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ABSTRACT Purpose To assess the incidence of the most common intra- and early postoperative complications following RIRS in a large series of patients with kidney stones. Methods We conducted a retrospective analysis of patients with kidney stones who underwent RIRS across 21 centers from January 2018 to August 2021, as part of the Global Multicenter Flexible Ureteroscopy Outcome (FLEXOR) Registry. Results Among 6669 patients undergoing RIRS, 4.5% experienced intraoperative pelvicalyceal system bleeding without necessitating blood transfusion. Only 0.1% of patients, required a blood transfusion. The second most frequent intraoperative complication was ureteric injury due to the ureteral access sheath requiring stenting (1.8% of patients). Postoperatively, the most prevalent early complications were fever/infections requiring antibiotics (6.3%), blood transfusions (5.5%), and sepsis necessitating intensive care unit admission (1.3%). In cases of ureteric injury, a notably higher percentage of patients exhibited multiple stones and stone(s) in the lower pole, and these cases were correlated with prolonged lasing and overall surgical time. Hematuria requiring a blood transfusion was associated with an increased prevalence of larger median maximum stone diameters, particularly among patients with stones exceeding 20 mm. Furthermore, these cases exhibited a significant prolongation in surgical time. Sepsis necessitating admission to the intensive care unit was more prevalent among the elderly, concomitant with a significantly larger median maximum stone diameter. Conclusions Our analysis showed that RIRS has a good safety profile but bleeding requiring transfusions, ureteric injury, fever, and sepsis are still the most common complications despite advancements in technology.

Abstract Introduction Atrial fibrillation (AF) represents the most common arrhythmia in the postoperative setting. We aimed to investigate the incidence of postoperative AF (POAF) and determine its predictors, with a specific focus on inflammation markers. Methods We performed a retrospective single tertiary center cohort study including consecutive adult patients who underwent a major surgical procedure between January 2016 and January 2020. Patients were divided into four subgroups according to the type of surgery. Results Among 53,387 included patients (79.4% male, age 64.5 ± 9.5 years), POAF occurred in 570 (1.1%) with a mean latency after surgery of 3.4 ± 2.6 days. Ninety patients died (0.17%) after a mean of 13.7 ± 8.4 days. The 28‐day arrhythmia‐free survival was lower in patients undergoing lung and cardiovascular surgery (p

Abstract Introduction Cefiderocol is a siderophore cephalosporin showing activity against various carbapenem-resistant Gram-negative bacteria (CR-GNB). No data currently exist about real-world use of cefiderocol in terms of types of therapy (e.g., empirical or targeted, monotherapy or combined regimens), indications, and patient characteristics. Methods In this multicenter, prospective study, we aimed at describing the use of cefiderocol in terms of types of therapy, indications, and patient characteristics. Results Cefiderocol was administered as empirical and targeted therapy in 27.5% (55/200) and 72.5% (145/200) of cases, respectively. Overall, it was administered as monotherapy in 101/200 cases (50.5%) and as part of a combined regimen for CR-GNB infections in the remaining 99/200 cases (49.5%). In multivariable analysis, previous isolation of carbapenem-resistant Acinetobacter baumannii odds ratio (OR) 2.56, with 95% confidence interval (95% CI) 1.01–6.46, p = 0.047] and previous hematopoietic stem cell transplantation (OR 8.73, 95% CI 1.05–72.54, p = 0.045) were associated with administration of cefiderocol as part of a combined regimen, whereas chronic kidney disease was associated with cefiderocol monotherapy (OR 0.38 for combined regimen, 95% CI 0.16–0.91, p = 0.029). Cumulative 30-day mortality was 19.8%, 45.0%, 20.7%, and 22.7% in patients receiving targeted cefiderocol for infections by Enterobacterales, A. baumannii, Pseudomonas aeruginosa, and any metallo-β-lactamase producers, respectively. Conclusions Cefiderocol is mainly used for targeted treatment, although empirical therapies account for more than 25% of prescriptions, thus requiring dedicated standardization and guidance. The almost equal distribution of cefiderocol monotherapy and cefiderocol-based combination therapies underlines the need for further study to ascertain possible differences in efficacy between the two approaches.

Abstract Prostate cancer (PC) is an age-related disease and represents, after lung cancer, the second cause of cancer death in males worldwide. Mortality is due to the metastatic disease, which mainly involves the bones, lungs, and liver. In the last 20 years, the incidence of metastatic PC has increased in Western Countries, and a further increase is expected in the near future, due to the population ageing. Current treatment options, including state of the art cancer immunotherapy, need to be more effective to achieve long-term disease control. The most significant anatomical barrier to overcome to improve the effectiveness of current and newly designed drug strategies consists of the prostatic stroma, in particular the fibroblasts and the extracellular matrix, which are the most abundant components of both the normal and tumor prostatic microenvironment. By weaving a complex communication network with the glandular epithelium, the immune cells, the microbiota, the endothelium, and the nerves, in the healthy prostatic microenvironment, the fibroblasts and the extracellular matrix support organ development and homeostasis. However, during inflammation, ageing and prostate tumorigenesis, they undergo dramatic phenotypic and genotypic changes, which impact on tumor growth and progression and on the development of therapy resistance. Here, we focus on the characteristics and functions of the prostate associated fibroblasts and of the extracellular matrix in health and cancer. We emphasize their roles in shaping tumor behavior and the feasibility of manipulating and/or targeting these stromal components to overcome the limitations of current treatments and to improve precision medicine’s chances of success.

Abstract We evaluate deconvolution methods, which infer levels of immune infiltration from bulk expression of tumor samples, through a community-wide DREAM Challenge. We assess six published and 22 community-contributed methods using in vitro and in silico transcriptional profiles of admixed cancer and healthy immune cells. Several published methods predict most cell types well, though they either were not trained to evaluate all functional CD8+ T cell states or do so with low accuracy. Several community-contributed methods address this gap, including a deep learning-based approach, whose strong performance establishes the applicability of this paradigm to deconvolution. Despite being developed largely using immune cells from healthy tissues, deconvolution methods predict levels of tumor-derived immune cells well. Our admixed and purified transcriptional profiles will be a valuable resource for developing deconvolution methods, including in response to common challenges we observe across methods, such as sensitive identification of functional CD4+ T cell states.

Abstract Background Milk is essential for mammalian nutrition because it provides vital nutrients for growth and development. Milk composition, which is influenced by genetic and environmental factors, supports lactation, a complex process crucial for milk production and quality. Recent research has focused on noncoding RNAs, particularly microRNAs (miRNAs), which are present in body fluids and regulate gene expression post-transcriptionally. This study comprehensively characterizes miRNAs in milk of four livestock species, namely Bubalus bubalis, Capra hircus, Equus asinus, and Ovis aries and identifies potential target genes. Results High-throughput sequencing of milk RNA resulted in distinct read counts across species: B. bubalis (8,790,441 reads), C. hircus (12,976,275 reads), E. asinus (9,385,067 reads), and O. aries (7,295,297 reads). E. asinus had the highest RNA mapping rate (94.6%) and O. aries the lowest (84.8%). A substantially greater proportion of miRNAs over other small RNAs was observed for the donkey milk sample (7.74%) compared to buffalo (0.87%), goat (1.57%), and sheep (1.12%). Shared miRNAs, which included miR-200a, miR-200b, miR-200c, and miR-23a among others, showed varying expression levels across species, confirmed by qPCR analysis. Functional annotation of predicted miRNA target genes highlighted diverse roles, with an enrichment in functions linked to metabolism and immunity. Pathway analysis identified immune response pathways as significant, with several miRNAs targeting specific genes across species, suggesting their regulatory function in milk. Conclusions Both conserved and species-specific miRNAs were detected in milk of the investigated species. The identified target genes of these miRNAs have important roles in neonatal development, adaptation, growth, and immune response. Furthermore, they influence milk and meat production traits in livestock.

