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Unsaturated fatty acids (UFA) play a crucial role in central cellular processes in animals, including membrane function, development, and disease. Disruptions in UFA homeostasis can contribute to the onset of metabolic, cardiovascular, and neurodegenerative disorders. Consequently, there is a high demand for analytical techniques to study lipid compositions in live cells and multicellular organisms. Conventional analysis of UFA compositions in cells, tissues, and organisms involves solvent extraction procedures coupled with analytical techniques such as gas chromatography, MS and/or NMR spectroscopy. As a nondestructive and nontargeted technique, NMR spectroscopy is uniquely capable of characterizing the chemical profiling of living cells and multicellular organisms. Here, we use NMR spectroscopy to analyze Caenorhabditis elegans, enabling the determination of their lipid compositions and fatty acid unsaturation levels both in cell-free lipid extracts and in vivo. The NMR spectra of lipid extracts from WT and fat-3 mutant C. elegans strains revealed notable differences due to the absence of Δ-6 fatty acid desaturase activity, including the lack of arachidonic and eicosapentaenoic acyl chains. Uniform 13C-isotope labeling and high-resolution 2D solution-state NMR of live worms confirmed these findings, indicating that the signals originated from fast-tumbling lipid molecules within lipid droplets. Overall, this strategy permits the analysis of lipid storage in intact worms and has enough resolution and sensitivity to identify differences between WT and mutant animals with impaired fatty acid desaturation. Our results establish methodological benchmarks for future investigations of fatty acid regulation in live C. elegans using NMR.

Summary: Three-dimensional (3D) ex vivo cultures allow the study of cancer progression and drug resistance mechanisms. Here, we present a protocol for measuring on-target drug sensitivity in a scaffold-free 3D culture system through quantification of apoptotic tumor cells. We provide detailed steps for sample processing, immunofluorescence staining, semi-high-throughput confocal imaging, and imaged-based quantification of 3D cultures. This protocol is versatile and can be applied in principle to any patient-derived material. : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

The TANDEM project is a European initiative funded under the EURATOM program. The project started on September 2022 and has a duration of 36 months. TANDEM stands for Small Modular ReacTor for a European sAfe aNd Decarbonized Energy Mix.Small Modular Reactors (SMRs) can be hybridized with other energy sources, storage systems and energy conversion applications to provide electricity, heat and hydrogen. Hybrid energy systems have the potential to strongly contribute to the energy decarbonization targeting carbon-neutrality in Europe by 2050. However, the integration of nuclear reactors, particularly SMRs, in hybrid energy systems, is a new R&D topic to be investigated. In this context, the TANDEM project aims to develop assessments and tools to facilitate the safe and efficient integration of SMRs into low-carbon hybrid energy systems. An open-source “TANDEM” model library of hybrid system components will be developed in Modelica language which, by coupling, will extend the capabilities of existing tools implemented in the project. The project proposes to specifically address the safety issues of SMRs related to their integration into hybrid energy systems, involving specific interactions between SMRs and the rest of the hybrid systems; new initiating events may have to be considered in the safety approach.TANDEM will study two hybrid systems covering the main trends of the European energy policy and market evolution at 2035's horizon: a district heating network and power supply in a large urban area, and an energy hub serving energy conversion systems, including hydrogen production; the energy hub is inspired from a harbor-like infrastructure. TANDEM will provide assessments on SMR safety, hybrid system operationality and techno-economics. Societal considerations will also be encased by analyzing European citizen engagement in SMR technology safety.The work will result in technical, economic and societal recommendations and policy briefs on the safety of SMRs and their integration into hybrid energy systems for industry, R&D teams, Technical Safety Organizations, regulators, Non-Governmental Organizations and policy makers. The TANDEM consortium will involve 17 partners from 8 European countries (Belgium, Czech Republic, Finland, France, Germany, Italy, Spain, Ukraine).The TANDEM project has the ambition to become a pioneer initiative in Europe in gathering efforts and expertise around development of SMRs integration into hybrid energy systems. The dissemination and the exploitation of the project outcomes as well as the proposed Education & Training activities shall serve as a basis for a number of new R&D and innovation projects addressing the safety issues of SMRs and their integration into hybrid energy systems.

Background & Aims: Long-term albumin (LTA) is currently standard of care for patients with decompensated cirrhosis in many Italian hepatology centres. In this real-life study, we aimed to describe patient, logistical and treatment-related characteristics in daily clinical practice and to identify predictors of response. Methods: We performed a multicentre, retrospective, observational study in patients with cirrhosis and ascites receiving LTA between 01/2016 and 02/2022 and followed until death, TIPS (transjugular intrahepatic portosystemic shunt) placement, transplantation or 02/2023. Results: A total of 312 patients, the majority with alcohol-related cirrhosis, were included. At baseline, median Child-Pugh, MELD, and MELD-Na were 8, 15, and 18, respectively. Ascites was grade 2 in 55% of patients, grade 3 in 35% and refractory in 27%, while 47% had received large volume paracentesis in the previous 6 months. Median LTA was 10 months with a median dose of 40 g/week. Ascites resolved to grade 0-1 in 34% of patients within the first 3 months and 56% by the end of treatment. Predictors of ascites resolution were age (p = 0.007), baseline grade of ascites (p = 0.007), no paracentesis in the previous 6 months (p = 0.001), aetiological treatment in the past 12 months or during LTA (p = 0.005), weekly albumin dose (p = 0.014) and serum albumin concentration of 40 g/L after 1 month of treatment (p = 0.017). Of the 83 patients with refractory ascites at inclusion, 26% had grade 0/1 ascites at the last observation. No severe albumin-related side-effects were reported and only 1% discontinued for logistical reasons. Conclusions: LTA is feasible as an outpatient treatment for the management of ascites. In the current study, ascites resolved in more than half of patients receiving LTA on top of diuretics, including in some with refractory ascites. Predictors of response to LTA provide useful information for tailoring treatment. Impact and implications:: The ANSWER randomised-controlled trial has shown that long-term albumin treatment (LTA) is an effective approach for the management of patients with cirrhosis and ascites. This observational study provides novel information on target patients, modalities and length of treatment, predictors of ascites resolution, stopping criteria, and clinical trajectories of patients on treatment. LTA is a feasible option in the daily clinical practice for the management of ascites when given on top of diuretics. Rather than an alternative therapy, LTA should be integrated with the other treatment options already available for patients with difficult-to-treat ascites. The predictive factors of response identified in the present study can help physicians to individualise LTA and optimise the decision-making process.

