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Abstract In the last years, major progress has occurred in heart failure (HF) management. The 2023 ESC focused update of the 2021 HF guidelines introduced new key recommendations based on the results of the last years of science. First, two drugs, sodium–glucose co‐transporter‐2 (SGLT2) inhibitors and finerenone, a novel nonsteroidal, selective mineralocorticoid receptor antagonist (MRA), are recommended for the prevention of HF in patients with diabetic chronic kidney disease (CKD). Second, SGLT2 inhibitors are now recommended for the treatment of HF across the entire left ventricular ejection fraction spectrum. The benefits of quadruple therapy in patients with HF with reduced ejection fraction (HFrEF) are well established. Its rapid and early up‐titration along with a close follow‐up with frequent clinical and laboratory re‐assessment after an episode of acute HF (the so‐called ‘high‐intensity care’ strategy) was associated with better outcomes in the STRONG‐HF trial. Patients experiencing an episode of worsening HF might require a fifth drug, vericiguat. In the STEP‐HFpEF‐DM and STEP‐HFpEF trials, semaglutide 2.4 mg once weekly administered for 1 year decreased body weight and significantly improved quality of life and the 6 min walk distance in obese patients with HF with preserved ejection fraction (HFpEF) with or without a history of diabetes. Further data on safety and efficacy, including also hard endpoints, are needed to support the addition of acetazolamide or hydrochlorothiazide to a standard diuretic regimen in patients hospitalized due to acute HF. In the meantime, PUSH‐AHF supported the use of natriuresis‐guided diuretic therapy. Further options and most recent evidence for the treatment of HF, including specific drugs for cardiomyopathies (i.e., mavacamten in hypertrophic cardiomyopathy and tafamidis in transthyretin cardiac amyloidosis), device therapies, cardiac contractility modulation and percutaneous treatment of valvulopathies, with the recent finding from the TRILUMINATE Pivotal trial, are also reviewed in this article.

Abstract Recently, modular multilevel converters (MMCs) gained popularity for the grid integration of photovoltaic (PV), due to their many advantages, including low total harmonic distortion, high control flexibility, and distributed maximum power point (MPP) tracking capability. Two distinguished families of MMCs exist: voltage source and current source. Voltage source MMCs are mostly studied, but current source MMCs offer advantages under certain operating conditions. This article compares voltage and current source MMCs, for PV integration. To this aim, several key indicators are identified: number of components, energy stored in passive elements, semiconductor power rating, and the number of MPP trackers. The results of the analysis, performed in MATLAB©, show that for a fixed number of output voltage levels, power rating, and switching frequency, voltage source MMCs have simpler control and higher number of MPP trackers. In contrast, current source MMCs minimize the semiconductor power rating, the number of components and the energy stored in passive elements. Regarding efficiency, in the analyzed case study, voltage source MMCs perform better under both homogeneous and non‐homogenous irradiance conditions. This article provides a tool to select the optimal solution based on the required target (e.g. efficiency, energy storage etc.), given the specific characteristics of the application.

Abstract In the last three decades, ablation of atrial fibrillation (AF) has become an evidence‐based safe and efficacious treatment for managing the most common cardiac arrhythmia. In 2007, the first joint expert consensus document was issued, guiding healthcare professionals involved in catheter or surgical AF ablation. Mounting research evidence and technological advances have resulted in a rapidly changing landscape in the field of catheter and surgical AF ablation, thus stressing the need for regularly updated versions of this partnership which were issued in 2012 and 2017. Seven years after the last consensus, an updated document was considered necessary to define a contemporary framework for selection and management of patients considered for or undergoing catheter or surgical AF ablation. This consensus is a joint effort from collaborating cardiac electrophysiology societies, namely the European Heart Rhythm Association, the Heart Rhythm Society, the Asia Pacific Heart Rhythm Society, and the Latin American Heart Rhythm Society

