Search

Abstract Lipid nanoparticles (LNPs) play a crucial role in addressing genetic disorders, and cancer, and combating pandemics such as COVID-19 and its variants. Yet, the ability of LNPs to effectively encapsulate large-size DNA molecules remains elusive. This is a significant limitation, as the successful delivery of large-size DNA holds immense potential for gene therapy. To address this gap, the present study focuses on the design of PEGylated LNPs, incorporating large-sized DNA, departing from traditional RNA and ionizable lipids. The resultant LNPs demonstrate a unique particle morphology. These particles were further engineered with a DNA coating and plasma proteins. This multicomponent bionanoconstruct exhibits enhanced transfection efficiency and safety in controlled laboratory settings and improved immune system evasion in in vivo tests. These findings provide valuable insights for the design and development of bionanoarchitectures for large-size DNA delivery, opening new avenues for transformative gene therapies.

Abstract Sea cucumbers are deposit feeding members of marine benthic communities. The over-exploitation of sea cucumber natural stocks, especially in the Mediterranean basin, is having negative impacts on the marine ecosystem. This concerns had led the Italian government to take legal actions to preserve these important marine resources. The aim of this study was to evaluate the level of genetic diversity and population structures within two sympatric Holothuria sea cucumber species, H. polii and H. tubulosa, across ten Mediterranean areas along Italy. A 323 bp portion of the COI mitochondrial gene was sequenced in a total of 441 holothurians (251 H. polii, 177 H. tubulosa and 13 from other species). Genetic diversity analyses and analysis of molecular variance (AMOVA) suggest that H. polii and H. tubulosa species are distinct, but within and among populations are homogeneous, indicating active gene flows across the Mediterranean areas investigated. H. polii showed a lower genetic diversity than H. tubulosa, probably related to differences in life history traits. Phylogenetic analyses showed a clear differentiation between the two species, even if six specimens morphologically assigned to a species clustered within the other species, indicating a possible occurrence of hybridization events. These data will be useful in implementing conservation actions for these holothurian genetic resources.

Abstract Psoriasis is a chronic, immune-mediated, inflammatory skin disease, associated with multiple comorbidities and psychological and psychiatric disorders. The quality of life of patients with this disease is severely compromised, especially in moderate-to-severe plaque psoriasis. Secukinumab, a fully humanized monoclonal antibody, was the first anti-interleukin (IL)-17 biologic approved for treating psoriasis. Secukinumab demonstrated long-lasting efficacy and a good safety profile in individuals with plaque psoriasis, and it is associated with an improvement in health-related quality of life. While there is evidence that early treatment with systemic therapy can affect disease progression and improve long-term outcomes in other autoimmune diseases, evidence is limited in psoriasis, especially in real-world settings. This review provides an overview of studies describing the effectiveness of secukinumab in the treatment of psoriasis summarizing the literature and focusing on real-world evidence and early intervention.

Abstract Background The contemporary management of mass casualty incidents (MCIs) relies on the effective application of predetermined, dedicated response plans based on current best evidence. Currently, there is limited evidence regarding the factors influencing the accuracy of first responders (FRs) in applying the START protocol and the associated prehospital times during the response to MCIs. The objective of this study was to investigate factors affecting FRs’ accuracy in performing prehospital triage in a series of simulated mass casualty exercises. Secondly, we assessed factors affecting triage-to-scene exit time in the same series of exercises. Methods This retrospective study focused on simulated casualties in a series of simulated MCIs Full Scale Exercises. START triage was the triage method of choice. For each Full-Scale Exercise (FSEx), collected data included exercise and casualty-related information, simulated casualty vital parameters, simulated casualty anatomic lesions, scenario management times, and responder experience. Results Among the 1090 casualties included in the primary analysis, 912 (83.6%) were correctly triaged, 137 (12.6%) were overtriaged, and 41 (3.7%) were undertriaged. The multinomial regression model indicated that increasing heart rate (RRR = 1.012, p = 0.008), H-AIS (RRR = 1.532, p

Abstract The historical restriction of magnetic resonance imaging (MRI) for patients with cardiac implantable electronic devices (CIEDs) has been lifted by certified MRI-conditional systems in recent years. Mixed-brand CIED systems consisting of a generator from one manufacturer and at least one lead from another manufacturer are not certified for MRI. We evaluated the temporal trend in the prevalence of mixed-brand systems in the era of MRI-conditional systems. Data were analyzed on 5853 CIEDs implanted de novo between 2012 and 2022 in 81 Italian centers linked to the nationwide Home Monitoring Expert Alliance network. The percentage of mixed-brand implants was calculated by device type (pacemaker, implantable cardioverter-defibrillator [ICD], cardiac resynchronization therapy [CRT] device) and over time. A mixed-brand system was implanted in 4.1% (95% CI, 3.6-4.6%) of analyzed patients or, by device type, in 4.5% (3.5-5.7%) of pacemaker patients, 1.1% (0.7-1.7%) of ICD patients, and 6.8% (5.7-7.9%) of CRT pacemaker/defibrillator patients (p

Abstract Background . The present study aimed at deriving regression-based reliable change indices (RCIs) for the Montreal Cognitive Assessment (MoCA) in an Italian cohort of non-demented Parkinson’s disease (PD) patients. Methods N = 33 consecutive, non-demented PD patients were followed-up at a 5-to-8-month interval (M = 6.6; SD = 0.6) with the MoCA. Practice effects and test-retest reliability were assessed via dependent-sample t-tests and intra-class correlation (ICC) coefficients, respectively. RCIs were derived separately for raw and demographically adjusted MoCA scores according to a standardized regression-based approach by accounting for both baseline confounders (i.e., demographics, disease duration and Unified Parkinson’s Disease Rating Scale scores) and retest interval. Results No practice effects were found (t(32) = 0.29; p = .778), with acceptable test-retest reliability being detected (ICC = 0.67). MoCA scores at T0 proved to be the only significant predictor of T1 MoCA performances within both the model addressing raw scores and that addressing adjusted scores (ps