Abstract The two main Afrotropical malaria vectors - Anopheles coluzzii and An. gambiae – are genetically distinct and reproductively isolated across West Africa. However, populations at the western extreme of their range are assigned as “intermediate” between the two species by whole genome sequence (WGS) data, and as hybrid forms by conventional molecular diagnostics. By exploiting WGS data from 1190 specimens collected across west Africa via the Anopheles gambiae 1000 Genomes network, we identified a putative taxon in the far-west (provisionally named Bissau molecular form), which did not arise by admixture but rather may have originated at the same time as the split between An. coluzzii and An. gambiae. Intriguingly, this taxon lacks insecticide resistance mechanisms commonly observed in the two main species. These findings lead to a change of perspective on malaria vector species in the far-west region with potential for epidemiological implications, and a new challenge for genetic-based mosquito control approaches.

Abstract Background Multicomponent interventions based on a comprehensive geriatric assessment (CGA) could promote active aging and improve health status in older people with Noncommunicable Chronic Diseases (NCDs), but conflicting evidences are available. Aim To evaluate the efficacy of a CGA-based multicomponent personalized preventive program (PPP) in reducing unplanned hospitalization rates during 12-month follow-up in community-dwelling older people with NCDs. Materials and methods In this randomized clinical trial (RCT), 1216 older adults recruited by 33 general practitioners (GPs) will be randomly allocated to intervention group (IG) or usual care control group (CG). The IG will receive a multicomponent PPP developed on the findings of the CGA-based Multidimensional Prognostic Index short-form (Brief-MPI), including structured interventions to improve functional, physical, cognitive, and nutritional status, to monitor NCDs and vaccinations, and to prevent social isolation. Participants in the CG will receive usual care. Brief-MPI, resilience, and health-related quality of life will be assessed after 6 and 12 months. Moreover, saliva samples will be collected at baseline in IG to measure biomarkers of oxidative stress, inflammatory cytokines, and oral microbiome. Expected results The CGA-based PPP might reduce unplanned hospitalization rates and potentially institutionalization rates, emergency department (ED) and unplanned GP visits, and mortality. Further outcomes explored in the IG will be the adherence to PPP, resilience, health-related quality of life, and multidimensional frailty as assessed by the Brief-MPI. Conclusions Results will suggest whether the CGA-based multicomponent PPP is able to improve specific outcomes in a primary care setting. Trial registration ClinicalTrials.gov; identifier: NCT06224556 ; Registered January 25, 2024.

Abstract Intravital 2P-microscopy enables the longitudinal study of brain tumor biology in superficial mouse cortex layers. Intravital microscopy of the white matter, an important route of glioblastoma invasion and recurrence, has not been feasible, due to low signal-to-noise ratios and insufficient spatiotemporal resolution. Here, we present an intravital microscopy and artificial intelligence-based analysis workflow (Deep3P) that enables longitudinal deep imaging of glioblastoma up to a depth of 1.2 mm. We find that perivascular invasion is the preferred invasion route into the corpus callosum and uncover two vascular mechanisms of glioblastoma migration in the white matter. Furthermore, we observe morphological changes after white matter infiltration, a potential basis of an imaging biomarker during early glioblastoma colonization. Taken together, Deep3P allows for a non-invasive intravital investigation of brain tumor biology and its tumor microenvironment at subcortical depths explored, opening up opportunities for studying the neuroscience of brain tumors and other model systems.

Abstract DNA data storage is a potential alternative to magnetic tape for archival storage purposes, promising substantial gains in information density. Critical to the success of DNA as a storage media is an understanding of the role of environmental factors on the longevity of the stored information. In this paper, we evaluate the effect of exposure to ionizing particle radiation, a cause of data loss in traditional magnetic media, on the longevity of data in DNA data storage pools. We develop a mass action kinetics model to estimate the rate of damage accumulation in DNA strands due to neutron interactions with both nucleotides and residual water molecules, then utilize the model to evaluate the effect several design parameters of a typical DNA data storage scheme have on expected data longevity. Finally, we experimentally validate our model by exposing dried DNA samples to different levels of neutron irradiation and analyzing the resulting error profile. Our results show that particle radiation is not a significant contributor to data loss in DNA data storage pools under typical storage conditions.

Abstract The large mid-infrared (MIR) spectral region, ranging from 2.5 µm to 25 µm, has remained under-exploited in the electromagnetic spectrum, primarily due to the absence of viable transceiver technologies. Notably, the 8–14 µm long-wave infrared (LWIR) atmospheric transmission window is particularly suitable for free-space optical (FSO) communication, owing to its combination of low atmospheric propagation loss and relatively high resilience to turbulence and other atmospheric disturbances. Here, we demonstrate a direct modulation and direct detection LWIR FSO communication system at 9.1 µm wavelength based on unipolar quantum optoelectronic devices with a unprecedented net bitrate exceeding 55 Gbit s−1. A directly modulated distributed feedback quantum cascade laser (DFB-QCL) with high modulation efficiency and improved RF-design was used as a transmitter while two high speed detectors utilizing meta-materials to enhance their responsivity are employed as receivers; a quantum cascade detector (QCD) and a quantum-well infrared photodetector (QWIP). We investigate system tradeoffs and constraints, and indicate pathways forward for this technology beyond 100 Gbit s−1 communication.

Abstract In the last two decades, an exponentially growing number of meta-analyses (MAs) synthesize thousands of peer-reviewed studies on the environmental impacts of farming practices (FPs). This paper describes the iMAP-FP evidence library, a comprehensive dataset on the effects of 34 categories of FPs (such as agronomic practices, cropping and livestock systems, land management options and mitigation techniques) on 34 impacts including climate mitigation, soil health, environmental pollution, water use, nutrients cycling, biodiversity, and agricultural productivity. Through systematic screening, 570 MAs published since 2000 were selected and categorized according to the type of FP. We assessed their impacts, the geographic regions covered, and their quality. We extracted 3,811 effects and their statistical significance associated with sustainable FPs (intervention) compared to a control (typically conventional agriculture) across 223 different intervention-control pairs. Our dataset is accompanied with an online free-access library, which includes a catalogue of synthetic reports summarizing the available evidence on each evaluated FP.

