. This review resumes the latest advancements in MN devices and provides a strategic outlook that can guide future research directions, promote partnerships, and inform stakeholders involved in the development of TDDS.

Not available.

BackgroundPostoperative perineal hernia (PH) is an uncommon complication after abdominoperineal resection (APR). Different techniques have been described in literature and there is no consensus regarding the optimal repair approach. In the present study, we reported a case of a laparoscopic combined repair of a perineal hernia and abdominal parastomal hernia (PSH) with mesh. Studies have shown that the prosthetic PSH and PH repair can be performed at the same time by laparoscopy with the same trocars positioning, adding the advantages of minimally invasive surgery and avoiding large laparotomy.MethodsA literature search in Pubmed was performed. All articles in English describe laparoscopic repair of combined perineal and parastomal hernias. A case presentation of an 83-year-old woman with combined parastomal and perineal hernias after abdominoperineal resection (APR) shown in a video vignette is provided.ResultsThree single patient case reports published between 2016 and 2023 were found in literature. Two patients with rectal cancer underwent APR procedure, while the third patient underwent an anterior pelvic exenteration (APE) for carcinoma of the urinary bladder (CUB). The laparoscopic procedures did not require conversion and all procedures successfully closed the defect using a mesh. In our case, the operative time was 3 h with the major time spent for PH repair. The intraoperative blood loss was non-significant and the postoperative course was regular. The patient has been discharged on the fourth postoperative day. At 1 year follow-up, the patient noticed a great improvement in her daily-life due to the absence of the previous discomforts and there was no evidence of early recurrence or other postoperative complications.ConclusionCombined laparoscopic transabdominal PH and PSH repair with the use of synthetic mesh was shown to be a safe and effective repair for this rare disorder. To accurately compare techniques, we require prospective studies with longer follow up durations.

Background While the prognostic role of tertiary lymphoid structures (TLS) has been well studied in solid cancers, the prevalence and impact of immature precursor lymphoid structures known as lymphoid aggregates (LA) remain unresolved in relation to the disease process. In this study, we examined characteristics and the prognostic utility of LA and TLS status in histological samples from patients with melanoma.Methods We assessed The Cancer Genomic Atlas-skin cutaneous melanoma digital slides and melanoma specimens from the University of Pittsburgh for the presence of LA and TLS using H&E staining, multiplex immunofluorescence (mIF) and transcriptomic analyses. Cox proportional hazard regression models were used to assess the prognostic value associated with the presence of lymphoid structures in melanomas.Results A total of 278 evaluable samples were analyzed and split into primary melanomas in skin (N=195) and metastatic melanomas involving skin/subcutaneous/soft tissue sites (N=83). 72% of tumor specimens contained histologically defined LA located in peritumoral (34%), intratumoral (5.6%) or stromal (6.1%) locations, with the remaining samples (54.3%) exhibiting LA in multiple locations. In contrast to LA which tended to form more commonly in primary melanoma samples, TLS with germinal centers predominantly formed in peritumoral (45.2%) or stromal (35.5%) locations in metastatic melanomas (p=0.02), with TLS observed in 11% of all melanoma specimens evaluated. mIF analyses revealed cellular heterogeneity of lymphoid structures, with CD20+ (B) cells present in nodule-shaped and stromal locations where they exhibited a high degree of colocalization with CD4+ and CD8+ T cells. A previously defined 12-chemokine gene expression score was significantly higher in samples with evidence of LA versus none (p

Abstract Ordered, quasi-ordered, and even disordered nanostructures can be identified as constituent components of several protists, plants and animals, making possible an efficient manipulation of light for intra- and inter- species communication, camouflage, or for the enhancement of primary production. Diatoms are ubiquitous unicellular microalgae inhabiting all the aquatic environments on Earth. They developed, through tens of millions of years of evolution, ultrastructured silica cell walls, the frustules, able to handle optical radiation through multiple diffractive, refractive, and wave-guiding processes, possibly at the basis of their high photosynthetic efficiency. In this study, we employed a range of imaging, spectroscopic and numerical techniques (including transmission imaging, digital holography, photoluminescence spectroscopy, and numerical simulations based on wide-angle beam propagation method) to identify and describe different mechanisms by which Pleurosigma strigosum frustules can modulate optical radiation of different spectral content. Finally, we correlated the optical response of the frustule to the interaction with light in living, individual cells within their aquatic environment following various irradiation treatments. The obtained results demonstrate the favorable transmission of photosynthetic active radiation inside the cell compared to potentially detrimental ultraviolet radiation.