Abstract Background Seafood is increasingly traded worldwide, but its supply chain is particularly prone to frauds. To increase consumer confidence, prevent illegal trade, and provide independent validation for eco-labelling, accurate tools for seafood traceability are needed. Here we show that the use of microbiome profiling (MP) coupled with machine learning (ML) allows precise tracing the origin of Manila clams harvested in areas separated by small geographic distances. The study was designed to represent a real-world scenario. Clams were collected in different seasons across the most important production area in Europe (lagoons along the northern Adriatic coast) to cover the known seasonal variation in microbiome composition for the species. DNA extracted from samples underwent the same depuration process as commercial products (i.e. at least 12 h in open flow systems). Results Machine learning-based analysis of microbiome profiles was carried out using two completely independent sets of data (collected at the same locations but in different years), one for training the algorithm, and the other for testing its accuracy and assessing the temporal stability signal. Briefly, gills (GI) and digestive gland (DG) of clams were collected in summer and winter over two different years (i.e. from 2018 to 2020) in one banned area and four farming sites. 16S DNA metabarcoding was performed on clam tissues and the obtained amplicon sequence variants (ASVs) table was used as input for ML MP. The best-predicting performances were obtained using the combined information of GI and DG (consensus analysis), showing a Cohen K-score > 0.95 when the target was the classification of samples collected from the banned area and those harvested at farming sites. Classification of the four different farming areas showed slightly lower accuracy with a 0.76 score. Conclusions We show here that MP coupled with ML is an effective tool to trace the origin of shellfish products. The tool is extremely robust against seasonal and inter-annual variability, as well as product depuration, and is ready for implementation in routine assessment to prevent the trade of illegally harvested or mislabeled shellfish.

Abstract A genomic database of all Earth’s eukaryotic species could contribute to many scientific discoveries; however, only a tiny fraction of species have genomic information available. In 2018, scientists across the world united under the Earth BioGenome Project (EBP), aiming to produce a database of high-quality reference genomes containing all ~1.5 million recognized eukaryotic species. As the European node of the EBP, the European Reference Genome Atlas (ERGA) sought to implement a new decentralised, equitable and inclusive model for producing reference genomes. For this, ERGA launched a Pilot Project establishing the first distributed reference genome production infrastructure and testing it on 98 eukaryotic species from 33 European countries. Here we outline the infrastructure and explore its effectiveness for scaling high-quality reference genome production, whilst considering equity and inclusion. The outcomes and lessons learned provide a solid foundation for ERGA while offering key learnings to other transnational, national genomic resource projects and the EBP.

Abstract We present an updated analysis on the incidence of primary brain tumors in the Metropolitan Area of Genova, the capital of the northwestern Italian region Liguria. The number of cases and incidence rates for all malignant brain tumors, glioblastoma, malignant brain tumors other than glioblastoma, and brain tumors not otherwise specified were calculated for each of seven three-year and one-eighth four-year periods in which the quarter century 1993–2017 was divided. The rates were age-adjusted (AAR) using the 2013 European standard population, presented per 100,000 person-years and the average percentage change over the three-year period was calculated. The number of cases of all malignant brain tumors and glioblastoma was higher in males than in females in each three-year period and in the entire quarter century 1993–2017. During the latter, the average three-year percentage change in AARs for all brain tumors was minimal [0.6 (95% C.I. = -1.0/2.1) %] while for glioblastoma there was a change of 5.3 (95% C.I. = -0.4/11.3) %. The partially concurrent decline in the incidence rates of malignant brain tumors other than glioblastoma or not otherwise specified suggests that the observed increase in the incidence rate of glioblastoma during 1993–2017 may have been at least partially linked to the improvement during the same period in sensitivity and specificity of the diagnosis of glioblastoma, depleting the reservoirs of other malignant or unspecified brain tumors. Research into possibly increased environmental risk factors (e.g., population exposure to ionizing radiation) for glioblastoma in Genova remains warranted.

Abstract This paper shows that the level and timing of fertility are converging strongly over different measures of educational attainment using 65 years of data from 146 countries. Global convergence patterns are primarily driven by high-income societies, while sub-Saharan Africa is the world region that is converging most slowly, if not converging at all. Most importantly, levels of education matter heavily for explaining strength and variation in global fertility convergence, with two intersecting educational gradients suggesting: (i) stronger convergence over tertiary education followed, in turn, by secondary and primary; (ii) stronger convergence over education completed relative to education attended. Our findings provide important insights for addressing key challenges in global development and demography, and for informing policymakers as they evaluate the suitability of specific educational policies aimed at further narrowing inequalities between societies—such as supporting higher education as well as the successful completion of targeted educational cycles.

Abstract The potential of the island of La Palma (Canary Islands) to host geothermal resources is very high, mainly due to its high volcanic activity. The primary goal of this study is to get a tridimensional image of the seismic intrinsic attenuation using ambient seismic noise and to identify anomalies that may be linked to active geothermal reservoirs on La Palma island. For this purpose, we developed a new Ambient Noise Attenuation Tomography (ANAT) technique, which uses seismic ambient noise for imaging intrinsic attenuation in 3-D at a local scale down to 5 km depth. Our research identifies two areas with high attenuation in the island’s southern region. One area could be associated with hydrothermal alteration zones beneath the Cumbre Vieja volcanic complex. Another high-attenuation zone was observed in the island’s southern part, which could be associated with extensively fractured rocks that might facilitate the circulation of heated fluids. Furthermore, we discuss the geothermal relevance of such anomalies, making a comparison with previous resistivity, S-wave velocity and density models. This study confirms that intrinsic attenuation retrieved from the coda of Rayleigh waves is more sensitive to the presence of fluids than velocity. Fluids being a key component of active geothermal reservoirs, it is reasonable to expect intrinsic attenuation anomalies in these systems. Therefore, we conclude that ANAT can be useful for geothermal exploration.

Abstract This study aims to investigate the changes in bioenergetic pathway contributions during repeated sprint exercises with an increasing number of repetitions. Twelve male amateur soccer players executed a single 20 m sprint and three repeated-sprint protocols (5 × 20 m, 10 × 20 m, 15 × 20 m with 15-second rest intervals), analyzing oxidative, glycolytic, and ATP-PCr energy pathways using the PCr-LA-O2 method. Findings revealed a significant decline in energy expenditure and performance outputs as the number of sprint repetitions increased. While the oxidative and ATP-PCr pathways’ energy contributions significantly rose with more sprints, the glycolytic pathway’s contribution notably increased only up to the 10 × 20 m protocol, then stabilized. Although the ATP-PCr pathway’s energy contribution decreased slightly from sprints 1–5 to 11–15, it remained significantly higher than the oxidative and glycolytic pathways throughout. Initially, glycolytic contribution surpassed oxidative in sprints 1–5, equaled it in sprints 6–10, and fell below in sprints 11–15. Glycolytic activity, a major energy source initially (about 36%), diminished substantially with more sprints (below 7% in the 15th sprint). This indicates that the decrease in non-mitochondrial pathway energy, particularly glycolytic, outstrips the aerobic system’s increased tolerance. These findings offer physiological insights into the relationship between performance decrement and bioenergetic metabolism in repeated sprints.