Abstract Do cities have a collective identity? The latest advancements in generative artificial intelligence (AI) models have enabled the creation of realistic representations learned from vast amounts of data. In this study, we test the potential of generative AI as the source of textual and visual information in capturing the place identity of cities assessed by filtered descriptions and images. We asked questions on the place identity of 64 global cities to two generative AI models, ChatGPT and DALL·E2. Furthermore, given the ethical concerns surrounding the trustworthiness of generative AI, we examined whether the results were consistent with real urban settings. In particular, we measured similarity between text and image outputs with Wikipedia data and images searched from Google, respectively, and compared across cases to identify how unique the generated outputs were for each city. Our results indicate that generative models have the potential to capture the salient characteristics of cities that make them distinguishable. This study is among the first attempts to explore the capabilities of generative AI in simulating the built environment in regard to place-specific meanings. It contributes to urban design and geography literature by fostering research opportunities with generative AI and discussing potential limitations for future studies.

Abstract The significant impact of acute respiratory tract infections on healthcare systems is well-documented, given their contribution to emergency department admissions, hospitalizations, and increased use of antibiotics and other medications. However, further research is needed to understand the burden of acute respiratory tract infections in pediatric community care to develop effective public health interventions and improve child health outcomes. Real-world data were retrieved from Pedianet, an Italian network of over 200 family pediatricians. Acute respiratory tract infection visits were identified and analysed using an infection-duration algorithm to extract individual cases. The number of follow-up visits per 100 cases was calculated to assess the burden on the Italian National Health Service. Comparisons were made overall and stratified by type of acute respiratory tract infections and epidemiological season. A total of 1,402,953 acute respiratory infections-related visits were recorded, with an overall rate of 12 visits per 100 cases. Upper respiratory tract infections had an average of 9 visits per 100 cases. Lower respiratory tract infections exhibited a higher burden, with 29 visits per 100 cases. Pneumonia showed a declining trend in the pre-pandemic era (62 to 48 visits) but rebounded in the post-COVID-19 years (32 to 42 visits). This study underscores the importance of monitoring and managing acute respiratory infections, especially lower respiratory tract infections, in pediatric care.

Thyroid storm is a clinical diagnosis characterized by life-threatening multisystemic organ involvement in the setting of uncontrolled hyperthyroidism. Current estimates suggest a mortality rate of up to 30%. Treatment often consists of the administration of thionamide medications, iodine solution(s), corticosteroids, and beta-blockers; in extreme circumstances, both plasmapheresis and thyroidectomy are subsequent therapeutic options. Thionamides are typically administered orally, with the intent of preventing further thyroid hormone synthesis; however, in the literature, there are instances whereby oral access cannot be obtained, and alternative routes of administration are required. We present a case of a patient who presented with a thyroid storm due to lack of adherence to methimazole. During admission, he was found to have significant abdominal pain and ultimately a duodenal perforation requiring strict nil-per-os (NPO) status, due to which he was unable to receive oral thionamides. Due to the lack of availability of intravenous formulations of thionamides in the United States, this patient was treated with an enema compound of propylthiouracil for a total of five per rectum (PR) doses. He would later develop hepatocellular injury, requiring discontinuation and eventual transition to oral methimazole. The literature pertaining to alternative-route thionamide administration is scant, and therefore this case report and literature review is written to provide an up-to-date review and further educate all levels of clinicians about this infrequent (but emergent) situation.

Summary: Soft tissue defects of the distal third of the leg are challenging and management with simple split thickness skin graft or conservative measures is often difficult. The peroneus brevis muscle flap is well described in the literature to cover such defects. The aim of our study was to review the different applications and potential complications of the peroneus brevis muscle flap.A comprehensive review of all existing evidence on the use of peroneus brevis muscle flaps for coverage of defects in the distal third of the leg in adult populations was performed.Two hundred forty-eight records were identified in the literature search, among which 15 met the PICOS (Patient, Intervention, Comparison, Outcome and Study design) criteria. All selected studies were retrospective. Overall, 222 patients who received peroneus brevis muscle flaps were analyzed. Indications for reconstruction were post-traumatic defects, infected wounds, and chronic wounds. The overall complication rate was 21% (46/222) with the most commonly reported complication being skin graft loss. We observed 2 cases of partial flap loss, 17 cases of skin graft loss, 2 cases of post-operative hematoma, 2 cases of recurrent infection, 12 cases of partial flap necrosis, 3 cases of skin graft necrosis, and 8 cases of delayed wound healing. Overall, 16 patients (7%) required revision surgery. No cases of donor site morbidity were described.The current review shows that the peroneus brevis muscle flap is a versatile and reliable option for the coverage of small to medium sized defects of the distal leg, ankle, and foot with low complication rates and donor site morbidity.

ABSTRACT: Objectives: We report the use of IV dalbavancin in Canadian patients using data captured by the national CLEAR registry. Methods: The CLEAR registry uses the web-based data management program, REDCap™ (online survey https://rcsurvey.radyfhs.umanitoba.ca/surveys/?s=TPMWJX98HL) to facilitate clinicians entering details associated with their clinical experiences using IV dalbavancin. Results: Data were available for 40 patients. The most common infections treated were acute bacterial skin and skin structure infection (ABSSSI) (62.5% of patients), bone/joint infection (22.5%), bloodstream/vascular infection (7.5%) and endocarditis (5.0%). Dalbavancin was used as directed (75.0%) and empiric therapy (25.0%). MRSA was the most common identified pathogen (70.0%). Dalbavancin was used both in outpatient (e.g., emergency department) (65.0%), and inpatient treatment settings (e.g., hospital ward) (35.0%). Dalbavancin was used due to the convenience of a single dose treatment (77.5%) as well as to facilitate hospital discharge (7.5%). Dalbavancin was primarily used alone (90.0%), and most commonly using a single 1500 mg dose (77.5%). Microbiological success (pathogen eradicated or presumed eradicated) occurred in 88.2% of known cases, while clinical success (cure and/or improvement) occurred in 93.3% of known cases. No adverse events were reported. Conclusions: In Canada, IV dalbavancin is used as both directed and empiric therapy to treat ABSSSI as well as off-label (bone/joint, bacteremia/vascular, endocarditis, device-related) infections. It is used in both outpatient and inpatient settings due primarily to its convenience as a single-dose treatment regimen and to facilitate early hospital discharge. Dalbavancin use is associated with high microbiological and clinical cure rates along with an excellent safety profile.

Abstract Background Sharing and fairness are important prosocial behaviors that help us navigate the social world. However, little is known about how and whether individuals with Williams Syndrome (WS) engage in these behaviors. The unique phenotype of individuals with WS, consisting of high social motivation and limited social cognition, can also offer insight into the role of social motivation in sharing and fairness when compared to typically developing (TD) individuals. The current study used established experimental paradigms to examine sharing and fairness in individuals with WS and TD individuals. Methods We compared a sample of patients with WS to TD children (6-year-olds) matched by mental age (MA) on two experimental tasks: the Dictator Game (DG, Experiment 1, N = 17 WS, 20 TD) with adults modeling giving behaviors used to test sharing and the Inequity Game (IG, Experiment 2, N = 14 WS, 17 TD) used to test fairness. Results Results showed that the WS group behaved similarly to the TD group for baseline giving in the DG and in the IG, rejecting disadvantageous offers but accepting advantageous ones. However, after viewing an adult model giving behavior, the WS group gave more than their baseline, with many individuals giving more than half, while the TD group gave less. Combined these results suggest that social motivation is sufficient for sharing and, in particular, generous sharing, as well as the self-focused form of fairness. Further, individuals with WS appear capable of both learning to be more generous and preventing disadvantageous outcomes, a more complex profile than previously known. Conclusions In conclusion, the present study provides a snapshot into sharing and fairness-related behaviors in WS, contributing to our understanding of the intriguing social-behavioral phenotype associated with this developmental disorder.