Background: Heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF) are challenging conditions to treat due to complex pathophysiology and associated comorbidities. However, recent trials have demonstrated improved outcomes with guideline-directed medical therapy (GDMT) for each subtype of heart failure. Objective: We investigated the relationship of determinants of health and risk factors with GDMT use for HFrEF and HFpEF in a large, diverse US cohort. Methods: Using the NIH-sponsored All of Us Program, we compared demographics, risk factors (e.g., hypertension, diabetes, smoking), and SDOH measures between HFrEF and HFpEF in US adults aged 18 years and older. We examined the proportions of HFrEF patients receiving fewer than four or all four GDMTs. HFpEF patients receiving two medications were compared with those receiving less than two recommended medications. Multiple logistic regression was used for data analysis. Result: Of 6049 HFrEF patients, 5838 (97 %) received fewer than four GDMTs, and 210 (3 %) received quadruple therapy. Of 3774 HFpEF patients, 162 (4 %) were on 2/3 GDMT, and only 38 (1 %) were on all three recommended medications. Patients with ASCVD and diabetes had higher odds of being on more than half of the recommended GDMT for both HFrEF and HFpEF. Additionally, females had higher odds of being on 2/3 GDMT for HFpEF (1.46 [1.08, 2.00]). Race, income, education, and health insurance types did not predict GDMT optimization. Conclusion: HFrEF and HFpEF GDMT remain underutilized. Future efforts to address comorbidities and system-wide healthcare interventions may improve heart failure GDMT.

High energy states in the self-conjugate 16O nucleus were investigated by analyzing 13C(3He,α)12C reactions in the bombarding energy range 1.4–2.2 MeV. Thanks to a low-threshold and high-resolution array, we succeed in measuring cross sections of the decay channel where an α particle is emitted in coincidence with a 12C nucleus in the Hoyle state, leading to 4α particles in the final channel. The analysis of angular distributions indicates the occurrence of two low-spin resonant states, respectively with Jπ=2+ and 3−, at energies of ≈ 24.1 and 24.5 MeV. In this energy window, the observed branching ratios for the transition involving the emission of the Hoyle state are well larger than calculations based on barrier penetration, signaling the possible occurrence of high-energy states in 16O with a large cluster component.

Objective: This study investigates the psychological factors influencing somatic symptoms following the end of a romantic relationship. We hypothesize that affective temperaments may predict attachment styles and depressive rumination components in individuals who have experienced abandonment. Furthermore, we postulate that gender differences exist in the variables under investigation. Methods: The administered tests included: Temperament Evaluation of Memphis, Pisa, Paris and San Diego Questionnaire (TEMPS-A), Attachment Style Questionnaire (ASQ) and Ruminative Response Scale (RRS). The differences between the groups were assessed using Student's t-test for independent samples. In addition, regression analysis, in which the RRS (Brooding, Reflection and Depression) and ASQ (Confidence, Discomfort with Closeness, Need for Approval, Preoccupation with Relationships, and Relationships as Secondary) variables were considered dependent variables and all the TEMPS-A factors were included in the equation. Results: Subjects at the end of a love affair presented the following psychosomatic symptoms: difficulty breathing, chest pain, feeling faint, sweating, dizziness, fatigue, palpitations, air hunger, difficulty sleeping, and swollen legs and ankles. The Anxious and Hyperthymic temperaments were negative predictors of the ruminative depressive dimension, and of “Confidence” and “Discomfort with Closeness” in the ASQ. The Cyclothymic and Anxious temperaments were predictors of “Discomfort with Closeness”, “Need for Approval”, “Preoccupation with Relationships”, and “Relationships as Secondary”. Conclusion: Affective temperaments play a crucial role in determining how an individual deals abandonment in a romantic relationship, significantly influencing attachment styles and the tendency towards depressive rumination.

