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PURPOSE OF REVIEW: Glioblastoma remains resistant to most conventional treatments. Despite scientific advances in the past three decades, there has been a dearth of effective new treatments. New approaches to drug delivery and clinical trial design are needed. RECENT FINDINGS: We discuss how the blood-brain barrier and tumor microenvironment pose challenges for development of effective therapies for glioblastoma. Next, we discuss treatments in development that aim to overcome these barriers, including novel drug designs such as nanoparticles and antibody-drug conjugates, novel methods of drug delivery, including convection-enhanced and intra-arterial delivery, and novel methods to enhance drug penetration, such as blood-brain barrier disruption by focused ultrasound and laser interstitial thermal therapy. Lastly, we address future opportunities, positing combination therapy as the best strategy for effective treatment, neoadjuvant and window-of-opportunity approaches to simultaneously enhance therapeutic effectiveness with interrogation of on-treatment biologic endpoints, and adaptive platform and basket trials as imperative for future trial design. New approaches to GBM treatment should account for the blood-brain barrier and immunosuppression by improving drug delivery, combining treatments, and integrating novel clinical trial designs.

Abstract Background Although little is yet known about the long-term maintenance of very low-energy ketogenic therapy (VLEKT) effects on body composition, muscle strength and inflammation, it is plausible to assume that changes may occur, particularly during the steps following the ketogenic step, due to the loss of the protective effects of ketones and the concomitant reintroduction of carbohydrates. For this reason, the present study aimed to evaluate the effects of supplementation with 8 g per day of essential amino acids (EAAs) on these parameters. Methods A total of 68 women of reproductive age and with grade I obesity who had completed 45 days of the ketogenic phase with VLEKT (KeNuT protocol) and 40 days of non-ketogenic phase of KeNuT protocol with VLEKT (phase 3, fruit reintroduction) were included in the study. Half of them (n = 34) followed this first step of the re-educational phase of KeNuT protocol with VLEKT with supplementation with EAAs (Aminotrofic®: 4 g twice daily). Anthropometric parameters, body composition via bioelectrical impedance analysis and high-sensitivity C-reactive protein (hs-CRP) levels were assessed at baseline, pre- and post both dietary interventions. Results At the end of 45 days of ketogenic phase with VLEKT (before fruit reintroduction and EAA supplementation), the two groups did not differ in any of the parameters assessed. At the end of the fruit reintroduction phase, the supplemented group showed greater magnitudes of reduction in weight, waist circumference, fat mass (FM) and hs-CRP (p

Abstract Background Despite the importance of Ultrasound-guided Regional Anaesthesia (UGRA) in Emergency Medicine (EM), there is significant variability in UGRA training among emergency physicians. We recently developed a one-day (8 h), simulation-based UGRA course, specifically tailored to help emergency physicians to integrate these skills into their clinical practice. Methods In this pre/post intervention study, emergency physicians attended a course consisting of a 4-hour teaching on background knowledge and a practical part structured as follows: a scanning session on a healthy individual; a needling station with an ex-vivo model (turkey thighs); a simulation-based learning experience on local anaesthetic toxicity (LAST); a session on the UGRA simulator BlockSim™. Participants rated their level of knowledge across several domains of UGRA practice; for this purpose, we used a 5-points Likert scale (from 0 to 4). Participants also rated the perceived utility of the practical sessions. We extrapolated baseline characteristics of participants, and we paired the answers of pre- and post-course questionnaires using Wilcoxon signed-rank test. Results Seventy-four emergency physicians across ten Italian regions and Switzerland completed the pre-and post- course questionnaire. Most of them were EM residents (75.68%) who had never performed UGRA. Median self-reported knowledge significantly improved from 1 to 3 in the following domains of UGRA indications: Knowledge of contraindications and UGRA techniques [pre-course 1 (IQR 1–2), post-course 3 (IQR 2–3)]; Equipment and drugs [pre-course 1(IQR 1–1), post-course 3 (IQR2-3)]; LAST recognition [pre-course 1 (IQR 1–2), post-course 3 (IQR 2–4)]; LAST management [pre-course 1 (IQR 1–1,75), post-course 3 (IQR 2–3)] (p