Abstract The overarching challenge of this research is setting up a procedure to select the most appropriate fraction from complex, heterogeneous materials such as historic mortars in case of radiocarbon dating. At present, in the international community, there is not a unique and fully accepted way of mortar sample preparation to systematically obtain accurate results. With this contribution, we propose a strategy for selecting suitable mortar samples for radiocarbon dating of anthropogenic calcite in binder or lump. A four-step procedure is proposed: (I) good sampling strategies along with architectural and historical surveys; (II) mineralogical, petrographic, and chemical characterization of mortars to evaluate the feasibility of sample dating; (III) a non-destructive multi-analytical characterization of binder-rich portions to avoid geogenic calcite contamination; (IV) carbonate micro-sample preparation and accelerator mass spectrometer (AMS) measurements. The most innovative feature of the overall procedure relies on the fact that, in case of positive validation in step III, exactly the same material is treated and measured in step IV. The paper aims to apply this procedure to the ancient mortar of the Florentine historical building (Trebbio Castle), selecting micro-samples suitable for dating in natural hydraulic mortars. The discussion of the mortar dating results with the historical-archaeological hypotheses provided significant insights into the construction history of the building.

Abstract This study critically examines the use of geodetic strain rates for forecasting long-term earthquake rates in a slow-deforming region such as Italy, challenging the prevailing assumption of their temporal stationarity in interseismic stages for seismic hazard analyses. Typically, earthquake-rate models derived from geodesy assume stationary interseismic loading rates, with stress rates in the upper crust proportional to geodetic strain rates, leading to earthquake rates directly proportional to these strain rate tensors. However, our analysis unveils a pronounced correlation between the epicenters of earthquakes that occurred in the past 60–120 years and areas forecasted for higher future earthquake rates based on geodetic strain rates. This correlation appears weak and scattered in analyses of even older earthquakes. To corroborate our findings, we select the 2009 L’Aquila earthquake (mw = 6.3) to prove that its apparently marginal viscoelastic relaxation significantly alters the time series of adjacent benchmarks for the following ~ 30–60 years, explaining the high correlation between recent earthquakes and strain rate peaks. Our findings require a methodological shift in interpreting geodetic data for earthquake forecasting, emphasizing the two-component (plate-tectonics-driven stationary long-term deformation, and decadal transient viscoelastic relaxation after an earthquake) nature of crustal stress accumulation recorded in geodetic data. We underscore the potential of geodesy-derived forecasts to provide deeper insights into seismic hazards, stressing the importance of acknowledging the long-term temporal variability inherent in geodetic measurements.

Abstract Background Health disparities have been highlighted among patient with prostate adenocarcinoma (PRAD) due to ethnicity. Mexican men present a more aggressive disease than other patients resulting in less favorable treatment outcome. We aimed to identify the mutational landscape which could help to reduce the health disparities among minority groups and generate the first genomics exploratory study of PRAD in Mexican patients. Methods Paraffin-embedded formalin-fixed tumoral tissue from 20 Mexican patients with early-stage PRAD treated at The Instituto Nacional de Cancerología, Mexico City from 2017 to 2019 were analyzed. Tumoral DNA was prepared for whole exome sequencing, the resulting files were mapped against h19 using BWA-MEM. Strelka2 and Lancet packages were used to identify single nucleotide variants (SNV) and insertions or deletions. FACETS was used to determine somatic copy number alterations (SCNA). Cancer Genome Interpreter web interface was used to determine the clinical relevance of variants. Results Patients were in an early clinical stage and had a mean age of 59.55 years (standard deviation [SD]: 7.1 years) with 90% of them having a Gleason Score of 7. Follow-up time was 48.50 months (SD: 32.77) with recurrences and progression in 30% and 15% of the patients, respectively. NUP98 (20%), CSMD3 (15%) and FAT1 (15%) were the genes most frequently affected by SNV; ARAF (75%) and ZNF419 (70%) were the most frequently affected by losses and gains SNCA’s. One quarter of the patients had mutations useful as biomarkers for the use of PARP inhibitors, they comprise mutations in BRCA, RAD54L and ATM. SBS05, DBS03 and ID08 were the most common mutational signatures present in this cohort. No associations with recurrence or progression were identified. Conclusions This pilot study reveals the mutational landscape of early-stage prostate adenocarcinoma in Mexican men, providing a first approach to understand the mutational patterns and actionable mutations in early prostate cancer can inform personalized treatment approaches and reduce the underrepresentation in genomic cancer studies.

Abstract We report the long-term results of a randomized trial (GITMO, AML-R2), comparing 1:1 the combination of busulfan and cyclophosphamide (BuCy2, n = 125) and the combination of busulfan and fludarabine (BuFlu, n = 127) as conditioning regimen in acute myeloid leukemia patients (median age 51 years, range 40–65) undergoing allogeneic hematopoietic stem cell transplantation. With a median follow-up of 6 years, significantly better non-relapse mortality (NRM) was confirmed in BuFlu recipients, which is sustained up to 4 years after transplant (10% vs. 20%, p = 0.0388). This difference was higher in patients older than 51 years (11% in BuFlu vs. 27% in BuCy2, p = 0.0262). The cumulative incidence of relapse, which was the first cause of death in the entire study population, did not differ between the two randomized arms. Similarly, the leukemia-free survival (LFS) and overall survival (OS) were not different in the two cohorts, even when stratifying patients per median age. Graft-and relapse-free survival (GRFS) in BuFlu arm vs. the BuCy2 arm was 25% vs. 20% at 4 years and 20% vs. 17% at 10 years. Hence, the benefit gained by NRM reduction is not offsets by an increased relapse. Leukemia relapse remains a major concern, urging the development of new therapeutic approaches.

Abstract Background Histone deacetylases (HDACs) are crucial regulators of gene expression, DNA synthesis, and cellular processes, making them essential targets in cancer research. HDAC6, specifically, influences protein stability and chromatin dynamics. Despite HDAC6’s potential therapeutic value, its exact role in gene regulation and chromatin remodeling needs further clarification. This study examines how HDAC6 inactivation influences lysine acetyltransferase P300 stabilization and subsequent effects on chromatin structure and function in cancer cells. Methods and results We employed the HDAC6 inhibitor ITF3756, siRNA, or CRISPR/Cas9 gene editing to inactivate HDAC6 in different epigenomic backgrounds. Constantly, this inactivation led to significant changes in chromatin accessibility, particularly increased acetylation of histone H3 lysines 9, 14, and 27 (ATAC-seq and H3K27Ac ChIP-seq analysis). Transcriptomics, proteomics, and gene ontology analysis revealed gene changes in cell proliferation, adhesion, migration, and apoptosis. Significantly, HDAC6 inactivation altered P300 ubiquitination, stabilizing P300 and leading to downregulating genes critical for cancer cell survival. Conclusions Our study highlights the substantial impact of HDAC6 inactivation on the chromatin landscape of cancer cells and suggests a role for P300 in contributing to the anticancer effects. The stabilization of P300 with HDAC6 inhibition proposes a potential shift in therapeutic focus from HDAC6 itself to its interaction with P300. This finding opens new avenues for developing targeted cancer therapies, improving our understanding of epigenetic mechanisms in cancer cells.

