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Ocean liming has gained attention as a potential solution to mitigate climate change by actively removing carbon dioxide (CO2) from the atmosphere. The addition of hydrated lime to oceanic surface water leads to an increase in alkalinity, which in turn promotes the uptake and sequestration of atmospheric CO2. Despite the potential of this technique, its effects on the marine ecosystem are still far from understood, and there is currently no information on the potential impacts on the concentration and quality of dissolved organic matter (DOM), which is one of the largest, most complex and yet least understood mixtures of organic molecules on Earth. The aim of this study is to provide the first experimental evidence about the potential effects of hydrated lime addition on DOM dynamics in the oceans by assessing changes in its concentration and optical properties (absorption and fluorescence). To investigate the effects of liming on DOM pools with different concentrations and quality, seawater was collected from two contrasting environments: the oligotrophic Mediterranean Sea, known for its dissolved organic carbon (DOC) concentration comparable to that observed in the oceans, and the eutrophic Baltic Sea, characterized by high DOM concentration mostly of terrestrial origin. Hydrated lime was added to both waters to reach pH values of 9 and 10. Our findings reveal that the addition of hydrated lime has a noticeable effect on DOM dynamics in both the Mediterranean Sea and Baltic Sea, determining a reduction in DOC concentration and a change in the optical properties (absorption and fluorescence) of DOM. These effects, detectable at pH 9, become significant at pH 10 and are more pronounced in the Mediterranean Sea than in the Baltic Sea. These potential short-term effects should be considered within the context of the physicochemical properties of seawater and the seasonal variability.

Abstract Patients with HER2(+) early breast cancer (EBC) receiving neoadjuvant systemic therapy (NAST) have poorer outcomes if they have residual disease (RD). We analyzed IDFS and brain metastasis (BM) rates in patients with HER2(+) EBC treated with NAST and report the outcomes of patients with HER2(−) RD. Patients with HER2(+) EBC who received NAST between 1 Jan 2019 and 31 Jan 2022 were reviewed. IDFS was defined as the time from surgery until first occurrence of invasive breast cancer recurrence, distant recurrence, or death from any cause. The total cohort was 594 patients. pCR (ypT0/isN0) was achieved in 325(55%) and RD was seen in 269(45%) patients. In 269 patients with RD, 45(17%) did not have HER2 retesting and were excluded. In the remaining 224 patients, 143(64%) were HER2(+) and 81(36%) were HER2(−). With a median follow up of 24 months, 8 patients developed BM at initial recurrence, 4/325(1.2%) with pCR and 4/143(2.8%) with HER2(+) RD. IDFS events occurred in 22/594(3%) patients; 14/269(5%) in RD and 8/325(2%) in pCR (p = 0.04). There was no difference in IDFS between 9/143(6%) patients with HER2(+) RD or 5/81(6%) with HER2(−) RD (p = 0.10). Patients with RD had higher IDFS events than those with pCR. In those with RD, 36% lost HER2(+) status; IDFS events appeared similar in those with HER2(+) RD versus those with HER2(−) RD. The BM events seen in those with RD and pCR highlights the need for more effective therapy in NAST and adjuvant setting to minimize BM risk.

Abstract Wildlife tagging provides critical insights into animal movement ecology, physiology, and behavior amid global ecosystem changes. However, the stress induced by capture, handling, and tagging can impact post-release locomotion and activity and, consequently, the interpretation of study results. Here, we analyze post-tagging effects on 1585 individuals of 42 terrestrial mammal species using collar-collected GPS and accelerometer data. Species-specific displacements and overall dynamic body acceleration, as a proxy for activity, were assessed over 20 days post-release to quantify disturbance intensity, recovery duration, and speed. Differences were evaluated, considering species-specific traits and the human footprint of the study region. Over 70% of the analyzed species exhibited significant behavioral changes following collaring events. Herbivores traveled farther with variable activity reactions, while omnivores and carnivores were initially less active and mobile. Recovery duration proved brief, with alterations diminishing within 4–7 tracking days for most species. Herbivores, particularly males, showed quicker displacement recovery (4 days) but slower activity recovery (7 days). Individuals in high human footprint areas displayed faster recovery, indicating adaptation to human disturbance. Our findings emphasize the necessity of extending tracking periods beyond 1 week and particular caution in remote study areas or herbivore-focused research, specifically in smaller mammals.