Assessing the degree of genetic diversity and differentiation of rare or endangered endemic species is essential to evaluate the conservation status of populations and successively implement appropriate conservation strategies. We investigated the population structure of Salvia ceratophylloides Ard., a scapose hemicryptophyte endemic to Calabria (southern Italy), both to answer questions about its genetic structure and to determine whether the actual population size has undergone significant demographic changes in the near past. The data obtained from the census showed that the populations are characterised by a greater number of adult individuals than juveniles and are on declining. The genetic analysis carried out on 99 individuals from four populations of the species under study, shows a mean expected heterozygosity value of 0.50 and an overall differentiation value of 0.083. The population structure shows that the four studied populations are distinct genetic units, genetically linked to four different ancestral gene pools. Bayesian analysis based on ABC models indicates that the present populations underwent a significant reduction in size in the past. This corresponds to the demographic decline at the end of the 19th century, which according to the literature, was due to the strong anthropic pressure (agriculture, grazing, fire and plantations) of Reggio Calabria suburbs. We can therefore conclude that populations are not affected by inbreeding and low genetic diversity and that there is no immediate danger of genetic erosion, and that the problems associated with population decline, past and present, are exclusively due to anthropogenic causes.

There is an urgent need for accurate and effective Landslide Early Warning Systems (LEWS). Most LEWS are currently based on temporally-aggregated measures of rainfall derived from either in-situ measurements or satellite-based rainfall estimates. Relying on a summary metric of precipitation may not capture the complexity of the rainfall signal and its dynamics in space and time in triggering landslides. Here, we present a proof-of-concept for constructing a LEWS based on an integrated spatio-temporal modelling framework. Our proposed methodology builds upon a recent approach that uses a daily rainfall time series instead of the traditional scalar aggregation. Specifically, we partition the study area into slope units and use a Gated Recurrent Unit (GRU) to process satellite-derived rainfall time series and combine the output features with a second neural network (NN) tasked with capturing the effect of terrain characteristics. To assess if our approach enhances accuracy, we applied it in Vietnam and benchmarked it against a modelling counterpart where we replaced the rainfall time series with the corresponding scalar representative of the cumulated precipitation. The corresponding duration was set at 14 days as it proved to produce the best performance. Our results show that our protocol leads to better performance in hindcasting landslides when making use of the rainfall as a continuous signal over time. While not tested here, our approach can be extended to rainfall obtained from weather forecasts, potentially leading to actual landslide forecasts.

Background: Hemodynamic impact of residual mitral regurgitation (MR) after transcatheter edge-to-edge repair (TEER) is not always univocally measured by transesophageal echocardiographic (TEE) assessment alone. When analyzing TEER procedure result, operators often encounter discrepancy between TEE guidance and invasive hemodynamic monitoring. Objectives: This study sought to investigate the role of invasive hemodynamic monitoring during mitral valve TEER procedure on top of TEE guidance. Methods: We analyzed 78 patients with moderate-to-severe or severe MR who underwent TEER. Mitral pulse pressure fraction (MPF) was extracted from intraprocedural continuous left atrial pressure monitoring. Twenty-three patients with the same grade of MR not undergoing TEER were included as a control group. At follow-up, clinical and functional status in the majority of patients undergoing TEER were reassessed by NYHA classification and the 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ). Results: TEER significantly reduced MR burden on both TEE guidance and invasive hemodynamic monitoring. Post-TEER MPF was significantly reduced compared to both pre-TEER setting (P

Under what conditions do originators of innovation benefit from knowledge spillover by learning from knowledge recipients, and when do they not? This study examines how originator firms’ learning from recipients differs depending on their spillover characteristics. These characteristics were captured using the Spillover Knowledge Pool (SKP). It also examines how technological alliances moderate the relationship between SKP characteristics and originator follow-on innovations. An analysis of 62 firms over 10 years confirms that while the technological diversity of the SKP has a positive impact on the originator's innovation, the technological overlap of the SKP relative to the originator's knowledge has a negative impact. Furthermore, technological alliances enhance the positive effect of technological diversity while exacerbating the adverse effects of technological overlap. This study contributes to the literature on knowledge spillover, particularly within the knowledge-based view of firms, by providing a balanced perspective that addresses the dual impact of knowledge spillover on originator firms. Furthermore, this research highlights the contingent effects of knowledge spillover by examining the interplay between spillover phenomena and strategic factors, specifically technological alliances. The findings have concrete managerial and policy implications conducive to enhancing firms’ innovation performance in the context of knowledge spillover.

Background: The affective temperaments are defined as the fundamental predisposition from which normal affective states originate or as the constitutional core of personality. Recently, researchers have started considering the role of affective temperament on the clinical expression of affective disorders. The aim of the study is to learn more about the role of affective temperaments on irritability, anxiety and depression symptoms. Methods: 748 subjects belonging to Italian population were included. Data were collected through an online survey including IDAS and TEMPS-A questionnaire. Two correlation analysis were performed to assess sex differences in the affective patterns. A linear regression analysis was performed to assess how age, sex and temperamental dimensions could play a role as predictors of depression, anxiety and irritability symptoms. Results: The correlation analysis shows that ''Cyclothymic,'' ''Depressive,'' ''Irritable'', and ''Anxious'' temperaments, in both genders, positively correlate with Anxiety, Depression, and Irritability. Hyperthymic temperament, instead, negatively correlates with Depression in men and with both Anxiety and Depression in women. Linear regression show that Cyclothymic, depressive and anxious temperaments are significant predictors of anxiety symptoms while depressive and cyclothymic temperaments are predictors of depressive symptoms. The irritability was found to be a significant predictor of depression and anxiety disorders. The results of the linear regression analysis show that the Cyclothymic and Irritable temperaments significantly predicted “Irritability”. Finally, female sex was found to be a predictor of anxiety (β = 0.090, t = 2.906, p =