The paper analises the historical work of Filippo de’ Nerli (1476-1556), a fervent follower of Medici, who took part in the Orti Oricellari’s meetings. He was friend and correspondent of Machiavelli. Nerli and Machiavelli had very different political ideas, but Nerli seems to have well understood the Machiavelli’s lesson: and he is very proud about it. We can obtain this information from the telling of antityrannical plots in Nerli’s Commentari de’ fatti civili: the plot against cardinal Giulio de’ Medici (1522) and the plot organized by Lorenzino against Alessandro de’ Medici, the first Duke of Florence (1537). In both these cases, Machiavelli’ political lesson becomes a clever interpretation of human action, in witch Nerli reads the recent events of Florentine politics openly using the Machiavellian method: to read ancient history (and the biblical telling too) to define the rules useful to understand events and protagonists of recent historical events.

Abstract Background Given the geographical sparsity of Rare Diseases (RDs), assembling a cohort is often a challenging task. Common data models (CDM) can harmonize disparate sources of data that can be the basis of decision support systems and artificial intelligence-based studies, leading to new insights in the field. This work is sought to support the design of large-scale multi-center studies for rare diseases. Methods In an interdisciplinary group, we derived a list of elements of RDs in three medical domains (endocrinology, gastroenterology, and pneumonology) according to specialist knowledge and clinical guidelines in an iterative process. We then defined a RDs data structure that matched all our data elements and built Extract, Transform, Load (ETL) processes to transfer the structure to a joint CDM. To ensure interoperability of our developed CDM and its subsequent usage for further RDs domains, we ultimately mapped it to Observational Medical Outcomes Partnership (OMOP) CDM. We then included a fourth domain, hematology, as a proof-of-concept and mapped an acute myeloid leukemia (AML) dataset to the developed CDM. Results We have developed an OMOP-based rare diseases common data model (RD-CDM) using data elements from the three domains (endocrinology, gastroenterology, and pneumonology) and tested the CDM using data from the hematology domain. The total study cohort included 61,697 patients. After aligning our modules with those of Medical Informatics Initiative (MII) Core Dataset (CDS) modules, we leveraged its ETL process. This facilitated the seamless transfer of demographic information, diagnoses, procedures, laboratory results, and medication modules from our RD-CDM to the OMOP. For the phenotypes and genotypes, we developed a second ETL process. We finally derived lessons learned for customizing our RD-CDM for different RDs. Discussion This work can serve as a blueprint for other domains as its modularized structure could be extended towards novel data types. An interdisciplinary group of stakeholders that are actively supporting the project's progress is necessary to reach a comprehensive CDM. Conclusion The customized data structure related to our RD-CDM can be used to perform multi-center studies to test data-driven hypotheses on a larger scale and take advantage of the analytical tools offered by the OHDSI community.

Abstract Receptor tyrosine kinases (RTKs), a category of transmembrane receptors, have gained significant clinical attention in oncology due to their central role in cancer pathogenesis. Genetic alterations, including mutations, amplifications, and overexpression of certain RTKs, are critical in creating environments conducive to tumor development. Following their discovery, extensive research has revealed how RTK dysregulation contributes to oncogenesis, with many cancer subtypes showing dependency on aberrant RTK signaling for their proliferation, survival and progression. These findings paved the way for targeted therapies that aim to inhibit crucial biological pathways in cancer. As a result, RTKs have emerged as primary targets in anticancer therapeutic development. Over the past two decades, this has led to the synthesis and clinical validation of numerous small molecule tyrosine kinase inhibitors (TKIs), now effectively utilized in treating various cancer types. In this manuscript we aim to provide a comprehensive understanding of the RTKs in the context of cancer. We explored the various alterations and overexpression of specific receptors across different malignancies, with special attention dedicated to the examination of current RTK inhibitors, highlighting their role as potential targeted therapies. By integrating the latest research findings and clinical evidence, we seek to elucidate the pivotal role of RTKs in cancer biology and the therapeutic efficacy of RTK inhibition with promising treatment outcomes.

Abstract Castration-resistant prostate cancer (CRPC) is a frequently occurring disease with adverse clinical outcomes and limited therapeutic options. Here, we identify methionine adenosyltransferase 2a (MAT2A) as a critical driver of the androgen-indifferent state in ERG fusion-positive CRPC. MAT2A is upregulated in CRPC and cooperates with ERG in promoting cell plasticity, stemness and tumorigenesis. RNA, ATAC and ChIP-sequencing coupled with histone post-translational modification analysis by mass spectrometry show that MAT2A broadly impacts the transcriptional and epigenetic landscape. MAT2A enhances H3K4me2 at multiple genomic sites, promoting the expression of pro-tumorigenic non-canonical AR target genes. Genetic and pharmacological inhibition of MAT2A reverses the transcriptional and epigenetic remodeling in CRPC models and improves the response to AR and EZH2 inhibitors. These data reveal a role of MAT2A in epigenetic reprogramming and provide a proof of concept for testing MAT2A inhibitors in CRPC patients to improve clinical responses and prevent treatment resistance.

Abstract Anisotropic transport properties have been assessed in a number of cuprate superconductors, providing evidence for a nematic state. We have recently shown that in ultra-thin YBa2Cu3O7−δ films, where nematicity is induced via strain engineering, there is a suppression of charge density wave scattering along the orthorhombic a-axis and a concomitant enhancement of strange metal behavior along the b-axis. Here we develop a microscopic model, that is based on the strong interaction between the substrate facets and the thin film, to account for the unconventional phenomenology. Based on the atomic force microscopy imaging of the substrates’ surface, the model is able to predict the absence (presence) of nematicity and the resulting transport properties in films grown on SrTiO3 (MgO) substrates. Our result paves the way to new tuning capabilities of the ground state of high-temperature superconductors by substrate engineering.

Abstract Background Preterm infants are at high risk for retinopathy of prematurity (ROP), with potential life-long visual impairment. Low fetal hemoglobin (HbF) levels predict ROP. It is unknown if preventing the HbF decrease also reduces ROP. Methods BORN is an ongoing multicenter double-blinded randomized controlled trial investigating whether transfusing HbF-enriched cord blood-red blood cells (CB-RBCs) instead of adult donor-RBC units (A-RBCs) reduces the incidence of severe ROP (NCT05100212). Neonates born between 24 and 27 + 6 weeks of gestation are enrolled and randomized 1:1 to receive adult donor-RBCs (A-RBCs, arm A) or allogeneic CB-RBCs (arm B) from birth to the postmenstrual age (PMA) of 31 + 6 weeks. Primary outcome is the rate of severe ROP at 40 weeks of PMA or discharge, with a sample size of 146 patients. A prespecified interim analysis was scheduled after the first 58 patients were enrolled, with the main purpose to evaluate the safety of CB-RBC transfusions. Results Results in the intention-to-treat and per-protocol analysis are reported. Twenty-eight patients were in arm A and 30 in arm B. Overall, 104 A-RBC units and 49 CB-RBC units were transfused, with a high rate of protocol deviations. A total of 336 adverse events were recorded, with similar incidence and severity in the two arms. By per-protocol analysis, patients receiving A-RBCs or both RBC types experienced more adverse events than non-transfused patients or those transfused exclusively with CB-RBCs, and suffered from more severe forms of bradycardia, pulmonary hypertension, and hemodynamically significant patent ductus arteriosus. Serum potassium, lactate, and pH were similar after CB-RBCs or A-RBCs. Fourteen patients died and 44 were evaluated for ROP. Ten of them developed severe ROP, with no differences between arms. At per-protocol analysis each A-RBC transfusion carried a relative risk for severe ROP of 1.66 (95% CI 1.06–2.20) in comparison with CB-RBCs. The area under the curve of HbF suggested that HbF decrement before 30 weeks PMA is critical for severe ROP development. Subsequent CB-RBC transfusions do not lessen the ROP risk. Conclusions The interim analysis shows that CB-RBC transfusion strategy in preterm neonates is safe and, if early adopted, might protect them from severe ROP. Trial registration Prospectively registered at ClinicalTrials.gov on October 29, 2021. Identifier number NCT05100212.