Abstract Resembling the morphology of Japanese polyp vessels, the classic form of Takotsubo cardiomyopathy is characterized by the presence of systolic dysfunction of the mid-apical portion of the left ventricle associated with basal hyperkinesia. It is believed that this may be due to a higher density of β-adrenergic receptors in the context of the apical myocardium, which could explain the greater sensitivity of the apex to fluctuations in catecholamine levels. The syndrome is precipitated by significant emotional stress or acute severe pathologies, and it is increasingly diagnosed during the perioperative period. Indeed, surgery, induction of general anaesthesia and critical illness represent potential harmful trigger of stress cardiomyopathy. No universally accepted guidelines are currently available, and, generally, the treatment of TTS relies on health care personal experience and/or local practice. In our daily practice, anaesthesiologists can be asked to manage patients with the diagnosis of new-onset Takotsubo before elective surgery or an emergent surgery in a patient with a concomitant stress cardiomyopathy. Even more, stress cardiomyopathy can arise as a complication during the operation. In this paper, we aim to provide an overview of Takotsubo syndrome and to discuss how to manage Takotsubo during surgery and in anaesthesiologic special settings.

Background: The bleeding risk of patients with atrial fibrillation (AF) changes over time. Most studies thus far evaluated only the baseline bleeding risk with discordant results. The impact of incident thrombocytopenia during direct oral anticoagulant (DOAC) therapy and its relation to bleeding has not been previously investigated. Objectives: To investigate the incidence rate of thrombocytopenia and major bleeding (MB) risk in AF patients on DOACs. Methods: Prospective ongoing ATHEROsclerosis in Atrial Fibrillation study including patients with nonvalvular AF on DOACs. Incident thrombocytopenia was defined as a platelet count

Background: We estimated the diagnostic accuracy of urinary NGAL for the diagnosis of AKI. Methods: Urinary NGAL and Creatinine were measured daily for up to 3 days. Doppler ultrasonography was performed within 24 h of admission and for the following 3 days. Results: Of the 21 patients, 44% had AKI during their ICU stay. The AKI group presented with higher values of serum Creatinine, renal length, MDRD as well as SAPS II already at admission. Urinary NGAL was significantly higher among patients with AKI and patients AKI-no at T0 (p < 0.0001) and increased steadily on T1 and T2. Urinary NGAL seemed to be a notable diagnostic marker for AKI from the first measurement (T0) with an area under the ROC of 0.93 (95% CI = 0.78–0.99) with a sensitivity of 99%. RRI levels were slightly higher in the AKI group at each time and increased gradually from T0 to T2 but reached statistical significance only at T2 (p = 0.02). Renal length and SAPS II at T0 showed high AuRoc and sensitivity. Conclusions: Urinary NGAL is a valuable marker for AKI in intensive care settings. It seemed that a pre-existing chronic renal disease, the SAPS II and the NGAL at admission represented the principal predictors of AKI.

Recently, there has been a growing focus on sustainability issues within the financial sector. However, quantitative analysis of social and governance aspects has been challenging due to difficulties in data modelling. With the recent regulatory updates for standardised disclosure, the next step could be the implementation of stress tests, given their widespread use in the supervisory environment. The article analyses the possibility of borrowing certain aspects of rating agency methodologies for a future exercise. It identifies common elements that need to be analyzed and highlights areas where institutional intervention will be necessary.

Abstract The influence of deep and regional geological structures is becoming increasingly important in superhot geothermal systems due to their proximity to the transition between brittleness and ductility. In the Los Humeros geothermal field in Mexico, where subsurface fluids reach temperatures of over 350 °C, the surface structures resulting from the collapse of calderas have so far only been interpreted at the local scale. The aim of this work is to place the recent tectonic and volcano-tectonic geomorphologic evolution and structures in the Los Humeros volcanic area in a regional context. NE- and NW-striking dominant structures resulting from a morpho-structural analysis on a regional scale are confirmed by negative and positive anomalies, respectively, after Butterworth filtering of gravity field data with different wavelengths over a local area of about 1000 km2. By analyzing the slip and dilation trends of the observed directions, we show the relevance of the regional context for reservoir exploration. The magnitudes of the principal stresses we estimate indicate a trans-tensional fault regime, a combination of strike-slip and normal faulting. The structures derived from the gravity and morpho-structural analyses, which are parallel to the maximum horizontal stress, have the highest potential for tensile and shear failure. Therefore, the corresponding negative gravity anomalies could be related to fracture porosity. Consequently, we hypothesize that these structures near the transition between brittleness and ductility control fluid flow in the Los Humeros geothermal field.