Rosa Bellavita,1,* Marialuisa Piccolo,1,* Linda Leone,2 Maria Grazia Ferraro,1,3 Principia Dardano,4 Luca De Stefano,4 Flavia Nastri,2 Carlo Irace,1 Annarita Falanga,5 Stefania Galdiero1,* 1Department of Pharmacy, School of Medicine, University of Naples ‘Federico II’, Napoli, Italy; 2Department of Chemical Sciences, University of Napoli “Federico II”, Naples, Italy; 3School of Infection and Immunity, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK; 4Institute of Applied Sciences and Intelligent Systems, Consiglio Nazionale delle Ricerche, Naples, Italy; 5Department of Agricultural Science, University of Naples “Federico II”, Portici, Italy*These authors contributed equally to this workCorrespondence: Stefania Galdiero, Email stefania.galdiero@unina.itIntroduction: The design of delivery tools that efficiently transport drugs into cells remains a major challenge in drug development for most pathological conditions. Triple-negative breast cancer (TNBC) is a very aggressive subtype of breast cancer with poor prognosis and limited effective therapeutic options.Purpose: In TNBC treatment, chemotherapy remains the milestone, and doxorubicin (Dox) represents the first-line systemic treatment; however, its non-selective distribution causes a cascade of side effects. To address these problems, we developed a delivery platform based on the self-assembly of amphiphilic peptides carrying several moieties on their surfaces, aimed at targeting, enhancing penetration, and therapy.Methods: Through a single-step self-assembly process, we used amphiphilic peptides to obtain nanofibers decorated on their surfaces with the selected moieties. The surface of the nanofiber was decorated with a cell-penetrating peptide (gH625), an EGFR-targeting peptide (P22), and Dox bound to the cleavage sequence selectively recognized and cleaved by MMP-9 to obtain on-demand drug release. Detailed physicochemical and cellular analyses were performed.Results: The obtained nanofiber (NF-Dox) had a length of 250 nm and a diameter of 10 nm, and it was stable under dilution, ionic strength, and different pH environments. The biological results showed that the presence of gH625 favored the complete internalization of NF-Dox after 1h in MDA-MB 231 cells, mainly through a translocation mechanism. Interestingly, we observed the absence of toxicity of the carrier (NF) on both healthy cells such as HaCaT and TNBC cancer lines, while a similar antiproliferative effect was observed on TNBC cells after the treatment with the free-Dox at 50 μM and NF-Dox carrying 7.5 μM of Dox.Discussion: We envision that this platform is extremely versatile and can be used to efficiently carry and deliver diverse moieties. The knowledge acquired from this study will provide important guidelines for applications in basic research and biomedicine. Keywords: self-assembling peptides, triple negative breast cancer, nanofiber, on-demand strategy, doxorubicin

الملخص: مع التقدم في علوم طب الأسنان والحاجة المتزايدة لتحسين صحة الأسنان، أصبح من الضروري تطوير مواد زراعة جديدة تمتلك خصائص هندسية وميكانيكية وفيزيائية أفضل. البيئة الفموية هي بيئة أكالة، كما أن الحركة النسبية بين الأسنان تجعل البيئة أكثر عدائية. لذلك، يجب دراسة التآكل المشترك وعلم الاحتكاك المعروف باسم تآكل الغرسات. إن الأشكال المعقدة لزراعة الأسنان ومتطلبات الأداء العالي لهذه الغرسات تجعل التصنيع صعبا من خلال عمليات التصنيع التقليدية. مع ظهور التصنيع الإضافي أو الطباعة ثلاثية الأبعاد، أصبح تطوير الغرسات أمرا سهلا. ومع ذلك، فإن المتطلبات المختلفة مثل خشونة السطح، والقوة الميكانيكية، ومقاومة التآكل تزيد من صعوبة تصنيع الغرسات. تستعرض الورقة الحالية الدراسات المختلفة المتعلقة بالغرسات المطبوعة ثلاثية الأبعاد. كما تحاول الورقة تسليط الضوء على الدور الذي يمكن أن تلعبه الطباعة ثلاثية الأبعاد في مجال زراعة الأسنان. هناك حاجة إلى مزيد من الدراسات التجريبية والعددية لاستنباط الظروف المثلى لغرسات الطباعة ثلاثية الأبعاد لتطوير الغرسات ذات الخصائص الميكانيكية والتآكل والبيولوجية المحسنة. Abstract: With the advancements in dental science and the growing need for improved dental health, it has become imperative to develop new implant materials which possess better geometrical, mechanical, and physical properties. The oral environment is a corrosive environment and the relative motion between the teeth also makes the environment more hostile. Therefore, the combined corrosion and tribology commonly known as tribocorrosion of implants needs to be studied. The complex shapes of the dental implants and the high-performance requirements of these implants make manufacturing difficult by conventional manufacturing processes. With the advent of additive manufacturing or 3D-printing, the development of implants has become easy. However, the various requirements such as surface roughness, mechanical strength, and corrosion resistance further make the manufacturing of implants difficult. The current paper reviews the various studies related to3D-printed implants. Also, the paper tries to highlight the role of 3D-Printing can play in the area of dental implants. Further studies both experimental and numerical are needed to devise optimized conditions for 3D-printing implants to develop implants with improved mechanical, corrosion, and biological properties.