Abstract Background Human bone marrow is a source of mesenchymal stem cells (MSCs), other progenitor cells, and factors with anti-inflammatory and regenerative capacity. Though the fraction of MSCs out of the nucleated cells is very small, bone marrow aspirate (BMA) for osteoarthritis (OA) has noteworthy effects. BMA is usually collected from the posterior or anterior iliac crest, and rarely from the proximal tibia. We investigated the clinically beneficial concentration of ex vivo MSCs, derived from BM harvested from the posterior iliac crest and proximal tibia by Marrow Cellution™ Aspiration System, and their phenotypic differences, in comparison to autologous Platelet-Rich Plasma (PRP) treatment prepared with a manual, closed system. Methods A single-center, parallel, randomized controlled study was designed to investigate the efficacy of BMA from the posterior iliac crest compared to BMA from the proximal tibia, against a control group treated with PRP, in knee OA. Thirty patients with knee OA grade I-IV, according to Kellgren-Lawrence (KL), were distributed into each group. Visual Analog Scale (VAS) and Western Ontario & McMaster Universities Arthritis Index (WOMAC) score were used for clinical outcome evaluation. Results Data from an intermediate analysis of 6-months follow-up, involving 15 patients in each arm, showed that the posterior iliac crest was significantly more densely populated with mononuclear cells, than the proximal tibia (p = 0.005). Flow cytometric analysis on ex vivo BMA showed a significantly greater number of MSCs in the BM-derived from the posterior iliac crest when compared with the proximal tibia (p 0.05). A better outcome, in terms of ΔVAS, was observed in patients classified as KL I-II, when treated with BMA from crest (p

In agriculture, abiotic and biotic stress reduce yield by 51–82% and 10–16%, respectively. Applications of biological agents such as plant growth-promoting rhizobacteria (PGPR) and arbuscular mycorrhizal fungi (AMF) can improve plant growth. Applications of lone PGPR and AMF also help plants resist abiotic and biotic stressors. The reports for dual inoculation of AMF and PGPR to benefit plants and tackle stressors are largely unknown. It is speculated that PGPR colonization in plants enhances AMF infection during dual AMF and PGPR application, although increased AMF colonization does not always correlate with the increased benefits for the plant hosts. Further research is needed regarding molecular mechanisms of communication during dual inoculations, and dual-inoculation enhancement of induced systemic resistance under pathogen stress, to understand how dual inoculations can result in enhanced plant benefits. The influence of application timing of AMF and PGPR dual inoculations on mitigating abiotic and biotic stress is also not well understood. This review documents the factors that govern and modulate the dual application of AMF and PGPR for plant benefits against stress responses, specifically abiotic (drought) stress and stress from pathogen infection.

Abstract Background to analyze, at one year, the efficacy and safety of treat-and-extend (T&E) intravitreal (IV) Brolucizumab in patients affected by macular neovascularization (MNV). Both naïve and previously treated (i.e., switched) patients were included, and the data from the two groups were compared. Methods anatomical (i.e., central subfoveal thickness, CST; presence of fluid), functional (i.e., best corrected visual acuity, BCVA) and treatment-related (i.e., number of IV injections within the study period; number of patients reaching a 12-weeks interval between treatments) data from 41 eyes of 41 subjects (20 naïve and 21 switched) were analyzed. Patients were treated with 3 monthly IV injections followed by a T&E regimen based on a disease activity assessment performed at each scheduled IV treatment. Results significant CST reduction (from 412.1 ± 115.8 to 273.2 ± 61.6; p