Abstract The mammalian plasma membrane is known to contain domains with varying lipid composition and biophysical properties. However, studying these membrane lipid domains presents challenges due to their predicted morphological similarity to the bulk membrane and their scale being below the classical resolution limit of optical microscopy. To address this, we combine the solvatochromic probe di-4-ANEPPDHQ, which reports on its biophysical environment through changes in its fluorescence emission, with spectrally resolved single-molecule localisation microscopy. The resulting data comprises nanometre-precision localisation coordinates and a generalised polarisation value related to the probe’s environment – a marked point pattern. We introduce quantification algorithms based on topological data analysis (PLASMA) to detect and map nano-domains in this marked data, demonstrating their effectiveness in both artificial membranes and live cells. By leveraging environmentally sensitive fluorophores, multi-modal single molecule localisation microscopy, and advanced analysis methods, we achieve nanometre scale mapping of membrane properties and assess changes in response to external perturbation with methyl-β-cyclodextrin. This integrated methodology represents an integrated toolset for investigating marked point pattern data at nanometre spatial scales.

Abstract A variety of scientific fields like proteomics and spintronics have created a new demand for on-chip devices capable of sensing parameters localized within a few tens of micrometers. Nano and microelectromechanical systems (NEMS/MEMS) are extensively employed for monitoring parameters that exert uniform forces over hundreds of micrometers or more, such as acceleration, pressure, and magnetic fields. However, they can show significantly degraded sensing performance when targeting more localized parameters, like the mass of a single cell. To address this challenge, we present a MEMS device that leverages the destructive interference of two topological radiofrequency (RF) counter-propagating wave modes along a piezoelectric Aluminum Scandium Nitride (AlScN) Su-Schrieffer-Heeger (SSH) interface. The reported MEMS device opens up opportunities for further purposes, including achieving more stable frequency sources for communication and timing applications.

Abstract Sore throat represents one of the main causes of antibiotic overprescription in children. Its management is still a matter of debate, with countries considering streptococcal pharyngotonsillitis a benign and self-limiting condition and others advocating for its antibiotic treatment to prevent suppurative complications and acute rheumatic fever. Italian paediatricians frequently prescribe antibiotics on a clinical basis regardless of microbiological results. Moreover, broad-spectrum antibiotics are inappropriately prescribed for this condition. In this regard, an intersociety consensus conference was issued to promote the judicious use of antibiotic therapy in paediatric outpatient settings. A systematic review of the literature was performed, and updated recommendations were developed according to the GRADE methodology. Antibiotic treatment with amoxicillin (50 mg/kg/day) for 10 days is recommended in all children with proven streptococcal pharyngitis. Benzathine-penicillin could be prescribed in children with impaired intestinal absorption or inability to tolerate enteral intake and in those at high risk of suppurative complications with low compliance to oral therapy. In children with suspected amoxicillin allergy, third-generation cefalosporins for five days are recommended in low-risk patients, and macrolides are recommended in high-risk ones. Candidates for tonsillectomy due to recurrent pharyngitis could be treated with amoxicillin-clavulanic acid, clindamycin, or combined therapy with amoxicillin plus rifampicin for four days, in an attempt to avoid surgery.

Abstract Photoacoustic computed tomography (PACT) can harvest diffusive photons to image the optical absorption contrast of molecules in a scattering medium, with ultrasonically-defined spatial resolution. PACT has been extensively used in preclinical research for imaging functional and molecular information in various animal models, with recent clinical translations. In this review, we aim to highlight the recent technical breakthroughs in PACT and the emerging preclinical and clinical applications in deep tissue imaging.

Abstract Photoacoustic microscopy (PAM) is a key implementation of photoacoustic imaging (PAI). PAM merges rich optical contrast with deep acoustic detection, allowing for broad biomedical research and diverse clinical applications. Recent advancements in PAM technology have dramatically improved its imaging speed, enabling real-time observation of dynamic biological processes in vivo and motion-sensitive targets in situ, such as brain activities and placental development. This review introduces the engineering principles of high-speed PAM, focusing on various excitation and detection methods, each presenting unique benefits and challenges. Driven by these technological innovations, high-speed PAM has expanded its applications across fundamental, preclinical, and clinical fields. We highlight these notable applications, discuss ongoing technical challenges, and outline future directions for the development of high-speed PAM.

Abstract Background Although second-generation antipsychotics (SGAs) have proven to be effective therapeutic options for patients with schizophrenia, there is a notable lack of evidence on patients’ subjective perspectives regarding their well-being, quality of life, and satisfaction with these medications. This study aimed to evaluate the treatment satisfaction and effectiveness of lurasidone on quality of life and functioning in adult patients with schizophrenia in real-world Italian clinical practice. Methods This was a multicentre, national, non-interventional, single-arm, 3-month prospective study. Patients who were naive to lurasidone treatment and whose treating physician had decided to start them on this medication were enrolled and evaluated over a 3-month period. Eligible patients were adults (≥ 18 years of age) with a primary diagnosis of schizophrenia who were being treated with lurasidone (for the first time [i.e., they were lurasidone naive]) as part of routine clinical practice. Efficacy endpoints were changes in patient/caregiver treatment satisfaction (seven-point Likert scale from the Treatment Satisfaction Questionnaire for Medication), patient quality of life and functioning (QLS), investigator-rated global assessment of functioning (CGI-S, IAQ) after 6 weeks and 3 months of lurasidone, and number of relapses and hospitalizations. Results Sixty-one patients were enrolled and 59 completed the study. The median dosage of lurasidone at baseline was 37.00 mg/day. The median duration of titration was 86.0 days (Min 28; Max 115 days); the median number of dosage changes was 1.0. At the end of 3-month observation period, the median dose of lurasidone was 74.00 mg/day. QoL and Functioning Score showed a trend of improvement over time, reaching a mean change from baseline of 9.8 at the end of the study. According to the CGI-S, the percentage of patients who were “markedly or severely ill” showed a continuous decrease from baseline to 3 months, from 62.29% to 8.20%. Patient satisfaction increased over time, with 80.32% of patients reporting that they were somewhat, fairly, or very satisfied (including 63.93% who were completely or very satisfied) at the end of the study. No relapses/hospitalizations for psychiatric reasons were reported. Lurasidone was well tolerated with no safety concerns or discontinuations due to AEs. Conclusions Lurasidone represents a valid option for the treatment of schizophrenia and positively affects subjective well-being, quality of life and satisfaction. Trial registration NCT06527885 retrospectively registered (01/08/2024).