Abstract Background Exosomes are nanosized vesicles released from all cells into surrounding biofluids, including cancer cells, and represent a very promising direction in terms of minimally invasive approaches to early disease detection. They carry tumor-specific biological contents such as DNA, RNA, proteins, lipids, and sugars, as well as surface molecules that are able to pinpoint the cellular source. By the above criteria, exosomes may be stratified according to the presence of tissue and disease-specific signatures and, due to their stability in such biofluids as plasma and serum, they represent an indispensable source of vital clinical insights from liquid biopsies, even at the earliest stages of cancer. Therefore, our work aimed to isolate and characterize LCa patients’ derived exosomes from serum by Flow Cytometry in order to define a specific epitope signature exploitable for early diagnosis. Methods Circulating exosomes were collected from serum collected from 30 LCa patients and 20 healthy volunteers by the use of antibody affinity method exploiting CD63 specific surface marker. Membrane epitopes were then characterized by Flow cytometry multiplex analysis and compared between LCa Patients and Healthy donors. Clinical data were also matched to obtain statistical correlation. Results A distinct overexpression of CD1c, CD2, CD3, CD4, CD11c, CD14, CD20, CD44, CD56, CD105, CD146, and CD209 was identified in LCa patients compared to healthy controls, correlating positively with tumor presence. Conversely, CD24, CD31, and CD40, though not overexpressed in tumor samples, showed a significant correlation with nodal involvement in LCa patients (p < 0.01). Conclusion This approach could allow us to set up a cost-effective and less invasive liquid biopsy protocol from a simple blood collection in order to early diagnose LCa and improve patients’ outcomes and quality of life. Graphical Abstract

Abstract Belantamab mafodotin is the first‐in‐class antibody‐drug conjugates targeting B‐cell maturation antigen to have demonstrated effectiveness in triple‐class refractory multiple myeloma (TCR‐MM) patients. We performed a retrospective study including 78 TCR patients, with at least four prior lines of therapy (LOTs), who received belantamab mafodotin within named patient program and expanded access program in Italy between 2020 and 2022. Median age was 65 years (range 42–86 years), ECOG performance status was ≥1 in 45% of patients. Overall, a clinical benefit was obtained in 36 out of 74 evaluable patients (49%), with 43%, 28%, and 13.5% achieving at least partial response, very good partial response, and complete response, respectively. After a median follow‐up of 12 months (range 6–21 months), median duration of response, progression‐free survival (PFS), and overall survival (OS) were 14, 5.5, and 12 months, respectively. Age >70 years, good performance status and response were associated with longer PFS and OS. Keratopathy occurred in 58% of patients (G3 2.5%), corneal symptoms in 32% (G3 1.2%) and a reduction in visual acuity in 14%. Grade 3 thrombocytopenia occurred in 9% of patients. Only 3% of patients discontinued belantamab mafodotin because of side effects. This real‐life study demonstrated significant and durable responses of belantamab in TCR‐MM patients with four prior LOTs, otherwise ineligible for novel immunotherapies.

Purpose: Pudendal neuropathy is an uncommon condition that exhibits several symptoms depending on the site of nerve entrapment. This study aims to evaluate the efficacy of pudendal nerve neurolysis (PNN) in improving lower urinary tract symptoms, anal and/or urinary incontinence, and sexual dysfunctions. Materials and Methods: A systematic literature search was performed on 20 May 2023 using Scopus, PubMed, and Embase. Only English and adult papers were included. Meeting abstracts and preclinical studies were excluded. Results: Twenty-one papers were accepted, revealing significant findings in the field. The study identified four primary sites of pudendal nerve entrapment (PNE), with the most prevalent location likely being at the level of the Alcock canal. Voiding symptoms are commonly exhibited in patients with PNE. PNN improved both urgency and voiding symptoms, and urinary and anal incontinence but is less effective in cases of long-standing entrapment. Regarding sexual function, the recovery of the somatic afferent pathway results in an improvement in erectile function early after neurolysis. Complete relief of persistent genital arousal disorder occurs in women, although bilateral PNN is necessary to achieve the efficacy. PNN is associated with low-grade complications. Conclusions: PNN emerges as a viable option for addressing urinary symptoms, fecal incontinence, erectile dysfunction, and female sexual arousal in patients suffering from PNE with minimal postoperative morbidity.