Background: Endothelial function declines with age and plays a critical role in cardiovascular health. Therefore, investigating endothelial function in successful aging models, such as centenarians, is of interest. Flow-mediated dilation (FMD) of the brachial artery is the gold standard for measuring endothelial function in vivo in humans. Therefore, we investigated, for the first time, the FMD of the brachial artery in a group of healthy centenarians. Methods: Selected as part of the ABCD project (nutrition, cardiovascular wellness, and diabetes) centenarians (aged ≥100 years) living in the municipalities of Madonie (Palermo, Italy) were compared with a younger (aged

Background: To investigate the short-term dentoalveolar effects on the mandibular arch of a modified, aesthetic lip bumper (ALBAa). The study sample comprised 23 patients (13 boys and 10 girls, with a mean age of 9.5 ± 1.8 years) in mixed dentition, with no previous orthodontic treatment. For each patient, a scan of the mandibular arch was digitally acquired pre-treatment (T0), and at 3 months (T1), 6 months (T2) and 9 months (T3) post-treatment. Linear intra-arch measurements, Little’s irregularity index of the amount of mandibular anterior crowding, and the crown tipping values on all mandibular teeth were measured and compared statistically between time points. ANOVA and subsequent post-hoc tests were performed, considering a p-value of

Background: Binge-watching is a new type of behaviour that has started to gain popularity since 2013 and is defined as “watching multiple episodes of TV series (at least two to six) in a single session”. Binge-watching is a phenomenon that affects the general population up to over 65 years of age, with a trend in the 18–39 age group. It is plausible to think that affective temperament dimensions may have an impact on the excessive use of watching serious TV. The affective temperaments play a significant role on motivated behaviour, impulsivity, and decision-making of binge watching. This behaviour provides instant gratification, leading a person to lose self-control.The aim of the present study is to learn about the possible role of affective temperaments on motivated behaviour, impulsivity, and decision-making of binge watching in the general Italian population. Methods: The sample consisted of 1,701 subject belonging Italian population. Data were collected by an online survey including the Binge-Watching Addiction Questionnaire (BWAQ) and the short form of the Temperament Evaluation of Memphis, Pisa, Paris and San Diego (TEMPS-A) questionnaire. A multivariate regression analysis, in which the BWAQ variables (Anticipation, Avoidance, Craving, Dependency) were considered dependent variables and all the TEMPS-A factors were included in the equation, was performed to assess what kind of temperamental dimension could play the role of specific predictor towards the different aspects of binge watching. Results: Anxious and cyclothymic temperaments are highly significant. The factors that have a weaker impact on the dependent variables (significance at the 5 % level) are depressive and hyperthymic temperaments on the craving and avoidance dimensions, respectively. The irritable temperament is significant at the 5 % level for the models associated with the avoidance and dependency dimensions. Conclusion: In summary, the results of multivariate regression analysis show that subjects with anxious and cyclothymic temperaments have a higher risk of engaging in binge-watching behaviour. It is important to obtain further knowledge on the psychological consequences of this phenomenon for future diagnosis, prevention and therapeutic implementations.

Background: Late dumping syndrome (LDS) refers to reactive hyperinsulinemic hypoglycemia episodes that occur one to 3 h following a high-carbohydrate meal in persons who have had gastric surgery. Dietary adjustments (such as regular composite meals containing lipids, protein, and carbohydrates with a low glycemic index) are effective in treating the majority of LDS patients; however, pharmaceutical interventions are required in some cases. Case presentation: We describe the case of a 60-year-old woman with type 2 diabetes (T2DM) who developed late dumping syndrome symptoms following a gastric cancer gastrectomy. Both the 75-g oral glucose tolerance test (OGTT) and the mixed-meal tolerance test (MMTT) revealed reactive hyperinsulinemic hypoglycemia. We began therapy with canagliflozin, a sodium glucose-cotransporter (SGLT) inhibitor 300 mg before lunch after realizing that dietary changes were insufficient in reducing the occurrence of symptomatic hypoglycemic episodes. We repeated the OGTT after treatment, and the results showed still the presence of symptomatic hypoglycemia without significant differences in peak insulin values compared to the OGTT performed before treatment. Instead, the MMT showed a small, flattened insulin response without any hypoglycemic episodes. Furthermore, improvements were observed in glucose trends/targets as demonstrated by time in (TIR), above (TAR) and below (TBR) range and glucose variability (e.g. coefficient of variation) based on data collected from Flash Glucose Monitoring (FGM) before and during canagliflozin therapy. Conclusion: The rapid transit of inadequately digested chyme from the stomach into the small intestine is one of the most important pathophysiological processes in LDS. Canagliflozin, unlike other molecules in the same family, inhibits intestine SGLT-1. By delaying glucose absorption at that level, it may reduce postprandial glucose and insulin rises. Our case report, however, demonstrates that the effect of canagliflozin on glucose homeostasis is determined by appropriate dietary habits, which seem to be critical for successfully reducing symptoms related to reactive hyperinsulinemic hypoglycemia following a gastric bypass surgery.