Abstract Exposure to altered gravity influences cellular behaviour in cell cultures. Hydrogels are amongst the most common materials used to produce tissue-engineering scaffolds, and their mechanical properties play a crucial role in cell-matrix interaction. However, little is known about the influence of altered gravity on hydrogel properties. Here we study the mechanical properties of Poly (ethylene glycol) diacrylate (PEGDA) and PEGDA incorporated with graphene oxide (GO) by performing tensile tests in micro and hypergravity during a Parabolic flight campaign, and by comparing them to the same tests performed in Earth gravity. We show that gravity levels do not result in a statistically significant difference in Young’s modulus.

Abstract The present study aimed to verify whether psychopathological symptoms, such as anxiety and depression, among hypertensive patients mediate anger expression and mental health. To this purpose, one hundred hypertensive patients completed the State and Trait Anger Inventory-2, the Symptom Checklist-90-Revised, and the 36-Item Short Form Health Survey. Fifty percent of the participants reported higher levels of psychopathological symptoms and lower levels of quality of life. A correlation analysis described positive associations between most of the scales of anger and psychopathological symptoms, including anxiety and depression. In contrast, mental health was negatively associated with anger expression and trait anger. A serial mediation model revealed that anxiety and depression fully mediated the relationship between anger expression and mental health. Our findings highlight the importance of conducting a multidimensional and multidisciplinary assessment to describe the mental health of hypertensives and prevent their psychological distress through the management of their emotional states. Taking care of the mental health of these patients may help them reduce psychological factors that influence their medical conditions.

Abstract Acinetobacter baumannii is a critical opportunistic pathogen associated with nosocomial infections. The high rates of antibiotic-resistance acquisition make most antibiotics ineffective. Thus, new medical countermeasures are urgently needed. Outer membrane proteins (OMPs) are prime candidates for developing novel drug targets and antibacterial strategies. However, there are substantial gaps in our knowledge of A. baumannii OMPs. This study reports the impact of OmpA-like protein on bacterial physiology and virulence in A. baumannii strain AB5075. We found that PsaB (ABUW_0505) negatively correlates to stress tolerance, while ArfA (ABUW_2730) significantly affects bacterial stiffness, cell shape, and cell envelope thickness. Furthermore, we expand our knowledge on YiaD (ABUW_3045), demonstrating structural and virulence roles of this porin, in addition to meropenem resistance. This study provides solid foundations for understanding how uncharacterized OMPs contribute to A. baumannii's physiological and pathological processes, aiding the development of innovative therapeutic strategies against A. baumannii infections.

Abstract Objective To investigate the Italian experience on the surgical and radiosurgical treatment of drug‐resistant epilepsy due to hypothalamic hamartoma (HH) in the period 2011–2021 in six Italian epilepsy surgery centers, and to compare safety and efficacy profiles of the different techniques. Methods We collected pseudo‐anonymized patient's data with at least 12 months of follow‐up. Surgical outcome was defined according to Engel classification of seizure outcome. Univariate analysis was performed to assess the risk of post‐operative seizures, categorized in dichotomous variable as favorable and unfavorable; explanatory variables were considered. Mann–Whitney or Chi‐squared test were used to assess the presence of an association between variables (p

Abstract Background Understanding the complex interactions between genes and their causal effects on diseases is crucial for developing targeted treatments and gaining insight into biological mechanisms. However, the analysis of molecular networks, especially in the context of high-dimensional data, presents significant challenges. Methods This study introduces MRdualPC, a computationally tractable algorithm based on the MRPC approach, to infer large-scale causal molecular networks. We apply MRdualPC to investigate the upstream causal transcriptomics influencing hypertension using a comprehensive dataset of kidney genome and transcriptome data. Results Our algorithm proves to be 100 times faster than MRPC on average in identifying transcriptomics drivers of hypertension. Through clustering, we identify 63 modules with causal driver genes, including 17 modules with extensive causal networks. Notably, we find that genes within one of the causal networks are associated with the electron transport chain and oxidative phosphorylation, previously linked to hypertension. Moreover, the identified causal ancestor genes show an over-representation of blood pressure-related genes. Conclusions MRdualPC has the potential for broader applications beyond gene expression data, including multi-omics integration. While there are limitations, such as the need for clustering in large gene expression datasets, our study represents a significant advancement in building causal molecular networks, offering researchers a valuable tool for analyzing big data and investigating complex diseases.

Abstract Surface display of functional groups with specific reactivity around living cells is an emerging, low cost and highly eco-compatible technology that serves multiple applications, ranging from basic biochemical studies to biomedicine, therapeutics and environmental sciences. Conversely to classical methods exploiting hazardous organic synthesis of precursors or monovalent functionalization via genetics, here we perform functional decoration of individual living microalgae using suitable biocoatings based on polydopamine, a melanin-like synthetic polymer. Here we demonstrate the one-pot synthesis of a functional polydopamine bearing phenylboronic units which can decorate the living cell surfaces via a direct ester formation between boronic units and surface glycoproteins. Furthermore, biosorption of fluorescent sugars on functionalized cell membranes is triggered, demonstrating that these organic coatings act as biocompatible soft shells, still functional and reactive after cell engineering.

Spine pain (SP) is the most common musculoskeletal disorder that causes transitional forms of motor disability. Considering its affordability and safety, manipulative therapy (MT) stands as one of the primary therapeutic approaches for SP and the related dysfunctional consequences. However, it is still difficult to assess and quantify the results of this treatment since there is a lack of objective evaluation tools in the available scientific literature. Thus, the purpose of this comprehensive review is to summarize the main outcomes used to evaluate the effectiveness of spine manipulations, focusing on their strengths and weaknesses. An extensive review of the PubMed, Cochrane, and Embase databases was performed to identify the literature of the last ten years regarding MT and the related assessment tools. A total of 12 studies met the inclusion criteria. The analyzed literature indicates that a wide range of outcome measures have been used to assess the effectiveness of spine MT. Pain is the main aspect to be investigated but it remains difficult to elucidate since it is strongly linked to various dimensions such as self-perception and psychological aspects. Therefore, it seems necessary to include new tools for evaluating the effects of spine MT, with the aim of exploiting new technologies and taking into consideration the SP biomechanical and biopsychosocial aspects.