Spinal cord (SC) atrophy obtained from structural magnetic resonance imaging has gained relevance as an indicator of neurodegeneration in various neurological disorders. The common method to assess SC atrophy is by comparing numerical differences of the cross-sectional spinal cord area (CSA) between time points. However, this indirect approach leads to considerable variability in the obtained results. Studies showed that this limitation can be overcome by using a registration-based technique.The present study introduces the Structural Image Evaluation using Normalization of Atrophy on the Spinal Cord (SIENA-SC), which is an adapted version of the original SIENA method, designed to directly calculate the percentage of SC volume change over time from clinical brain MRI acquired with an extended field of view to cover the superior part of the cervical SC.In this work, we compared SIENA-SC with the Generalized Boundary Shift Integral (GBSI) and the CSA change. On a scan-rescan dataset, SIENA-SC was shown to have the lowest measurement error than the other two methods. When comparing a group of 190 Healthy Controls with a group of 65 Multiple Sclerosis patients, SIENA-SC provided significantly higher yearly rates of atrophy in patients than in controls and a lower sample size when measured for treatment effect sizes of 50%, 30% and 10%.Our findings indicate that SIENA-SC is a robust, reproducible, and sensitive approach for assessing longitudinal changes in spinal cord volume, providing neuroscientists with an accessible and automated tool able to reduce the need for manual intervention and minimize variability in measurements.

Summary: Background: NOTCH3 encodes a transmembrane receptor critical for vascular smooth muscle cell function. NOTCH3 variants are the leading cause of hereditary cerebral small vessel disease (SVD). While monoallelic cysteine-involving missense variants in NOTCH3 are well-studied in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), patients with biallelic variants in NOTCH3 are extremely rare and not well characterised. Methods: In this study, we present clinical and genetic data from 25 patients with biallelic NOTCH3 variants and conduct a literature review of another 25 cases (50 patients in total). Brain magnetic resonance imaging (MRI) were analysed by expert neuroradiologists to better understand the phenotype associated with biallelic NOTCH3 variants. Findings: Our systematic analyses verified distinct genotype-phenotype correlations for the two types of biallelic variants in NOTCH3. Biallelic loss-of-function variants (26 patients) lead to a neurodevelopmental disorder characterised by spasticity, childhood-onset stroke, and periatrial white matter volume loss resembling periventricular leukomalacia. Conversely, patients with biallelic cysteine-involving missense variants (24 patients) fall within CADASIL spectrum phenotype with early adulthood onset stroke, dementia, and deep white matter lesions without significant volume loss. White matter lesion volume is comparable between patients with biallelic cysteine-involving missense variants and individuals with CADASIL. Notably, monoallelic carriers of loss-of-function variants are predominantly asymptomatic, with only a few cases reporting nonspecific headaches. Interpretation: We propose a NOTCH3-SVD classification depending on dosage and variant type. This study not only expands our knowledge of biallelic NOTCH3 variants but also provides valuable insight into the underlying mechanisms of the disease, contributing to a more comprehensive understanding of NOTCH3-related SVD. Funding: The Wellcome Trust, the MRC.

The application of plant growth regulators, primarily gibberellin inhibitors, is the main approach used for controlling the growth of ornamental plants. However, there is a growing interest in alternative products due to the risk of environmental toxicity associated with traditional methods. Methyl jasmonate (MeJa) is a natural substance found in plants and is considered to have low toxicity when used appropriately. Its use as a growth regulator has shown promise for controlling plant growth, but its effects have not been extensively explored in ornamental growth restriction. This study investigated the effects of foliar application of different concentrations of MeJa (0, 50, 100, and 150 µM) on the growth and leaf anatomy of Begonia ‘Dragon Wing’ Pink and Red. Plant growth parameters were evaluated, and qualitative-quantitative histological analyses of Begonia leaves were conducted. MeJa was efficient in compacting the plants, reducing height in 17.57% and diameter in 8.98% without compromising biomass, root growth, and flowering aspects. The average concentration studied also caused changes in leaf anatomy, increasing the thickness of the abaxial epidermis, reducing mesophyll thickness, the number of calcium oxalate crystals, and the size and number of stomata. The results demonstrated the promising effect of MeJa on controlling the growth of potted ornamental plants.