Human epidermal growth factor receptor 2 (HER2) gene amplification and subsequent protein overexpression is a strong prognostic and predictive biomarker in invasive breast carcinoma (IBC). ASCO/CAP recommended tests for HER2 assessment include immunohistochemistry (IHC) and/or in situ hybridization (ISH). Accurate HER2 IHC scoring (0, 1+, 2+, 3+) is key for appropriate classification and treatment of IBC. HER2-targeted therapies, including anti-HER2 monoclonal antibodies and antibody drug conjugates (ADC), have revolutionized the treatment of HER2-positive IBC. Recently, ADC have also been approved for treatment of HER2-low (IHC 1+, IHC 2+/ISH-) advanced breast carcinoma, making a distinction between IHC 0 and 1+ crucial. In this focused study, 32 IBC with HER2 IHC scores from 0 to 3+ and HER2 FISH results formed a calibration dataset, and 77 IBC with HER2 IHC score 2+ and paired FISH results (27 amplified, 50 non-amplified) formed a validation dataset. H&E and HER2 IHC whole slide images (WSI) were scanned. Regions of interest were manually annotated and IHC scores generated by the software QuantCenter (MembraneQuant application) by 3DHISTECH Ltd. (Budapest, Hungary) and compared to the microscopic IHC score. H-scores [(3×%IHC3+) +(2×%IHC2+) +(1×%IHC1+)] were calculated for semi-automated (MembraneQuant) analysis. Concordance between microscopic IHC scoring and 3DHISTECH MembraneQuant semi-automated scoring in the calibration dataset showed a Kappa value of 0.77 (standard error 0.09). Microscopic IHC and MembraneQuant image analysis for the detection of HER2 amplification yielded a sensitivity of 100% for both and a specificity of 56% and 61%, respectively. In the validation set of IHC 2+ cases, only 13 of 77 cases (17%) had discordant results between microscopic and MembraneQuant images, and various artifacts limiting the interpretation of HER2 IHC, including cytoplasmic/granular staining and crush artifact were noted. Semi-automated analysis using WSI and microscopic evaluation yielded similar HER2 IHC scores, demonstrating the potential utility of this tool for interpretation in clinical practice and subsequent accurate treatment. In this study, it was shown that semi-automatic HER2 IHC interpretation provides an objective approach to a test known to be quite subjective.

Background: Atrial fibrillation (AF) is associated with an increased risk of hospital admission, but few data on reasons for hospitalization and on the role of anti-arrhythmic drugs are available. Objectives: The purpose of this study was to investigate the incidence rate and factors associated with all-cause, cardiovascular, and AF-related hospitalizations. Methods: Prospective ongoing ATHERO-AF (Atherosclerosis in Atrial Fibrillation) cohort study enrolling AF patients on oral anticoagulants. Primary end points were all-cause, cardiovascular, and AF-related hospitalization, the latter defined as AF recurrences for paroxysmal AF and high-rate symptomatic AF episodes for persistent/permanent AF patients. Results: 2,782 patients were included (43.5% female; mean age was 74.6 ± 9.1 years). During a mean follow-up of 31 ± 26.8 months, 1,205 (12.1%/year) all-cause, 533 cardiac (5.7%/year), and 180 (2.0%/year) AF-related hospitalizations occurred. Predictors of AF-related hospitalizations were the use of flecainide/propafenone in both paroxysmal and persistent/permanent AF patients (HR: 1.861; 95% CI: 1.116 to 3.101 and 1.947; 95% CI: 1.069 to 3.548, respectively). Amiodarone (HR: 3.012; 95% CI: 1.835-4.943), verapamil/diltiazem (HR: 2.067; 95% CI: 1.117-3.825), and cancer (HR: 1.802; 95% CI: 1.057-3.070) but not beta-blockers and digoxin were associated with an increased risk of AF-related hospitalizations in persistent/permanent AF patients. Conclusions: Elderly AF patients frequently undergo hospitalizations for both cardiovascular and noncardiovascular causes. The use of anti-arrhythmic drugs was associated with an increased risk of AF-related hospitalization suggesting a scarce effect of these drugs in preventing AF episodes. Therefore, their use should be carefully considered and reserved for symptomatic patients with frequent AF recurrences.