Objective: Compare the bonding survival rate of two distinct bonding materials: Ortho Solo + Gradia LoFlo Resin and single component GC Ortho Connect. Materials and Methods: Indirect bonding fixed appliance treatment was required for 26 consecutive patients, 8 males and 18 females, with a mean age of 22.1 +/- 4.2 years. All patients were treated with SWM (Straight-Wire Mirabella) technique (Sweden and Martina, Due Carrare, Padova, Italy). Each patient's bonding process followed a contralateral pattern. Firstly, a 37 % orthophosphoric acid etching gel was used for 20 s, subsequently the single or two components light-cured adhesives were applied through a split-mouth cross-arch procedure. The patients underwent a 12-month follow-up period and brackets failures were rebounded, but not further included in the study. Statistical analysis was performed to analyse the survival rate of the bonding materials and the influence of the variables, with a significant level of α = 0,05. Results: The GC Connect group was used on 349 teeth, while the Ortho Solo + Gradia group was used on 351 teeth, and the indirect debonding rate was respectively 17.5% and 12.8%. With respect to the total sample, statistically significant values were found for both sex and dental arch. The bracket’s survival rate for incisors, canines, premolars and molars was not significant. However, a higher debonding rate was clinically appreciable in upper and lower molars. Conclusion: In a 12-months observation period, considering all maxillary and mandibular teeth the indirect survival rate for the group GC Ortho Connect and Ortho Solo + Gradia was respectively 82.5% and 87.2%. Although the difference was not significant, a pronounced tendency to debonding for the single component group was appreciable from a clinically point of view.

Exposure to asbestiform fibers, including chrysotile and amphibole, is carcinogenic, causing malignant pleural mesothelioma (MPM) when inhaled. Some populations globally face Naturally Occurring Asbestos (NOA) exposure, leading to MPM cases like in Biancavilla, Italy, from Fluoro-edenite (FE) contamination. Studies show NOA exposure causes epigenetic changes, focusing on mesothelin methylation, an MPM marker, and altered inflammation, emphasizing the health risks of FE and asbestos. This research, conducted from February 2022 to October 2022, studied 125 construction workers from Biancavilla and 125 controls from 40 km away without Biancavilla work history. With at least ten years in construction and no respiratory conditions, participants underwent medical assessments and gave blood samples for analysis, including inflammation markers, mesothelin methylation, and soluble mesothelin-related protein levels. The results showed similar demographics but differing inflammation and methylation levels in exposed workers, suggesting long-term cellular changes. Pearson correlation showed intricate biomarker relationships. Significant inflammatory differences were found between FE exposed and non-exposed workers, indicating potential health impacts from FE. This raises concerns for communities like Biancavilla, emphasizing the importance of extensive epigenetic research for public health.

The geoscientific community primarily focuses on predicting where landslides are likely to occur through data-driven susceptibility models. Recently, few researchers have turned to statistical estimation of landslide planimetric area within a given terrain unit and exploration of the spatiotemporal distribution of landslide occurrence. However, these data-driven approaches cannot fulfill the commonly accepted definition of landslide hazard and cannot predict the location, time/frequency, and magnitude of landslide occurrence simultaneously. This study proposes a unified and data-driven framework for landslide hazard spatiotemporal modeling, enabling dynamic and probabilistic estimation of landslide occurrence within a given slope unit at a specific time period and for a specific landslide magnitude. This framework not only involves static and dynamic factors in modelling, but also considers spatial and temporal interactions to explore the spatiotemporal variation effects of landslide hazard. We test this framework on the main island of Taiwan with a multi-temporal landslide inventory from 2004 to 2018. Specifically, this framework assumes that the occurrence and size of landslides spatiotemporally follows a binomial and a Log-Gaussian distribution, respectively, and then uses generalized additive models to achieve the estimation of landslide hazard probability. Finally, the performance is validated by a spatiotemporal leave-one-out cross-validation scheme. We believe that this framework will lay the foundation for the community to estimate landslide hazard in a unified and probabilistic data-driven prototype. We envision it could lead to studies of dynamic hazard responses to climate change.

There are more than 3,500 active pharmaceutical ingredients (APIs) on the global market for human and veterinary use. Residues of these APIs eventually reach the aquatic environment. Although an environmental risk assessment (ERA) for marketing authorization applications of medicinal products is mandatory in the European Union since 2006, an ERA is lacking for most medicines approved prior to 2006 (legacy APIs). Since it is unfeasible to perform extensive ERA tests for all these legacy APIs, there is a need for prioritization of testing based on the limited data available. Prioritized APIs can then be further investigated to estimate their environmental risk in more detail. In this study, we prioritized more than 1,000 APIs used in Europe based on their predicted risk for aquatic freshwater ecosystems. We determined their risk by combining an exposure estimate (Measured or Predicted Environmental Concentration; MEC or PEC, respectively) with a Predicted No Effect Concentration (PNEC). We developed several procedures to combine the limited empirical data available with in silico data, resulting in multiple API rankings varying in data needs and level of conservativeness. In comparing empirical with in silico data, our analysis confirmed that the PEC estimated with the default parameters used by the European Medicines Agency often – but not always – represents a worst-case scenario. Comparing the ecotoxicological data for the three main taxonomic groups, we found that fish represents the most sensitive species group for most of the APIs in our list. We furthermore show that the use of in silico tools can result in a substantial underestimation of the ecotoxicity of APIs. After combining the different exposure and effect estimates into four risk rankings, the top-ranking APIs were further screened for availability of ecotoxicity data in data repositories. This ultimately resulted in the prioritization of 15 APIs for further ecotoxicological testing and/or exposure assessment.