Abstract Background Considering differences in body composition and inflammatory status between sexes, as well as recent recommendations advocating for personalized dietary approaches, this study aimed to explore how sex influences weight loss, changes in body composition, and inflammatory status in subjects with grade I and II obesity undergoing a 45-day of the Very Low-Energy Ketogenic Therapy (VLEKT). Methods Participants (21 premenopausal females and 21 males), included in the study adhered to the 45-day of the VLEKT and underwent assessments of anthropometric parameters (weight, height, body mass index—BMI –, and waist circumference), body composition via bioelectrical impedance analysis, and inflammatory status measured by high sensitivity C-reactive protein (hs-CRP) levels at baseline and post-intervention. Results At baseline, premenopausal females and males did not differ in BMI (p = 0.100) and hs-CRP levels (p = 0.948). Males demonstrated overall larger benefits than premenopausal females from the VLEKT in terms of weight loss (Δ% = − 11.63 ± 1.76 vs − 8.95 ± 1.65 kg, p

Background and trial design: Outcomes of out-of-hospital cardiac arrest vary significantly, often due to the quality of cardiopulmonary resuscitation (CPR) provided. Automated real-time feedback devices have been explored to enhance CPR skills, but few devices currently ensure proper chest recoil. This study aimed to assess whether a double-click metronome could improve chest compressions (CC) metrics and particularly CC release velocity (CCRV) during CPR manikin simulation. Methods: We developed and tested a double-click metronome for CPR, where the first click signals the compression and the second click marks the end of chest release. We performed a multicenter non-blinded, randomized, controlled trial including volunteers with different levels of CPR expertise. Three CC metrics—depth, rate, and CCRV—were measured using an automated external defibrillator equipped with pads for CPR quality analysis. Results: 503 volunteers participated in the study, with 54% being male and a mean age of 34 ± 12 years. The median CCRV and CC depth achieved with the double-click metronome were significantly higher compared to the standard metronome (median difference 6 mm/s, IQR-15.2, 28.5, +1.5%, p

Purpose: To evaluate the intermediate-term visual and safety outcomes of the small-incision second-generation implantable miniature telescope (SING IMT) in patients with late-stage age-related macular degeneration (AMD) at 6 months post-surgery. Design: Retrospective cohort study. Methods: Medical records of patients implanted with the SING IMT at two sites in Italy were reviewed. Outcomes evaluated up to 6 months post-surgery included best-corrected distance (BCDVA) and distance-corrected near (DCNVA) visual acuity, intraocular pressure (IOP), anterior chamber depth (ACD), corneal endothelial cell density (ECD), and adverse events. Results: The study involved 35 patients (mean age: 77.4 years). At 6 months post-surgery, the mean ± standard deviation (SD) change in BCDVA from baseline was −0.29 ± 0.142, and at least 1-, 2-, and 3-line gains in BCDVA were achieved in 97.1 %, 68.6 % and 51.4 %, of operated eyes, respectively. The percentage of patients able to read at near distance increased from 28.6 % at baseline to 97.1 % at 6 months post-surgery with a mean improvement of −0.57 ± 0.206. No clinically meaningful change from baseline was observed in terms of IOP or ACD. The mean (SD) change from baseline in ECD at 6 months in operated eyes was −280.7 (315.9) cells/mm2 (−11.4 %). The most frequent adverse event was corneal edema, and all cases were resolved with topical medications. Conclusions: This intermediate-term assessment confirms that SING IMT implantation improved distance and near vision, with a low impact on the corneal endothelium and an acceptable and manageable rate of complications and adverse effects.

Objective. Vagus nerve stimulation (VNS), which involves a surgical procedure to place electrodes directly on the vagus nerve (VN), is approved clinically for the treatment of epilepsy, depression, and to facilitate rehabilitation in stroke. VNS at surgically implanted electrodes is often limited by activation of motor nerve fibers near and within the VN that cause neck muscle contraction. In this study we investigated endovascular VNS that may allow activation of the VN at locations where the motor nerve fibers are not localized.Approach. We used endovascular electrodes within the nearby internal jugular vein (IJV) to electrically stimulate the VN while recording VN compound action potentials (CAPs) and neck muscle motor evoked potentials (MEPs) in an acute intraoperative swine experiment.Main Results. We show that the stimulation electrode position within the IJV is critical for efficient activation of the VN. We also demonstrate use of fluoroscopy (cone beam CT mode) and ultrasound to determine the position of the endovascular stimulation electrode with respect to the VN and IJV. At the most effective endovascular stimulation locations tested, thresholds for VN activation were several times higher than direct stimulation of the nerve using a cuff electrode; however, this work demonstrates the feasibility of VNS with endovascular electrodes and provides tools to optimize endovascular electrode positions for VNS.Significance. This work lays the foundation to develop endovascular VNS strategies to stimulate at VN locations that would be otherwise too invasive and at VN locations where structures such as motor nerve fibers do not exist.