Microservices gained momentum in enterprise IT, as they enable building cloud-native applications. At the same time, they come with new security challenges, including security smells, viz., symptoms of bad (though often unintentional) design decisions that might affect application security. This study aims to explore the impacts of microservice security smells –and of the refactorings known to mitigate their effects– beyond security. In particular, we systematically elicit possible impacts of smells and refactorings on applications’ maintainability, performance efficiency, and adherence to microservices’ key design principles. We then validate the elicited impacts through an online survey targeting experienced practitioners and researchers. Our main contributions include 35 validated impacts and a discussion of the survey results geared towards analyzing the (mis)alignment between practitioners and researchers. Finally, we also provide a holistic view of these impacts, through Softgoal Interdependency Graphs (SIGs).

The sensing of left ventricular (LV) activity is fundamental in the diagnosis and monitoring of cardiovascular health in high-risk patients after cardiac surgery to achieve better short- and long-term outcome. Conventional approaches rely on noninvasive measurements even if, in the latest years, invasive microelectromechanical systems (MEMS) sensors have emerged as a valuable approach for precise and continuous monitoring of cardiac activity. The main challenges in designing cardiac MEMS sensors are represented by miniaturization, biocompatibility, and long-term stability. Here, we present a MEMS piezoresistive cardiac sensor capable of continuous monitoring of LV activity over time following epicardial implantation with a pericardial patch graft in adult minipigs. In acute and chronic scenarios, the sensor was able to compute heart rate with a root mean square error lower than 2 BPM. Early after up to 1 month of implantation, the device was able to record the heart activity during the most important phases of the cardiac cycle (systole and diastole peaks). The sensor signal waveform, in addition, closely reflected the typical waveforms of pressure signal obtained via intraventricular catheters, offering a safer alternative to heart catheterization. Furthermore, histological analysis of the LV implantation site following sensor retrieval revealed no evidence of myocardial fibrosis. Our results suggest that the epicardial LV implantation of an MEMS sensor is a suitable and reliable approach for direct continuous monitoring of cardiac activity. This work envisions the use of this sensor as a cardiac sensing device in closed-loop applications for patients undergoing heart surgery.

Abstract CDH1 (E-cadherin) bi-allelic inactivation is the hallmark alteration of breast invasive lobular carcinoma (ILC), resulting in its discohesive phenotype. A subset of ILCs, however, lack CDH1 genetic/epigenetic inactivation, and their genetic underpinning is unknown. Through clinical targeted sequencing data reanalysis of 364 primary ILCs, we identified 25 ILCs lacking CDH1 bi-allelic genetic alterations. CDH1 promoter methylation was frequent (63%) in these cases. Targeted sequencing reanalysis revealed 3 ILCs harboring AXIN2 deleterious fusions (n = 2) or loss-of-function mutation (n = 1). Whole-genome sequencing of 3 cases lacking bi-allelic CDH1 genetic/epigenetic inactivation confirmed the AXIN2 mutation and no other cell-cell adhesion genetic alterations but revealed a new CTNND1 (p120) deleterious fusion. AXIN2 knock-out in MCF7 cells resulted in lobular-like features, including increased cellular migration and resistance to anoikis. Taken together, ILCs lacking CDH1 genetic/epigenetic alterations are driven by inactivating alterations in other cell adhesion genes (CTNND1 or AXIN2), endorsing a convergent phenotype in ILC.

The Metaverse is a three-dimensional digital space where users interact and communicate through their avatars, creating a sense of presence and immersion. The use of avatars allows to convey body language and to establish an object-based dialogue, improving the expressiveness of communication between users. However, existing metaverses are limited to digital interaction, as the avatar is not able to touch, perceive, grasp or manipulate the physical objects surrounding the remote interlocutor. In a previous work, we laid the foundation for the “Avatarm”, an avatar able to manipulate both the physical and the digital worlds. This was achieved through a robotic manipulator that remains hidden from the user’s view by means of diminished reality techniques. Building upon this groundwork, in this work we have advanced the capabilities of the Avatarm with the integration of force and vibrotactile haptic feedback, empowering the user to tangibly perceive manipulated objects, and gain a heightened sense of situational awareness. In addition, to increase the realism of the interaction, we have implemented a robot control algorithm capable of matching the position and orientation of physical objects with their digital counterparts. Furthermore, a digital avatar has been integrated into the augmented environment along with a newly designed virtual hand for more realistic manipulation of virtual objects. The enhanced version of the “Physical Metaverse” is tested in this work through an extensive experimental campaign considering both objective and subjective measures of performance.