Este ensayo explora el papel crucial de la experiencia en la interpretación arqueológica y su relevancia en la investigación científica del pasado. Destaco el análisis detallado de esta noción, a menudo pasada por alto en las discusiones filosóficas sobre el cono-cimiento arqueológico. La tesis principal sostiene que la experiencia, concebida como una acción que progresa a través de etapas de actos constitutivos controlados, desempeña un papel fundamental. El argumento central distingue la experiencia según la lógica de la investigación empírica de Dewey de las perspectivas pragmáticas en arqueología. Subrayo la necesidad de considerar la investigación arqueológica como una actividad dinámica y controlada en constante crecimiento. Expongo argumentos basados en el pensamiento de Dewey, destacando la importancia de regresar al pragmatismo clásico para obtener una comprensión más profunda del papel de la experiencia en la investigación arqueológica y su contribución al entendimiento del pasado.

Abstract Motor fatigue in Multiple Sclerosis (MS) is due to reduced motor cortex (M1) output and altered sensorimotor network (SMN) modulation. Natalizumab, a disease-modifying therapy, reduces neuroinflammation and improves fatigue. However, some patients treated with natalizumab experience fatigue recurrence (‘wearing-off’) before subsequent infusions. Wearing-off provides a valuable window into MS-related motor fatigue mechanisms in a controlled, clinically stable, setting. This study investigates whether wearing-off is associated with worsening motor fatigue and its neurophysiological mechanisms and assesses natalizumab’s effect on MS-related fatigue. Forty-five relapsing–remitting MS patients with wearing-off symptoms were evaluated pre- and post-natalizumab infusion. Assessments included evaluating disability levels, depressive symptoms, and the impact of fatigue symptoms on cognitive, physical, and psychosocial functioning. The motor fatigue index was computed through the number of blocks completed during a fatiguing task and peripheral, central, and supraspinal fatigue (M1 output) were evaluated by measuring the superimposed twitches evoked by peripheral nerve and transcranial magnetic stimulation of M1. Transcranial magnetic stimulation-electroencephalography assessed M1 effective connectivity by measuring TMS-evoked potentials (TEPs) within the SMN before- and after the task. We found that wearing-off was associated with increased motor fatigue index, increased central and supraspinal fatigue, and diminished task-related modulation of TEPs compared to post-natalizumab infusion. Wearing-off was also associated with worsened fatigue impact and depression symptom scores. We conclude that the wearing-off phenomenon is associated with worsening motor fatigue due to altered M1 output and modulation of the SMN. Motor fatigue in MS may reflect reversible, inflammation-related changes in the SMN that natalizumab can modulate. Our findings apply primarily to MS patients receiving natalizumab, emphasizing the need for further research on other treatments with wearing-off.

Abstract A fundamental challenge in mass spectrometry-based proteomics is the identification of the peptide that generated each acquired tandem mass spectrum. Approaches that leverage known peptide sequence databases cannot detect unexpected peptides and can be impractical or impossible to apply in some settings. Thus, the ability to assign peptide sequences to tandem mass spectra without prior information—de novo peptide sequencing—is valuable for tasks including antibody sequencing, immunopeptidomics, and metaproteomics. Although many methods have been developed to address this problem, it remains an outstanding challenge in part due to the difficulty of modeling the irregular data structure of tandem mass spectra. Here, we describe Casanovo, a machine learning model that uses a transformer neural network architecture to translate the sequence of peaks in a tandem mass spectrum into the sequence of amino acids that comprise the generating peptide. We train a Casanovo model from 30 million labeled spectra and demonstrate that the model outperforms several state-of-the-art methods on a cross-species benchmark dataset. We also develop a version of Casanovo that is fine-tuned for non-enzymatic peptides. Finally, we demonstrate that Casanovo’s superior performance improves the analysis of immunopeptidomics and metaproteomics experiments and allows us to delve deeper into the dark proteome.

Abstract Systemic light chain (LC) amyloidosis (AL) is a disease where organs are damaged by an overload of a misfolded patient-specific antibody-derived LC, secreted by an abnormal B cell clone. The high LC concentration in the blood leads to amyloid deposition at organ sites. Indeed, cryogenic electron microscopy (cryo-EM) has revealed unique amyloid folds for heart-derived fibrils taken from different patients. Here, we present the cryo-EM structure of heart-derived AL amyloid (AL59) from another patient with severe cardiac involvement. The double-layered structure displays a u-shaped core that is closed by a β-arc lid and extended by a straight tail. Noteworthy, the fibril harbours an extended constant domain fragment, thus ruling out the variable domain as sole amyloid building block. Surprisingly, the fibrils were abundantly concatenated with a proteinaceous polymer, here identified as collagen VI (COLVI) by immuno-electron microscopy (IEM) and mass-spectrometry. Cryogenic electron tomography (cryo-ET) showed how COLVI wraps around the amyloid forming a helical superstructure, likely stabilizing and protecting the fibrils from clearance. Thus, here we report structural evidence of interactions between amyloid and collagen, potentially signifying a distinct pathophysiological mechanism of amyloid deposits.

Abstract Compared to other malignancies, few studies have investigated the role of family history of cancer (FHC) in patients with lung cancer, yielding largely heterogeneous results. We performed a systematic literature review in accordance with PRISMA guidelines, searching the PubMed and Scopus databases from their inception to November 25, 2023, to identify studies reporting on the role of FHC in patients with lung cancer. A total of 53 articles were included, most with a retrospective design and encompassing a variety of geographical areas and ethnicities. Thirty studies (56.6%) assessed patients with non-small cell lung cancer (NSCLC), while 17 studies (32.1%) assessed patients with mixed histologies. Overall, the rates of FHC ranged from 8.3 to 68.9%, and the rates of family history of lung cancer ranged from 2 to 46.8%. Twenty-seven studies investigated FHC as a potential risk factor for lung cancer, with more than half reporting an increased risk for subjects with FHC. Five studies reported on the potential role of FHC in determining clinical outcomes, and twelve studies examined the relationship between FHC and germline mutations. Notably, only one study reported a significantly increased rate of germline mutations, including ATM, BRCA2, and TP53, for patients with a family history of lung cancer compared to those without, but both groups had a low prevalence of mutations (

Abstract Over centuries, European vintners have developed a profound knowledge about grapes, environment, and techniques that yield the most distinguishable wines. In many regions, this knowledge is reflected in the system of wine geographical indications (GI), but climate change is challenging this historical union. Here, we present a climate change vulnerability assessment of 1085 wine GIs across Europe and propose climate-resilient development pathways using an ensemble of biophysical and socioeconomic indicators. Results indicate that wine regions in Southern Europe are among the most vulnerable, with high levels also found in Eastern Europe. Vulnerability is influenced by the rigidity of the GI system, which restricts grape variety diversity and thus contributes to an increased sensitivity to climate change. Contextual deficiencies, such as limited socioeconomic resources, may further contribute to increased vulnerability. Building a climate-resilient wine sector will require rethinking the GI system by allowing innovation to compensate for the negative effects of climate change.