Abstract Inadequate blood supply to the expanding adipose tissue (AT) is involved in the unhealthy AT remodeling and cardiometabolic consequences of obesity. Because of the pathophysiological role of upregulated mineralocorticoid receptor (MR) signaling in the complications of obesity, this study tested the vasoactive properties of finerenone, a nonsteroidal MR antagonist, in arteries of human AT. Arteries isolated from the visceral AT of obese subjects were studied in a wire myograph. Finerenone resulted in a concentration‐dependent relaxation of arteries precontracted with either the thromboxane‐A2 analog U46619, ET‐1, or high‐K+ solution; the steroidal MR antagonist potassium canrenoate, by contrast, did not relax arteries contracted with either U46619 or high‐K+ solution. Finerenone‐induced relaxation after precontraction with U46619 was greater in the arteries of obese versus nonobese subjects. Mechanistically, the vasorelaxing response to finerenone was not influenced by preincubation with the nitric oxide synthase inhibitor L‐NAME or by endothelium removal. Interestingly, finerenone, like the dihydropyridine Ca2+‐channel blocker nifedipine, relaxed arteries contracted with the L‐type Ca2+‐channel agonist Bay K8644. In conclusion, finerenone relaxes arteries of human visceral AT, likely through antagonism of L‐type Ca2+ channels. This finding identifies a novel mechanism by which finerenone may improve AT perfusion, hence protecting against the cardiometabolic complications of obesity.

The ketogenic diet (KD) is marked by a substantial decrease in carbohydrate intake and an elevated consumption of fats and proteins, leading to a metabolic state referred to as “ketosis,” where fats become the primary source of energy. Recent research has underscored the potential advantages of the KD in mitigating the risk of various illnesses, including type 2 diabetes, hyperlipidemia, heart disease, and cancer. The macronutrient distribution in the KD typically entails high lipid intake, moderate protein consumption, and low carbohydrate intake. Restricting carbohydrates to below 50 g/day induces a catabolic state, prompting metabolic alterations such as gluconeogenesis and ketogenesis. Ketogenesis diminishes fat and glucose accumulation as energy reserves, stimulating the production of fatty acids. Neurodegenerative diseases, encompassing Alzheimer’s disease, Parkinson’s disease are hallmarked by persistent neuroinflammation. Evolving evidence indicates that immune activation and neuroinflammation play a significant role in the pathogenesis of these diseases. The protective effects of the KD are linked to the generation of ketone bodies (KB), which play a pivotal role in this dietary protocol. Considering these findings, this narrative review seeks to delve into the potential effects of the KD in neuroinflammation by modulating the immune response. Grasping the immunomodulatory effects of the KD on the central nervous system could offer valuable insights into innovative therapeutic approaches for these incapacitating conditions.

Background and purposeClinical outcomes of multiple sclerosis (MS) patients affected by coronavirus disease 2019 (COVID-19) have been thoroughly investigated, but a further analysis on main signs and symptoms and their risk factors still needs attention. The objective of this study was to group together and describe based on similarity the most common signs and symptoms of COVID-19 in MS patients and identify all factors associated with their manifestation.MethodLogistic and linear regression models were run to recognize factors associated with each pooled group of symptoms and their total number.ResultsFrom March 2020 to November 2021, data were collected from 1354 MS patients with confirmed infection of COVID-19. Ageusia and anosmia was less frequent in older people (odds ratio [OR] 0.98; p = 0.005) and more in smoker patients (OR 1.39; p = 0.049). Smoke was also associated with an incremental number of symptoms (OR 1.24; p = 0.031), substance abuse (drugs or alcohol), conjunctivitis and rash (OR 5.20; p = 0.042) and the presence of at least one comorbidity with shortness of breath, tachycardia or chest pain (OR 1.24; p = 0.008). Some disease-modifying therapies were associated with greater frequencies of certain COVID-19 symptoms (association between anti-CD20 therapies and increment in the number of concomitant symptoms: OR 1.29; p = 0.05). Differences in frequencies between the three waves were found for flu-like symptoms (G1, p = 0.024), joint or muscle pain (G2, p = 0.013) and ageusia and anosmia (G5, p