Summary: Platform trials bring the promise of making clinical research more efficient and more patient centric. While their use has become more widespread, including their prominent role during the COVID-19 pandemic response, broader adoption of platform trials has been limited by the lack of experience and tools to navigate the critical upfront planning required to launch such collaborative studies. The European Union-Patient-cEntric clinicAl tRial pLatform (EU-PEARL) initiative has produced new methodologies to expand the use of platform trials with an overarching infrastructure and services embedded into Integrated Research Platforms (IRPs), in collaboration with patient representatives and through consultation with U.S. Food and Drug Administration and European Medicines Agency stakeholders. In this narrative review, we discuss the outlook for platform trials in Europe, including challenges related to infrastructure, design, adaptations, data sharing and regulation. Documents derived from the EU-PEARL project, alongside a literature search including PubMed and relevant grey literature (e.g., guidance from regulatory agencies and health technology agencies) were used as sources for a multi-stage collaborative process through which the 10 more important points based on lessons drawn from the EU-PEARL project were developed and summarised as guidance for the setup of platform trials. We conclude that early involvement of critical stakeholder such as regulatory agencies or patients are critical steps in the implementation and later acceptance of platform trials. Addressing these gaps will be critical for attaining the full potential of platform trials for patients. Funding: Innovative Medicines Initiative 2 Joint Undertaking with support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.

The initial inception of the landslide susceptibility concept defined it as a static property of the landscape, explaining the proneness of certain locations to generate slope failures. Since the spread of data-driven probabilistic solutions though, the original susceptibility definition has been challenged to incorporate dynamic elements that would lead the occurrence probability to change both in space and in time. This is the starting point of this work, which combines the traditional strengths of the susceptibility framework together with the strengths typical of landslide early warning systems. Specifically, we model landslide occurrences in the norther sector of Vietnam, using a multi-temporal landslide inventory recently released by NASA. A set of static (terrain) and dynamic (cumulated rainfall) covariates are selected to explain the landslide presence/absence distribution via a Bayesian version of a binomial Generalized Additive Models (GAM). Thanks to the large spatiotemporal domain under consideration, we include a large suite of cross-validation routines, testing the landslide prediction through random sampling, as well as through stratified spatial and temporal sampling. We even extend the model test towards regions far away from the study site, to be used as external validation datasets. The overall performance appears to be quite high, with Area Under the Curve (AUC) values in the range of excellent model results, and very few localized exceptions.This model structure may serve as the basis for a new generation of early warning systems. However, the use of The Climate Hazards group Infrared Precipitation with Stations (CHIRPS) for the rainfall component limits the model ability in terms of future prediction. Therefore, we envision subsequent development to take this direction and move towards a unified dynamic landslide forecast. Ultimately, as a proof-of-concept, we have also implemented a potential early warning system in Google Earth Engine.

Summary: The lymph node (LN) is a critical biological site for immune maturation after vaccination as it includes several cell populations critical for priming the antibody response. Here, we present a protocol for sampling the LN and isolating cell populations to evaluate immunogens targeting germline cells. We describe steps for media and tube preparation and sample collection using an ultrasound-guided LN fine-needle aspiration procedure. This protocol is safe, quick, low-cost, and less invasive than excisional biopsy.For complete details on the use and execution of this protocol, please refer to Leggat et al. (2022).1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Introduction: Bone marrow adipose tissue (BMAT) is associated with aging, osteoporosis, and chronic kidney disease (CKD). To date, the association between BMAT and kidney function in postmenopausal women has not been thoroughly investigated. The main purpose of this study was to determine whether a relationship exists between proton density fat fraction (PDFF) and kidney function in postmenopausal women. Methods: We investigated the cross-sectional association between estimated glomerular filtration rate (eGFR) – calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation – and PDFF – measured at the lumbar spine and proximal femur using Water Fat Imaging (WFI) MRI – in 199 postmenopausal women from the ADIMOS cohort study. We also performed DXA scans and laboratory measurements of sclerostin and c-terminal Fibroblast Growth Factor 23 (cFGF23). Results: Participants' mean age was 67.5 (standard deviation, SD 10.0) years. Their median eGFR was 85.0 (interquartile range, IQR 72.2–95.0) ml/min/1.73 cm2, and their mean lumbar spine PDFF was 57.9 % (SD 9.6). When classified by eGFR-based CKD stages, 41.7 % of the cohort had an eGFR ≥ 90 (n = 83), 47.2 % had an eGFR of 60–89.9 (n = 94), and 11.1 % had an eGFR of 30–59.9 (n = 22). Participants with eGFR ≥ 90 had a lower lumbar spine PDFF than those with eGFR 60–89.9 (mean 55.8 % (9.8) vs. 58.9 % (9.0), p = 0.031) and those with eGFR 30–59.9 (55.8 % (9.8) vs. 60.8 % (9.8), p = 0.043). However, the differences did not remain significant after adjusting for predetermined confounders, including age, diabetes, Charlson comorbidity index, recent history of fragility fracture, appendicular lean mass, and lumbar spine BMD. The inclusion of sclerostin and/or cFGF23 as suspected mediators did not alter the findings. When proximal hip imaging-based PDFF was considered, no significant differences were found between the eGFR categories in the unadjusted and adjusted analyses. Conclusion: No evidence of an association between kidney function and bone marrow adiposity was found either in the lumbar spine or proximal femur in a cohort of postmenopausal women.