Human leishmaniasis is facing important epidemiological changes in Southern Europe, driven by increased urbanization, climate changes, emerging of new animal reservoirs, shifts in human behavior and a growing population of immunocompromised and elderly individuals. In this evolving epidemiological landscape, we analyzed the clinical and epidemiological characteristics of human leishmaniasis in the Tuscany region of Central Italy. Through a multicentric retrospective analysis, we collected clinical and demographic data about all cases of leishmaniasis recorded between 2018 and 2023. We observed 176 cases of human leishmaniasis, with 128 (72.7%) visceral leishmaniasis (VL) and 47 (26.7%) cutaneous leishmaniasis (CL). Among these, 92.2% of VL and 85.1% of CL cases were autochthonous. The cumulative incidence of autochthonous human leishmaniasis was 0.22 cases per 100,000 inhabitants in 2018, but reached 1.81/100,000 in 2023. We identified three main areas of transmission: around the city of Florence (North-East Tuscany), around Grosseto city (South-West Tuscany) and Elba Island. Our findings confirm that the epidemiology of leishmaniasis is undergoing significant changes in Central Italy. Awareness towards this emerging health threat and surveillance strategies need to be improved in order to reliably assess the disease’s burden. Further research is needed in a “One-Health” perspective, to clarify the epidemiological dynamics at the environmental, reservoir, vector and human levels. The role of climate change and specific climatic factors affecting the epidemiological patterns of human leishmaniasis should be assessed. Further knowledge in these fields would promote targeted control and prevention strategies at regional and national levels.

Introduction: Recently, a flow cytometric (FC) based test has been developed for detection of circulating fetal cells to replace the less accurate and reproducible Kleihauer-Betke test.FC test is easier to perform, it can distinguish the origin of fetal cells, but it is expensive and available in highly specialized laboratories. We evaluated the introduction of high-performance liquid chromatography (HPLC) approach as initial screening to identify patients who need an additional FC test to better discriminate the nature of haemoglobin-F (HbF) positive cells. Methods: Blood samples from 130 pregnant women suspected to have fetomaternal haemorrhage were analysed with HPLC and FC methods. The cut-off for HbF HPLC concentration was calculated. Statistical analyses for the evaluation of HPLC as a screening method were performed. The positivity cut-off of HbF to be used as decision-making value to continue the investigation was calculated. Results: An excellent agreement (R2 > 0.90) was observed between the percentage of HbF obtained by HPLC and the percentage of fetal cells detected by FC. Results obtained from each assay were compared to define the HPLC threshold below which it is not necessary to continue the investigations, confirming the maternal nature of the HbF positive cells detected. Our study demonstrated that a cut-off of 1.0 % HbF obtained by HPLC was associated with the lowest rate of false negative results in our patient cohort. Conclusions: This study provides a new FMH investigation approach that possibly leads to a reduction in times and costs of the analysis.

Objective: To convert manual ELISA kits to fully automated immunoassays that quantify serum drug levels and anti-drug antibodies levels of infliximab and adalimumab (CHORUS Promonitor kits). Desing and methods: CHORUS Promonitor INFLIXIMAB, CHORUS Promonitor ADALIMUMAB, CHORUS Promonitor ANTI-INFLIXIMAB, and CHORUS Promonitor ANTI-ADALIMUMAB kits were compared with the corresponding Promonitor kits to determine sensitivity and specificity of the assays. For the automated assays, the entire procedure -from samples dilution to final readouts-was performed by CHORUS TRIO instrument (DIESSE, Italy). Residual human serum samples from clinical laboratory investigations and samples resulting from the addition of specific drugs (IFX or ADL) or anti-drug antibodies (anti-IFX or anti-ADL) were used for the characterization and validation of the tests. Results: CHORUS Promonitor kits showed an excellent agreement (Cohen's coefficient = 1) with the Promonitor kits and were linear within predefined ranges. All assays were accurate and repeatable, as an acceptable variability were observed within runs, between runs, lots, and instruments. No difference in detecting the reference drug or biosimilars emerged. Conclusion: During preclinical development, these kits resulted as sensitive, specific, accurate, and able to quantify either the reference drug or the corresponding biosimilars. All these features support their use in clinical practice for therapeutic drug monitoring of patients with inflammatory diseases under treatment with IFX or ADL.