Abstract Background The construction of a pangenome graph is a fundamental task in pangenomics. A natural theoretical question is how to formalize the computational problem of building an optimal pangenome graph, making explicit the underlying optimization criterion and the set of feasible solutions. Current approaches build a pangenome graph with some heuristics, without assuming some explicit optimization criteria. Thus it is unclear how a specific optimization criterion affects the graph topology and downstream analysis, like read mapping and variant calling. Results In this paper, by leveraging the notion of maximal block in a Multiple Sequence Alignment (MSA), we reframe the pangenome graph construction problem as an exact cover problem on blocks called Minimum Weighted Block Cover (MWBC). Then we propose an Integer Linear Programming (ILP) formulation for the MWBC problem that allows us to study the most natural objective functions for building a graph. We provide an implementation of the ILP approach for solving the MWBC and we evaluate it on SARS-CoV-2 complete genomes, showing how different objective functions lead to pangenome graphs that have different properties, hinting that the specific downstream task can drive the graph construction phase. Conclusion We show that a customized construction of a pangenome graph based on selecting objective functions has a direct impact on the resulting graphs. In particular, our formalization of the MWBC problem, based on finding an optimal subset of blocks covering an MSA, paves the way to novel practical approaches to graph representations of an MSA where the user can guide the construction.

Abstract The Italian Society of Anesthesia, Analgesia, Resuscitation and Intensive Care (SIAARTI) has developed a good clinical practice to address the challenges of treating critically ill patients in resource-limited austere environments, exacerbated by recent pandemics, natural disasters, and conflicts. The methodological approach was based on a literature review and a modified Delphi method, which involved blind voting and consensus evaluation using a Likert scale. This process was conducted over two rounds of online voting. The document covers six critical topics: the overall impact of austere conditions on critical care, airway management, analgesia, bleeding control, vascular access, and medical devices and equipment. In these settings, it is vital to apply basic care techniques flexibly, focusing on immediate bleeding control, airway management, and hypothermia treatment to reduce mortality. For airway management, rapid sequence intubation with ketamine for sedation and muscle relaxation is suggested. Effective pain management involves a multimodal approach, including patient-controlled analgesia by quickly acting safe drugs, with an emphasis on ethical palliative care when other options are unavailable. Regarding hemorrhage, military-derived protocols like Tactical Combat Casualty Care significantly reduced mortality and influenced the development of civilian bleeding control devices. Establishing venous access is crucial, with intraosseous access as a swift option and central venous access for complex cases, ensuring aseptic conditions. Lastly, selecting medical equipment that matches the specific logistical and medical needs is essential, maintaining monitoring standards and considering advanced diagnostic tools like point-of-care ultrasounds. Finally, effective communication tools for coordination and telemedicine are also vital.

Abstract Individuals with rare skeletal disorders like Multiple Osteochondromas and Ollier Disease often experience physical and psychological burdens. Adventure therapy, with activities like sailing in outdoor settings, promotes personal growth and psychological well-being, potentially improving health-related quality of life (HRQoL). This study aimed to evaluate the impact of a sailing program on health-related quality of life and participant satisfaction in individuals with Multiple Osteochondromas and Ollier Disease. A quasi-experimental one-group pre-post design was employed, with HRQoL assessed using the EQ-5D® instrument and participant satisfaction measured via a feedback survey. Data were collected before and after the five-day sailing program conducted in the Mediterranean Sea in 2022 and 2023, involving participants diagnosed with Multiple Osteochondromas and Ollier Disease. Statistical analyses were performed using the Wilcoxon signed-rank test and McNemar’s test for paired data. A significance level of p

Abstract Neuronal communication involves small-molecule transmitters, gap junctions, and neuropeptides. While neurons often express multiple neuropeptides, our understanding of the coordination of their actions and their mutual interactions remains limited. Here, we demonstrate that two neuropeptides, NLP-10 and FLP-1, released from the same interneuron pair, AVKL/R, exert antagonistic effects on locomotion speed in Caenorhabditis elegans. NLP-10 accelerates locomotion by activating the G protein-coupled receptor NPR-35 on premotor interneurons that promote forward movement. Notably, we establish that NLP-10 is crucial for the aversive response to mechanical and noxious light stimuli. Conversely, AVK-derived FLP-1 slows down locomotion by suppressing the secretion of NLP-10 from AVK, through autocrine feedback via activation of its receptor DMSR-7 in AVK neurons. Our findings suggest that peptidergic autocrine motifs, exemplified by the interaction between NLP-10 and FLP-1, might represent a widespread mechanism in nervous systems across species. These mutual functional interactions among peptidergic co-transmitters could fine-tune brain activity.

Abstract Comprehensive care integrates individual patient needs and is highly valued for patients with pulmonary fibrosis (PF). The importance of a patient-centered care approach is rooted in the unpredictable progressiveness of the disease course in PF. The respiratory impairment associated with PF has a major impact on the quality of life for both patients and their caregivers. We believe that prioritizing patient preferences could improve the shared decision making process and may ultimately lead to better health outcomes. Despite the growing emphasis for this approach, it remains challenging to adopt it in clinical practice. In this review, we propose the comprehensive Triple A Care Model, consisting of the domains Access, Anticipate, and Act, which emphasizes core elements of patient-centered care for patients with PF. We will provide an overview of the unmet needs in care for patients with PF and elaborate on the current methods for delivering patient-centered care. The latest insights into symptom management and supportive measures and several approaches to improving access to care are discussed, in line with the most recent guidelines.

In the field of additive manufacturing (AM), a promising alloy that is gaining attention is the near-α Ti–6Al–2Sn–4Zr–2Mo (Ti6242) alloy. This alloy is known for its remarkable resistance to creep and corrosion at elevated temperatures. However, the production of Ti6242 components via Laser-based AM technologies faced with several challenges, such as the formation of residual stress in the as-built state that originates from the nature of these processes. Therefore, this study has a dual objective: first, to evaluate the microstructure and residual stresses in the as-built Ti6242 produced through laser powder bed fusion. Secondly, to investigate the impact of a promising post heat treatment on mitigating residual stresses, inducing alterations in the microhardness of the Ti6242 alloy and its ductility, phase transformations and microstructure evolution. The as-built specimen exhibited a significant residual stress of 1357 MPa, which was caused by the pronounced temperature gradients experienced during the fabrication process. It is interesting to note that this promising post heat treatment was highly effective in eliminating 99% of the residual stress. After heat treatment, the amount of α′ present in the as-built specimen decreased. This resulted in the activation of diffusion of elements such as molybdenum, causing a proportion of the α′ to decompose into the more ductile α+β structure. Additionally, it is revealed that the microstructural changes and relieved stresses from the heat treatment process caused a lower microhardness and a higher ductility under compressive loading, as the elongation and toughness reached 20.5% and 23.255 kJ/mm3 in the heat-treated samples, respectively. The outcomes of this work facilitate the use of this alloy in the production of complex shape components through laser-based AM technologies.