The Madonie district, in the inner Sicily, is composed of 21 villages, custodians of heritage, traditions, and values that constitute the identity of this area, now exclusively entrusted to the collective memory of an increasingly elderly and inactive population. In the study area, full of tangible and intangible heritage, technological tools, can revitalize and reuse examples of architecture, especially monumental, whose main problem is a deep rising damp affecting the masonry. That is particularly critical for the historic/traditional architectures. This research implements, in one of the villages of the enclave, a new technology system, namely Information and Communication Technology (ICT) tool, like Charge neutralisation Technology (CNT), in contrast to the usual application of the classic and well-known resolution systems. This kind of methodology has been already applied in many monumental buildings in Italy with brilliant results and supporting the protection, enhancement, and promotion of cultural heritage. In Sicily it was never used and represents, in line with the smart village approach, a viable technology to be applied. The smart village model is one of the increasingly popular research topics globally and provides technologies aimed at preserving the identity of the territory and the historical buildings. Culture, if usable and accessible to all, results as an economic resource, a tourist attraction, and a factor of identity. The goal is to develop these inner areas through the smart villages approach by implementing smart technologies and establishing a synergic union of centers to be more competitive in the Sicilian hinterland, but also at the national level, with respect to the wise use of administrative, political, and governmental strategies. Cultural heritage and innovation, together, retrace the past with a view to modernity. The country's cultural heritage recovered and enhanced is a virtuous strategy to safeguard the identity and value of historic places such as that one of ancient villages and a way to find smart resilient strategies and a sustainability assessment for future communities.

In-cell NMR spectroscopy has emerged as a powerful tool to evaluate protein conformations and dynamics in the native environment of live cells. Here we extend these studies to a multicellular developing vertebrate. Zebrafish (Danio rerio) embryos are complex organisms with dynamic tissue organization and may be well suited for the high resolution NMR analysis of microinjected, isotopically enriched proteins. We used the intrinsically disordered protein Alpha-synuclein (aSyn) as a test model. aSyn has been thoroughly evaluated inside bacterial and mammalian cells, providing good reference points for NMR comparisons and the critical analysis of the advantages and disadvantages of the zebrafish system. High resolution 2D 1H-15N NMR showed that aSyn in zebrafish embryos had the same conformational and biological features previously observed in mammalian cells, including conserved interactions with cellular biomolecules and the establishment of physiological protein post-translational modifications. A direct comparative analysis of gamma-synuclein (gSyn), a naturally occurring homolog of aSyn, in bacteria, mammalian cells and zebrafish embryos confirmed these observations. Our results showed that high resolution in-cell NMR is attainable in embryonic cells within the native environment of a live animal. This system provides more physiological cellular environments for high resolution, in situ protein biophysical studies.

Summary: Human brain size changes dynamically through early development, peaks in adolescence, and varies up to 2-fold among adults. However, the molecular genetic underpinnings of interindividual variation in brain size remain unknown. Here, we leveraged postmortem brain RNA sequencing and measurements of brain weight (BW) in 2,531 individuals across three independent datasets to identify 928 genome-wide significant associations with BW. Genes associated with higher or lower BW showed distinct neurodevelopmental trajectories and spatial patterns that mapped onto functional and cellular axes of brain organization. Expression of BW genes was predictive of interspecies differences in brain size, and bioinformatic annotation revealed enrichment for neurogenesis and cell-cell communication. Genome-wide, transcriptome-wide, and phenome-wide association analyses linked BW gene sets to neuroimaging measurements of brain size and brain-related clinical traits. Cumulatively, these results represent a major step toward delineating the molecular pathways underlying human brain size variation in health and disease.

Summary: Bacillus Calmette-Guérin (BCG) confers heterologous immune protection against viral infections and has been proposed as vaccine against SARS-CoV-2 (SCV2). Here, we tested intravenous BCG vaccination against COVID-19 using the golden Syrian hamster model. BCG vaccination conferred a modest reduction on lung SCV2 viral load, bronchopneumonia scores, and weight loss, accompanied by a reversal of SCV2-mediated T cell lymphopenia, and reduced lung granulocytes. BCG uniquely recruited immunoglobulin-producing plasma cells to the lung suggesting accelerated local antibody production. BCG vaccination also recruited elevated levels of Th1, Th17, Treg, CTLs, and Tmem cells, with a transcriptional shift away from exhaustion markers and toward antigen presentation and repair. Similarly, BCG enhanced recruitment of alveolar macrophages and reduced key interstitial macrophage subsets, that show reduced IFN-associated gene expression. Our observations indicate that BCG vaccination protects against SCV2 immunopathology by promoting early lung immunoglobulin production and immunotolerizing transcriptional patterns among key myeloid and lymphoid populations.

Purpose: The purpose of this study was to evaluate practice patterns of a single surgeon with respect to meniscectomy and meniscal repair over a 20-year period at a single institution. Methods: A cross-sectional descriptive study was carried out by reviewing the surgical data from the past 20 years (2002-2021) of patients who underwent arthroscopic primary meniscal surgery. Age, sex, knee and meniscus affected, morphology of the meniscal tear, meniscal radial location, location on the axial plane, tissue quality, and associated injuries were recorded. An analysis of the evolution of the characteristics of the meniscal lesions was performed according to the presence of degenerative tissue, the repairability of the lesion, and the treatment performed. Categorical data were represented in contingency tables and compared using the χ2 test for significance of differences, which was set at P < .05. Results: In total, 1,892 cases were included. A decrease in degenerative meniscal tears was found, from 63.2 in 2002 to 2006 to 9.7% in 2017 to 2021 (P < .001), while repairable tears increased from 1.6% to 82.3% P < .001); in the same periods, arthroscopic partial meniscectomy procedures declined from 75.7% to 17.7% (P < .001) while meniscal repair increased from 0.4% to 81.3% (P < .001). All types of tears increased significantly their repairability, although longitudinal tears, root tears, and ramp lesions showed the highest possibilities for repair. Conclusions: In the present study, a drastic change in the attitude toward meniscal preservation in the past 20 years was observed, with a large increase in the proportion of tears considered repairable found in primary arthroscopic surgery (to 80% of cases) and a decrease in degenerative meniscus tears (to less than 10%). Clinical Relevance: In the past 2 decades, arthroscopic knee surgery has evolved such that more meniscus tears are deemed repairable, and fewer tears considered degenerative are indicated for arthroscopy.