Purpose: To evaluate the feasibility and outcomes of implanting the Smaller-Incision New-Generation Implantable Miniature Telescope (SING IMT) in pseudophakic patients affected by late-stage dry AMD. Subjects: Five pseudophakic patients’ eyes with stable dry AMD were suitable for SING IMT implantation. Four eyes were excluded because of previous YAG laser capsulotomy. Patients underwent preoperative assessments, including visual acuity measurements and OCT scans. Methods: Surgical procedures were performed under peribulbar anesthesia, with careful IOL removal and SING IMT implantation. Postoperative follow-up was conducted at regular intervals to monitor visual acuity, device positioning and complications. Results: Postoperative outcomes demonstrated improvements in visual acuity for most patients with an average gain in CDVA (Corrected Distance Visual Acuity) and CNVA (Corrected Near Visual Acuity) of 16,8 ± 10,2 and 13,8 ± 7,4 ETDRS letters, respectively. Limited complications have been observed. In one case, we observed dislocation of the device into the vitreous chamber, which we managed through vitrectomy and scleral fixation of the SING IMT using GoreTex suture. Conclusions: Despite being traditionally contraindicated for pseudophakic patients, SING IMT implantation in selected cases yielded favorable outcomes, indicating potential benefits for this population. Further research with larger sample sizes and longer follow-up periods is warranted to refine patient selection criteria and optimize surgical techniques.

The improvements in connectivity, artificial intelligence, and automation and their increasing penetration into all aspects of society and economy require informed decisions based on rigorous research on the determinants and outcomes of the digital economy. This context has promoted policy incentives dedicated to the digital transformation of business models and societal settings with a potential to disrupt existing markets and form a backbone of future development. The interest in digital economy and the research domains strongly connected to it has generated a wide array of terms that created confusion over its theoretical foundations. Several bibliometric analyses in recent years have attempted to map scientific findings and provide guidelines for future research in this area. However, such analyses draw their conclusions from algorithms that focus on attributes common to all studies without looking at their content. Our study combines bibliometric and in-depth content analyses to shed light on the definition, theoretical underpinnings, and state of the art of research on the digital economy. Our findings show that research in this domain is still in its infancy and the stated focus of studies on digital economy is often not reflected in their content. The study design allows us to make an original contribution by more precisely identifying gaps in the existing knowledge, outlining a detailed research agenda, and providing guidelines for future studies as well as informed policy decisions based on rigorous research on the determinants and outcomes of the digital economy.

Abstract In the pursuit of unconventional binders that can reduce energy consumption in production, magnesium oxysulfate (MOS) cement emerges as a viable alternative. Moreover, carbon dioxide (CO2) has been employed in the curing process of certain MOS cement products, such as magnesia fiber cement, due to its capacity to enhance their performance. This study aims to assess the impact of pre-curing prior to accelerated carbonation on the physical-mechanical properties of magnesium oxide fiber cement boards. These boards were manufactured using the Hatschek process simulation and subjected to pre-curing periods of 24, 48, and 72 h post-production. The relationship between microstructural alterations and the physical-mechanical properties was examined through analyses including water absorption, apparent porosity, apparent density, four-point bending tests, X-ray diffraction, and scanning electron microscopy analyses. The results indicated that pre-curing had an influence on the physical-mechanical attributes of the manufactured boards. After 72 h, the carbonated materials exhibited a decline in mechanical performance, a phenomenon attributed to the carbonation reactions between CO2 and the hydration products responsible for enhancing the mechanical strength of the cementitious materials.