Abstract Unaccustomed eccentric exercise (EE) is protective against muscle damage following a subsequent bout of similar exercise. One hypothesis suggests the existence of an alteration in motor unit (MU) behaviour during the second bout, which might contribute to the adaptive response. Accordingly, the present study investigated MU changes during repeated bouts of EE. During two bouts of exercise where maximal lengthening dorsiflexion (10 repetitions × 10 sets) was performed 3 weeks apart, maximal voluntary isometric torque (MVIC) and MU behaviour (quantified using high‐density electromyography; HDsEMG) were measured at baseline, during (after set 5), and post‐EE. The HDsEMG signals were decomposed into individual MU discharge timings, and a subset were tracked across each time point. MVIC was reduced similarly in both bouts post‐EE (Δ27 vs. 23%, P = 0.144), with a comparable amount of total work performed (∼1,300 J; P = 0.905). In total, 1,754 MUs were identified and the decline in MVIC was accompanied by a stepwise increase in discharge rate (∼13%; P

Abstract The clinical utility of hemoglobin-based oxygen carriers (HBOC) is limited by adverse heme oxidative chemistry. A variety of tyrosine residues were inserted on the surface of the γ subunit of recombinant fetal hemoglobin to create novel electron transport pathways. This enhanced the ability of the physiological antioxidant ascorbate to reduce ferryl heme and decrease lipid peroxidation. The γL96Y mutation presented the best profile of oxidative protection unaccompanied by loss of protein stability and function. N-terminal deletions were constructed to facilitate the production of recombinant hemoglobin by fermentation and phenylalanine insertions in the heme pocket to decrease the rate of NO dioxygenation. The resultant mutant (αV1del. αL29F, γG1del. γV67F, γL96Y) significantly decreased NO scavenging and lipid peroxidation in vitro. Unlike native hemoglobin or a recombinant control (αV1del, γG1del), this mutation showed no increase in blood pressure immediately following infusion in a rat model of reperfusion injury, suggesting that it was also able to prevent NO scavenging in vivo. Infusion of the mutant also resulted in no meaningful adverse physiological effects apart from diuresis, and no increase in oxidative stress, as measured by urinary isoprostane levels. Following PEGylation via the Euro-PEG-Hb method to increase vascular retention, this novel protein construct was compared with saline in a severe rat reperfusion injury model (45% blood volume removal for 90 minutes followed by reinfusion to twice the volume of shed blood). Blood pressure and survival were followed for 4 h post-reperfusion. While there was no difference in blood pressure, the PEGylated Hb mutant significantly increased survival.

Beyond being used as fast and cheap annotators for otherwise complex classification tasks, LLMs have seen a growing adoption for generating synthetic data for social science and design research. Researchers have used LLM-generated data for data augmentation and prototyping, as well as for direct analysis where LLMs acted as proxies for real human subjects. LLM-based synthetic data build on fundamentally different epistemological assumptions than previous synthetically generated data and are justified by a different set of considerations. In this essay, we explore the various ways in which LLMs have been used to generate research data and consider the underlying epistemological (and accompanying methodological) assumptions. We challenge some of the assumptions made about LLM-generated data, and we highlight the main challenges that social sciences and humanities need to address if they want to adopt LLMs as synthetic data generators.

Abstract What is the bulk Hilbert space of quantum gravity? In this paper, we resolve this problem in 2d JT gravity, both with and without matter, providing an explicit definition of a non-perturbative Hilbert space specified in terms of metric variables. The states are wavefunctions of the length and matter state, but with a non-trivial and highly degenerate inner product. We explicitly identify the null states, and discuss their importance for defining operators non-perturbatively. To highlight the power of the formalism we developed, we study the non-perturbative effects for two bulk linear operators that may serve as proxies for the experience of an observer falling into a two-sided black hole: one captures the length of an Einstein-Rosen bridge and the other captures the center-of-mass collision energy between two particles falling from opposite sides. We track the behavior of these operators up to times of order e S BH $$ {e}^{S_{\textrm{BH}}} $$ , at which point the wavefunction spreads to the complete set of eigenstates of these operators. If these observables are indeed good proxies for the experience of an infalling observer, our results indicate an O(1) probability of detecting a firewall at late times that is self-averaging and universal.

Abstract The Peccei-Quinn (PQ) symmetry does not need to be exact, and even a tiny source of PQ breaking not aligned with the QCD anomaly might have significant phenomenological implications. In this study, we examine the effects of a general class of PQ-breaking operators on the axion cosmological production via misalignment, focussing on both temperature-dependent and independent PQ-breaking potentials. In particular, we show that a variant of the trapped misalignment mechanism can delay the onset of axion oscillation, leading to an axion dark matter window with m a ≫ 10 −5 eV. This scenario is testable through various experimental approaches, including standard axion haloscopes and helioscopes, as well as searches for electric dipole moments and axion-mediated forces.

Abstract In regenerating tissues, synthesis and remodeling of membranes rely on lipid turnover and transport. Our study addresses lipid adaptations in intestinal regeneration of Drosophila melanogaster and limb regeneration of Ambystoma mexicanum. We found changes in lipid profiles at different locations: transport, storage organs and regenerating tissues. We demonstrate that attenuating insulin signaling, exclusively in fat storage, inhibits the regeneration-specific response in both the fat storage and the regenerating tissue in Drosophila. Furthermore, in uninjured axolotls we found sex-specific lipid profiles in both storage and circulation, while in regenerating animals these differences subside. The regenerating limb presents a unique sterol profile, albeit with no sex differences. We postulate that regeneration triggers a systemic response, where organs storing lipids play a significant role in the regulation of systemic lipid traffic. Second, that this response may be an active and well-regulated mechanism, as observed when homeostatic sex-differences disappear in regenerating salamanders.

Abstract Rationale & objective End-stage kidney disease (ESKD) negatively affects patients’ physical, emotional, and social functioning. Furthermore, adjustment to dialysis require substantial lifestyle changes that may further impact on patients physical and emotional well-being. However, the relationship between Health-Related Quality of life impairment with future adverse outcomes in dialysis is not well characterized. Our study aims to investigate the relationship between Health-Related Quality of Life (HRQoL) and patients’ survival and hospitalization rates within a large European dialysis network. Methods A historical cohort study was conducted to evaluate association of HRQoL with hospitalization and mortality rates over a 12-month follow-up period. Patients responded to a self-administered survey as part of a Continuous Quality Improvement Program implemented in clinics affiliated with the Spanish FMC-Nephrocare organization. Health-Related Quality of Life (HRQoL) was measured with the KDQOL-36. Potential confounders included socio-demographic characteristics, comorbidities, biochemical parameters, dialysis treatment. We used Cox’s Proportional Hazard regression to assess the hazard of death and Logistic Regression to assess the likelihood of hospital admissions during 12-month follow-up period. Results A total of 2280 (51.5%) completed the self-administrated survey, and 1838 patients met the inclusion/exclusion criteria of the study. Higher HRQoL scores were associated with significantly lower mortality and hospitalization risk. Risk estimates were robust to adjustment for potential confounders. Conclusions Several dimensions of HRQoL are associated with patient-centered outcomes (i.e., mortality and hospitalizations at 1 year). Patient-Reported Outcomes contribute unique pieces of information characterizing patients’ health. Residual confounding cannot be fully ruled out; moreover, the high attrition rate could result in selection bias, which may limit the generalizability of the findings to a broader population.