Objective: To gain mechanistic insights into adverse effects of maternal hyperglycemia on the liver of neonates, we performed a multi-omics analysis of liver tissue from piglets developed in genetically diabetic (mutant INS gene induced diabetes of youth; MIDY) or wild-type (WT) pigs. Methods: Proteome, metabolome and lipidome profiles of liver and clinical parameters of serum samples from 3-day-old WT piglets (n = 9) born to MIDY mothers (PHG) were compared with those of WT piglets (n = 10) born to normoglycemic mothers (PNG). Furthermore, protein–protein interaction network analysis was used to reveal highly interacting proteins that participate in the same molecular mechanisms and to relate these mechanisms with human pathology. Results: Hepatocytes of PHG displayed pronounced lipid droplet accumulation, although the abundances of central lipogenic enzymes such as fatty acid-synthase (FASN) were decreased. Additionally, circulating triglyceride (TG) levels were reduced as a trend. Serum levels of non-esterified free fatty acids (NEFA) were elevated in PHG, potentially stimulating hepatic gluconeogenesis. This is supported by elevated hepatic phosphoenolpyruvate carboxykinase (PCK1) and circulating alanine transaminase (ALT) levels. Even though targeted metabolomics showed strongly elevated phosphatidylcholine (PC) levels, the abundances of multiple key enzymes involved in major PC synthesis pathways – most prominently those from the Kennedy pathway – were paradoxically reduced in PHG liver. Conversely, enzymes involved in PC excretion and breakdown such as PC-specific translocase ATP-binding cassette 4 (ABCB4) and phospholipase A2 were increased in abundance. Conclusions: Our study indicates that maternal hyperglycemia without confounding obesity induces profound molecular changes in the liver of neonatal offspring. In particular, we found evidence for stimulated gluconeogenesis and hepatic lipid accumulation independent of de novo lipogenesis. Reduced levels of PC biosynthesis enzymes and increased levels of proteins involved in PC translocation or breakdown may represent counter-regulatory mechanisms to maternally elevated PC levels. Our comprehensive multi-omics dataset provides a valuable resource for future meta-analysis studies focusing on liver metabolism in newborns from diabetic mothers.

Background and purpose:In radiotherapy, dose calculations based on 4D cone beam CTs (4DCBCTs) require image intensity corrections. This retrospective study compared the dose calculation accuracy of a deep learning, projection-based scatter correction workflow (ScatterNet), to slower workflows: conventional 4D projection-based scatter correction (CBCTcor) and a deformable image registration (DIR)-based method (4DvCT).Materials and methods:For 26 lung cancer patients, planning CTs (pCTs), 4DCTs and CBCT projections were available. ScatterNet was trained with pairs of raw and corrected CBCT projections. Corrected projections from ScatterNet and the conventional workflow were reconstructed using MA-ROOSTER, yielding 4DCBCTSN and 4DCBCTcor. The 4DvCT was generated by 4DCT to 4DCBCT DIR, as part of the 4DCBCTcor workflow. Robust intensity modulated proton therapy treatment plans were created on free-breathing pCTs. 4DCBCTSN was compared to 4DCBCTcor and the 4DvCT in terms of image quality and dose calculation accuracy (dose-volume-histogram parameters and 3%/3mm gamma analysis).Results:4DCBCTSN resulted in an average mean absolute error of 87HU and 102HU when compared to 4DCBCTcor and 4DvCT respectively. High agreement was observed in targets with median dose differences of 0.4Gy (4DCBCTSN-4DCBCTcor) and 0.3Gy (4DCBCTSN-4DvCT). The gamma analysis showed high average 3%/3mm pass rates of 96% for both 4DCBCTSN vs. 4DCBCTcor and 4DCBCTSN vs. 4DvCT.Conclusions:Accurate 4D dose calculations are feasible for lung cancer patients using ScatterNet for 4DCBCT correction. Average scatter correction times could be reduced from 10min (4DCBCTcor) to 3.9s, showing the clinical suitability of the proposed deep learning-based method.

As the recent COVID-19 pandemic has clearly demonstrated, appropriate state support policies are crucial for supporting industrial supply chains during crises to prevent viable businesses from defaulting. In this context, this study proposes a hybrid credit risk model to appropriately size public interventions for viable (worthy) businesses through systematic risk assessment during a period of turmoil. This study discusses the effects of the credit crunch-based economic downturn and proposes a methodology to assist policymakers in managing limited public resources to effectively support industrial supply chains. The proposed approach initially focuses on the dynamics of credit risk during economic recession periods, identifying the conditions that may justify a public intervention strategy based on public guarantees. Subsequently, a hybrid credit risk model is developed to appropriately size public interventions by quantifying systematic risk. Finally, a numerical application is presented to demonstrate the effectiveness of the proposed approach.