Background: Patients with severe asthma are often dependent on oral corticosteroids (OCS) and have frequent exacerbations. This article aims to report very long-term data of patients with severe eosinophilic asthma assessing asthma control, lung function, inhaled corticosteroid (ICS) dose reduction, and clinical and biological parameters of patients treated with mepolizumab. Methods: Four cases of adult patients with severe eosinophilic asthma who were treated for 60 months or more with mepolizumab 100 mg/4 weeks, leading to the stable discontinuation of OCS, are presented. ICS dose, OCS dose and withdrawal date, lung function, eosinophil count, fractional exhaled nitric oxide, and asthma control test were recorded as well as exacerbations in the 12 months before commencing mepolizumab and in the 12 months before the last follow-up visit. Results: Three of the patients were men, median age was 52.5 years (range 79–53), median length of asthma before mepolizumab start was 67.5 months (range 24–240), three had chronic rhinosinusitis without nasal polyposis and two were atopic. All had eosinophil counts >300 cells/μL at baseline. The median follow-up was 73.5 months (range 71–74), and OCS withdrawal from baseline occurred after a median of 13 months of mepolizumab treatment (range 12–39). A substantial reduction of ICS treatment was registered as well as improvement in asthma control test, fractional exhaled nitric oxide and functional parameters, and a significant reduction of exacerbations in the last 12 months before last visit was observed as compared to the 12 months before baseline (from a median of 4 (range 3–6) to 0; p=0.0286). Conclusions: Mepolizumab could be a ‘disease-modifying’ agent, with high tolerability and a good efficacy profile in the long term.

Abstract Marine ecosystems are facing a dramatic loss of biodiversity worldwide, together with a widespread collapse of habitats and their functionality. In this context, Marine Citizen Science (MCS) can be a powerful tool to monitor these changes over time. The flowering of very well-structured international projects is strengthening the scientific credibility of MCS data, especially when data are collected after specifically designed training programs and shared in public user-friendly repositories. Here we present a new perspective on the use of MCS in the Mediterranean area, along with the main benefits for the stakeholders (i.e., diving centers, trainers, and policymakers) and the users (i.e., divers), resumed in three pillars: Pillar I – MCS as a tool for the site valorization; Pillar II – MCS as a new career opportunity for graduated students; Pillar III – MCS as a business opportunity for diving centers. In the frame of the Quintuple Helix Approach, for which there is a strong need of a socioecological transition of the society and economy, we show how MCS can be a win-win-win solution for all the actors involved, providing the vision for new and highly qualified job and business opportunities for the diving sector.

Abstract Drug hypersensitivity reactions are common in children. Risk factors predisposing to IgE-mediated drug allergies and delayed drug reactions are a matter of debate. Gender, age, previous reactions to the same drug or to another drug, reduced drug metabolism, chronic diseases, polypharmacy, drug doses are linked with the onset of hypersensitivity reactions in some children. Novel advances in genetic polymorphisms can rapidly change the approach to the prevention of reactions since gene testing can be a useful screening test for severe cutaneous adverse reactions. Viral infections may act as cofactors in susceptible individuals. Polypharmacy, high doses, repeated doses and parental route of administration are also risk factors. Clinicians should take into account risk factors to allow the risk–benefit balance to be maintained.

Because the deformation parameters (temperature, strain rate) in the actual manufacturing process are non-constant. We investigate meta-dynamic recrystallization behavior under the transient mutation state. First, based on a single-pass thermal deformation experiment and electron backscatter diffraction (EBSD) technique, this study establishes a quantitative calculation method for the volume fraction of meta-dynamic recrystallization under different deformation conditions, and find the GOS threshold basis for judging the occurrence of meta-dynamic recrystallization. Comparing the experimental results with the numerical simulation results, it is found that the MDRX behavior of the material could be accurately described. The meta-dynamic recrystallization evolution law of the material in the thermal deformation insulation stage under the variable strain rate state is investigated by continuous variable rate thermal deformation experiment and numerical simulation. It is observed that an increase of the average strain rate in the continuous variable strain rate state would promote the meta-dynamic recrystallization softening behavior of the material in comparison with the steady state deformation stage, and vice versa.

Abstract Multiple sclerosis (MS) is a demyelinating and neurodegenerative disease due to an autoimmune chronic inflammatory response, yet the etiology is currently not completely understood. It is already known that physical activity plays an essential role in improving quality of life, especially in neuropathological conditions. The study was aimed to investigate the possible benefits of high-intensity interval training (HIIT) in bone and lipid metabolism markers, and neuromotor abilities in MS patients. 130 participants were recruited; 16 subjects with MS met the inclusion criteria and were included in the data analysis. The patients were randomly assigned to two groups: a Control group (CG) (34.88 ± 4.45 yrs) that didn’t perform any physical activity and the Exercise group (EG) (36.20 ± 7.80 yrs) that performed HIIT protocol. The training program was conducted remotely by a kinesiologist. It was performed three times a week for 8 weeks. At the beginning (T0) and the end of the study (T1) physical function tests, bone remodelling markers, and lipid markers analyses were performed. After 8 weeks of training the wall squat (s) (T0 = 27.18 ± 4.21; T1 = 41.68 ± 5.38, p ≤ 0.01) and Time Up and Go test (s) (T0 = 7.65 ± 0.43; T1 = 6.34 ± 0.38 p ≤ 0.01) performances improved; lipid markers analysis showed a decrease in Total (mg/dl) (T0 = 187.22 ± 15.73; T1 = 173.44 ± 13.03, p ≤ 0.05) and LDL (mg/dl) (T0 = 108 ± 21.08; T1 = 95.02 ± 17.99, p

Abstract Photoplethysmography (PPG) is a non-invasive optical technique that measures changes in blood volume in the microvascular tissue bed of the body. While it shows potential as a clinical tool for blood pressure (BP) assessment and hypertension management, several sources of error can affect its performance. One such source is the PPG-based algorithm, which can lead to measurement bias and inaccuracy. Here, we review seven widely used measures to assess PPG-based algorithm performance and recommend implementing standardized error evaluation steps in their development. This standardization can reduce bias and improve the reliability and accuracy of PPG-based BP estimation, leading to better health outcomes for patients managing hypertension.

Abstract Background Value-based healthcare (VBHC) is an approach that focuses on delivering the highest possible value for patients while driving cost efficiency in health services. It emphasizes improving patient outcomes and experiences while optimizing the use of resources, shifting the healthcare system’s focus from the volume of services to the value delivered. Our study assessed the effectiveness of implementing a VBHC-principled, tailored preoperative evaluation in enhancing patient care and outcomes, as well as reducing healthcare costs. Methods We employed a quality improvement, before-and-after approach to assessing the effects of implementing VBHC strategies on the restructuring of the preoperative evaluation clinics at Humanitas Research Hospital. The intervention introduced a VBHC-tailored risk matrix during the postintervention phase (year 2021), and the results were compared with those of the preintervention phase (2019). The primary study outcome was the difference in the number of preoperative tests and visits at baseline and after the VBHC approach. Secondary outcomes were patient outcomes and costs. Results A total of 9722 patients were included: 5242 during 2019 (baseline) and 4,480 during 2021 (VBHC approach). The median age of the population was 63 (IQR 51–72), 23% of patients were classified as ASA 3 and 4, and 26.8% (2,955 cases) were day surgery cases. We found a considerable decrease in the number of preoperative tests ordered for each patient [6.2 (2.5) vs 5.3 (2.6) tests, p