Abstract We present an ultraviolet (UV) - extreme-ultraviolet (XUV) pump-probe beamline with applications in ultrafast time-resolved photoelectron spectroscopy. The UV pump pulses, tuneable between 255 and 285 nm and with µJ-level energy, are generated by frequency up-conversion between ultrashort visible/infrared pulses and visible narrow-band pulses. Few-femtosecond XUV probe pulses are produced by a high-order harmonic generation source equipped with a state-of-the-art time-delay compensated monochromator. Two-colour UV-XUV sidebands are used for a complete in situ temporal characterization of the pulses, demonstrating a temporal resolution of better than 20 fs. We validate the performances of the beamline through a UV-XUV pump-probe measurement on 1,3-cyclohexadiene, resolving the ultrashort dynamics of the first conical intersection. This instrument opens exciting possibilities for investigating ultrafast UV-induced dynamics of organic molecules in ultrashort time scales.

Igor Lemos Moreira é graduado e mestre em História pela Universidade do Estado de Santa Catarina (UDESC). No momento, cursa o doutorado também em História pela mesma instituição, tendo feito período sanduíche na University of Miami, nos Estados Unidos. Sua trajetória de estudar a música pop na História do Tempo Presente inspirou a presente entrevista, que aconteceu no dia 23 de fevereiro de 2023 via Google Meet.

Abstract The prevalence of malignant cells in clinical specimens, or tumour purity, is affected by both intrinsic biological factors and extrinsic sampling bias. Molecular characterization of large clinical cohorts is typically performed on bulk samples; data analysis and interpretation can be biased by tumour purity variability. Transcription-based strategies to estimate tumour purity have been proposed, but no breast cancer specific method is available yet. We interrogated over 6000 expression profiles from 10 breast cancer datasets to develop and validate a 9-gene Breast Cancer Purity Score (BCPS). BCPS outperformed existing methods for estimating tumour content. Adjusting transcriptomic profiles using the BCPS reduces sampling bias and aids data interpretation. BCPS-estimated tumour purity improved prognostication in luminal breast cancer, correlated with pathologic complete response in on-treatment biopsies from triple-negative breast cancer patients undergoing neoadjuvant treatment and effectively stratified the risk of relapse in HER2+ residual disease post-neoadjuvant treatment.

Abstract Background The impact of air bubbles into the cerebral circulation after open heart surgery has been a topic of discussion since the introduction of the heart-lung machine. The aim of the study was to evaluate whether the use of a dedicated commercial sponge diffuser is better than a custom-made narrow section cannula or the absence of CO2 in preventing neurological events after aortic valve replacement via J mini-sternotomy. Methods Three cohorts of J-shaped mini-sternotomy performed at three different centers were prospectively compared: CO2 supplied via sponge diffuser, CO2 supplied via cannula, and no CO2 supply. Propensity matching was used to obtain comparable groups. The primary endpoints were postoperative stroke, transitory ischemic attack, convulsions, and dizziness. Secondary endpoints were 30-day mortality, duration of mechanical ventilation, and intensive care unit length of stay. Results 275 patients were enrolled in the study. After propensity matching, the sponge diffuser cohort had a significantly lower duration of mechanical ventilation (P

Abstract VO2 is a promising phase change material offering a large contrast of electric, thermal, and optical properties when transitioning from semiconductor to metallic phase. Here we show that a hybrid metamaterial obtained by proper combination of a VO2 layer and a nanodisk gold array provides a tunable plasmonic gap resonance in the infrared range. Specifically, we have designed and fabricated a metal–insulator-metal gap resonance by inserting sub-wavelength VO2 film between a flat gold layer and a gold nanodisk resonator array. The resonance of the hybrid metamaterial is centered in the useful 3–5 μm range when VO2 is in its semiconductor state. The experimental study highlights a monotonical spectral tuning of the resonance when increasing temperature up to 50 °C above the room temperature, providing a continuous resonance shift of almost 1 μm in the mid-infrared range. Wavelength range and intensity tunability can be further optimized by modifying the thicknesses of the layers and metamaterial parameters.

Abstract A Right Ear Advantage (REA) is well-established in perceptual tasks but it has been found also during imagery. It is ascribed to the left temporoparietal activity for language, and it can be absent/reversed in some clinical conditions including auditory hallucinations. We applied 1-Hz repetitive TMS over TP3/TP4 (left/right language areas) identified through neuronavigation in 18 healthy participants, before administering a modified white noise (WN) speech illusion paradigm: a voice was presented at one ear, at the same or lower intensities with respect to binaural WN. In some trials the voice was not presented, but participants were anyway instructed to report in which ear they believed perceiving it in all trials. Results confirmed the REA both when the voice was present (perceptual REA) and when it was absent (imaginative REA). Interestingly, results suggested that the correct localization of the voice when the stimulus was ambiguous (presented at low intensity and “masked” by WN) was better when TMS was applied over the right/left hemisphere, in male participants with a low/high proneness to unusual experiences (e.g., auditory hallucinations), respectively. This interaction must be further explored to shed light on the relationship between hemispheric asymmetries and auditory hallucinations, in healthy and clinical samples.

Abstract Systemic vaccination of macaques with V1-deleted (ΔV1) envelope immunogens reduce the risk of SIVmac251 acquisition by approximately 60%, with protective roles played by V2-specific ADCC and envelope-specific mucosal IL-17+NKp44+ innate lymphoid cells (ILCs). We investigated whether increased mucosal responses to V2 benefit vaccine efficacy by delivering oral nanoparticles (NPs) that release V2-scaffolded on Typhoid Toxin B (TTB) to the large intestine. Strikingly, mucosal immunization of male macaques abrogated vaccine efficacy with control TTB or empty NPs, but vaccine efficacy of up to 47.6% was preserved with V2-TTB NPs. The deleterious effects of NPs were linked to preferential recruitment of mucosal plasmacytoid dendritic cells (pDCs), reduction of protective mucosal NKp44+ ILCs, increased non-protective mucosal PMA/Ionomycin-induced IFN-γ+NKG2A-NKp44-ILCs, and increased levels of mucosal activated Ki67+CD4+ T cells, a potential target for virus infection. V2-TTB NP mucosal boosting rescued vaccine efficacy, likely via high avidity V2-specific antibodies mediating ADCC, and higher frequencies of mucosal NKp44+ ILCs and of ∆V1gp120 binding antibody-secreting B cells in the rectal mucosa. These findings emphasize the central role of systemic immunization and mucosal V2-specific antibodies in the protection afforded by ΔV1 envelope immunogens and encourage careful evaluation of vaccine delivery platforms to avoid inducing immune responses favorable to HIV transmission.

Abstract Implant surgeries are increasingly challenging due to their rising number. Achieving the desired biomaterial surface properties to ensure a strong bond with human tissue is a significant issue. This study investigates the influence of ultrasound (US) during the micro-arc oxidation (MAO) process on Ti13Zr13Nb bio-alloy, an area not previously explored, to enhance titanium alloy coatings’ properties for biomedical applications. Porous calcium-phosphate-based coatings were successfully deposited on Ti13Zr13Nb using MAO and ultrasound micro-arc oxidation (UMAO). Various properties such as morphology, chemical composition, topography, wettability, surface free energy, thickness, adhesion to the substrate, as well as mechanical and corrosion characteristics were thoroughly analyzed. Cytocompatibility was assessed using human osteoblasts. Using US during the MAO process increased coating roughness (up to ~ 17%), core height (up to 22%), isotropy (up to 17%), thickness (up to ~ 46%), and hardness (up to ~ 18%), depending on MAO parameters and US mode. Optimal coating performance was achieved at 136 mA, 600 s, and a sinusoidal US setting, resulting in the highest isotropy (~ 79%) and rutile quantity (2.6%), the lowest elastic modulus (~ 57 GPa), and the contact angle of ~ 70°, all of which could have contributed to enhancing osteoblast viability in vitro. This study, for the first time, underscores the importance of using the US during the MAO in tailoring the Ti13Zr13Nb for specific biomedical applications.

Abstract Background Facioscapulohumeral dystrophy (FSHD) is a myopathy characterized by the loss of repressive epigenetic features affecting the D4Z4 locus (4q35). The assessment of DNA methylation at two regions (DUX4-PAS and DR1) of D4Z4 locus proved to be an effective method to detect epigenetic signatures compatible with FSHD. The present study aims at validating the employment of this method into clinical practice and improving the protocol by refining the classification thresholds of 4qA/4qA patients. To this purpose, 218 subjects with clinical suspicion of FSHD collected in 2022–2023 were analyzed. Each participant underwent in parallel the traditional FSHD molecular testing (D4Z4 sizing) and the proposed methylation assay. The results provided by both analyses were compared to evaluate the concordance and calculate the performance metrics of the methylation test. Results Among the 218 subjects, the 4q variant type distribution was 54% 4qA/4qA, 43% 4qA/4qB and 3% 4qB/4qB. The methylation analysis was performed only on carriers of at least one 4qA allele. After refining the classification threshold, the test reached the following performance metrics: sensitivity = 0.90, specificity = 1.00 and accuracy = 0.93. These results confirmed the effectiveness of the methylation assay in identifying patients with genetic signature compatible with FSHD1 and FSHD2 based on their DUX4-PAS and DR1 profile, respectively. The methylation data were also evaluated with respect to the clinical information. Conclusions The study confirmed the ability of the method to accurately identify methylation profiles compatible with FSHD genetic signatures considering the 4q genotype. Moreover, the test allows the detection of hypomethylated profiles in asymptomatic patients, suggesting its potential application in identifying preclinical conditions in patients with positive family history and FSHD genetic signatures. Furthermore, the present work emphasizes the importance of interpreting methylation profiles considering the patients’ clinical data.

The Collisional Orogeny in the Scandinavian Caledonides (COSC) project focuses on processes related to the closure of the Iapetus Ocean, causing the OrdovicianâSilurian continentâcontinent collision between Baltica and Laurentia. The rock succession in the second drill core (COSC-2) from the Jämtland County, central Sweden, provides the base for detailed sedimentological, stratigraphic, geophysical, geochemical, geothermal and structural studies. The basement, comprising 1.66â1.65 Ga Transscandinavian Igneous Belt porphyries intruded by 1.47 Ga and 1.27â1.26 Ga mafic dykes and sills, is heavily weathered towards the top. Here it grades into typical saprock and saprolite (including immature soil reflecting the sub-Cambrian peneplain). The overlying sedimentary sequence starts with basal conglomerates and heterogeneous sediments with shell fragments, indicating an early Cambrian rather than a Neoproterozoic age for the marine transgression in the area. The developing early Cambrian basin was rapidly filled, initially by mostly coarse-grained sediment gravity flows. These strata are covered by sandstone turbidites that show an upward transition into the Alum Shale Formation, representing a tectonically quieter period (mid-Cambrian/Maolingian to Early Ordovician/Tremadocian). The upper part of the Alum Shale Formation is overlain by a late Early Ordovician turbidite succession. Local sources of sediments below the Alum Shale Formation and the extended deposition period may indicate continuous sedimentation in a pull-apart basin preserved in a window beneath the Caledonian thrust sheets.

Electrochemotherapy (ECT) is an emerging therapeutic approach gaining growing interest for its potential immunomodulatory effects in cancer treatment. This narrative review systematically examines the current state of knowledge regarding the interplay between ECT and the immune system. Through an analysis of preclinical and clinical studies, the review highlights ECT capacity to induce immunogenic cell death, activate dendritic cells, release tumor antigens, trigger inflammatory responses, and occasionally manifest systemic effects—the abscopal phenomenon. These mechanisms collectively suggest the ECT potential to influence both local tumor control and immune responses. While implications for clinical practice appear promising, warranting the consideration of ECT as a complementary treatment to immunotherapy, the evidence remains preliminary. Consequently, further research is needed to elucidate the underlying mechanisms, optimize treatment protocols, explore potential synergies, and decipher the parameters influencing the abscopal effect. As the field advances, the integration of ECT’s potential immunomodulatory aspects into clinical practice will need careful evaluation and collaboration among clinical practitioners, researchers, and policymakers.

Background: Obesity, a prevalent and multifactorial disease, is linked to a range of metabolic abnormalities, including insulin resistance, dyslipidemia, and chronic inflammation. These imbalances not only contribute to cardiometabolic diseases but also play a significant role in cancer pathogenesis. The rising prevalence of obesity underscores the need to investigate dietary strategies for effective weight management for individuals with overweight or obesity and cancer. This European Society for the Study of Obesity (EASO) position statement aimed to summarize current evidence on the role of obesity in cancer and to provide insights on the major nutritional interventions, including Mediterranean Diet (MedDiet), ketogenic diet (KD), and intermittent fasting (IF), that should be adopted to manage individuals with overweight or obesity and cancer. Results: The MedDiet, characterized by high consumption of plant-based foods and moderate intake of olive oil, fish, and nuts, has been associated with a reduced cancer risk. The KD and the IF are emerging dietary interventions with potential benefits for weight loss and metabolic health. KD, by inducing ketosis, and IF, through periodic fasting cycles, may offer anticancer effects by modifying tumor metabolism and improving insulin sensitivity. Key messages: Despite the promising results, current evidence on these dietary approaches in cancer management in individuals with overweight or obesity is limited and inconsistent, with challenges including variability in adherence and the need for personalized dietary plans.

Reducing the vulnerability of a platform, i.e., the risk of being affected by hostile objects, is of paramount importance in the design process of vehicles, especially aircraft. A simple and effective way to decrease vulnerability is to introduce protective structures to intercept and possibly stop threats. However, this type of solution can lead to a significant increase in weight, affecting the performance of the aircraft. For this reason, it is crucial to study possible solutions that allow reducing the vulnerability of the aircraft while containing the increase in structural weight. One possible strategy is to optimize the topology of protective solutions to find the optimal balance between vulnerability and the weight of the added structures. Among the many optimization techniques available in the literature for this purpose, multi-objective genetic algorithms stand out as promising tools. In this context, this work proposes the use of a in-house software for vulnerability calculation to guide the process of topology optimization through multi-objective genetic algorithms, aiming to simultaneously minimize the weight of protective structures and vulnerability. In addition to the use of the in-house software, which itself represents a novelty in the field of topology optimization of structures, the method incorporates a custom mutation function within the genetic algorithm, specifically developed using a graph-based approach to ensure the continuity of the generated structures. The tool developed for this work is capable of generating protections with optimized layouts considering two different types of impacting objects, namely bullets and fragments from detonating objects. The software outputs a set of non-dominated solutions describing different topologies that the user can choose from.

Abstract Background Non-specific interstitial pneumonia (NSIP) is an interstitial lung disease that can result in end-stage fibrosis. We investigated the influence of body composition and pulmonary fat attenuation volume (CTpfav) on overall survival (OS) in NSIP patients. Methods In this retrospective single-center study, 71 NSIP patients with a median age of 65 years (interquartile range 21.5), 39 females (55%), who had a computed tomography from August 2009 to February 2018, were included, of whom 38 (54%) died during follow-up. Body composition analysis was performed using an open-source nnU-Net-based framework. Features were combined into: Sarcopenia (muscle/bone); Fat (total adipose tissue/bone); Myosteatosis (inter-/intra-muscular adipose tissue/total adipose tissue); Mediastinal (mediastinal adipose tissue/bone); and Pulmonary fat index (CTpfav/lung volume). Kaplan–Meier analysis with a log-rank test and multivariate Cox regression were used for survival analyses. Results Patients with a higher (> median) Sarcopenia and lower (

Abstract Background Rib fractures are one of the most common traumatic injuries and may result in significant morbidity and mortality. Despite growing evidence, technological advances and increasing acceptance, surgical stabilization of rib fractures (SSRF) remains not uniformly considered in trauma centers. Indications, contraindications, appropriate timing, surgical approaches and utilized implants are part of an ongoing debate. The present position paper, which is endorsed by the World Society of Emergency Surgery (WSES), and supported by the Chest Wall Injury Society, aims to provide a review of the literature investigating the use of SSRF in rib fracture management to develop graded position statements, providing an updated guide and reference for SSRF. Methods This position paper was developed according to the WSES methodology. A steering committee performed the literature review and drafted the position paper. An international panel of experts then critically revised the manuscript and discussed it in detail, to develop a consensus on the position statements. Results A total of 287 studies (systematic reviews, randomized clinical trial, prospective and retrospective comparative studies, case series, original articles) have been selected from an initial pool of 9928 studies. Thirty-nine graded position statements were put forward to address eight crucial aspects of SSRF: surgical indications, contraindications, optimal timing of surgery, preoperative imaging evaluation, rib fracture sites for surgical fixation, management of concurrent thoracic injuries, surgical approach, stabilization methods and material selection. Conclusion This consensus document addresses the key focus questions on surgical treatment of rib fractures. The expert recommendations clarify current evidences on SSRF indications, timing, operative planning, approaches and techniques, with the aim to guide clinicians in optimizing the management of rib fractures, to improve patient outcomes and direct future research.

Abstract The RNA binding protein Human Antigen R (HuR) has been identified as a main regulator of the innate immune response and its inhibition can lead to beneficial anti-inflammatory effects. To this aim, we previously synthesized a novel class of small molecules named Tanshinone Mimics (TMs) able to interfere with HuR-RNA binding, and that dampen the LPS-induced immune response. Herein, we present a novel series of TMs, encompassing thiophene 3/TM9 and 4/TM10, furan 5/TM11 and 6/TM12, pyrrole 7b/TM13, and pyrazole 8. The furan-containing 5(TM11) showed the greatest inhibitory effect of the series on HuR-RNA complex formation, as suggested by RNA Electromobility Shift Assay and Time-Resolved FRET. Molecular Dynamics Calculation of HuR − 5/TM11 interaction, quantum mechanics approaches and Surface Plasmon Resonance data, all indicates that, within the novel heteroaryl substituents, the furan ring better recapitulates the chemical features of the RNA bound to HuR. Compound 5/TM11 also showed improved aqueous solubility compared to previously reported TMs. Real-time monitoring of cell growth and flow cytometry analyses showed that 5/TM11 preferentially reduced cell proliferation rather than apoptosis in murine macrophages at immunomodulatory doses. We observed its effects on the innate immune response triggered by lipopolysaccharide (LPS) in macrophages, showing that 5/TM11 significantly reduced the expression of proinflammatory cytokines as Cxcl10 and Il1b.

Abstract This study aimed to evaluate the impact of Fabry disease (FD) on retinal microvasculature using optical coherence tomography angiography (OCTA), arterial stiffness, and the resistive index (RI) of the central retinal artery (CRA) in early disease stages. Twenty-nine genetically confirmed FD patients and twenty-six healthy controls were enrolled. Vessel density (VD) values of the superficial, deep, and choriocapillaris plexuses (SCP, DCP, and CC) were measured via OCTA. CRA RI was studied using color Doppler and grayscale sonography, and aortic pulse wave velocity (PWV) was assessed with the Complior method. CRA RI was significantly lower in the control group compared to the Fabry group (p