Abstract Due to the central role of landscape connectivity in many ecological processes, evaluating and accounting for it has gained attention in both theoretical and applied ecological sciences. To address this challenge, researchers often use generic species to simplify multi‐species connectivity assessments. Yet, this approach tends to oversimplify movement behaviour, likely reducing realism and precision of connectivity model outputs. Also, the most widely used methods and theories for assessing landscape connectivity, namely circuit and network theories, have strong limitations. Finally, uncertainty or robustness estimates are rarely integrated in connectivity assessments. Here, we propose a versatile framework, which, instead of using arbitrary defined generic species, first identifies species groups based on species' environmental niches and morphological, biological, and ecological traits. Second, it combines circuit and network theories to take the best of the two methods to assess landscape connectivity for those groups, while integrating uncertainties in modelling choices. Specifically, ecological continuities (i.e. landscape elements contributing to connectivity) are calculated for these groups and used together with group dispersal capacities to derive network‐based connectivity metrics for conservation areas. We detailed our framework through a case study where we assess the connectivity of 1619 protected areas in metropolitan France for 193 vertebrate species. Our study revealed that both the protection of ecological continuities and the connectivity of protected areas for 11 mammal and 19 bird groups, respectively, were quite low, with variations among groups. Different protection types (i.e. national parks, reserves or prefectural orders) contributed unequally to the overall connectivity of group‐specific suitable habitats. Considering uncertainty propagation was crucial, as many connectivity metrics varied among repetitions. The proposed framework combines different connectivity tools to provide a more relevant and comprehensive assessment of landscape connectivity. It can be used to inform the decision‐making process for spatial planning, particularly in the context of connectivity conservation and management, or support theoretical studies to better understand the ecological role of landscape connectivity. Its flexibility allows easy application under various environmental conditions, including future scenarios.

The 23rd FEBS YSF was held from 26th to 29th June 2024 in Pavia, Italy. Over 100 PhD students and early postdoctoral researchers from around 30 different countries came together at the inspiring rooms of the University of Pavia for a four‐day event. This year's topic was ‘Biochemistry for bridging the gap’, meaning the opportunity to have a comprehensive perspective on all biochemistry applications. Four renowned keynote speakers presented their latest research, accompanied by four career‐focused speakers, as well as additional sessions on academic career opportunities, including fellowships, women in science, and laboratory sustainability. Additionally, 10 selected YSF participants gave short talks to a large audience, while the remaining attendees shared their research findings through flash talks and two dedicated poster sessions. Scientific exchange and networking were encouraged during the poster sessions, breaks, and the social events. The meeting was a prelude before attending the 48th FEBS congress, celebrated in Milan. The success of the series will be continued during the 24th YSF edition: ‘Inspired by nature, driven by science’, which will take place from 2nd to 5th July 2025 in Sapanca, Türkiye.

Abstract Background Solid organ transplant recipients (SOTRs) have an increased risk of developing non melanoma skin cancers (NMSCs). The use of Imiquimod, a toll‐like‐receptor agonist, is still debated in SOTRs. Objectives The aim of this study was to evaluate efficacy and safety of topical Imiquimod in two Dermatology Centres for skin cancers in SOTRs. Methods All SOTRs with age > 18 and a dermoscopic diagnosis of superficial basal cell carcinoma (BCC) and/or actinic keratose (AK), annually followed up between January 2022 and December 2022 were screened. Results 80 NMSCs (41 BCC and 39 AK) in 66 SOTRs were identified and treated. 57 (86.4%) were male. The mean age was 66.2 years (30−85). 60 patients (90.1%) had transplanted kidney, 1 (1.5%) lung, 3 (4.5%) liver, and 1 (1.5%) heart. The average time since first transplant was 17 years (3−40 years). Tacrolimus, steroids, and mycophenolate mofetil were the most frequently used immunosuppressants (71%; 67.7%; 53.2% of cases, respectively). Responses to the first course of treatment were CR in 64.3% of cases (53.6% in AK; 67.7% in BCC); PR in 28.6% of cases (42.9% in AK; 12.9% in BCC); NR in 12.5% of cases (3.6% in AK; 19.4% in BCC). Fourteen patients received a second course of imiquimod for a persistent lesion (1 AK, 4 BCC) or a new lesion (4 AK, 5 BCC). Responses to the second course of treatment were observed in 4 (80%) and 7 (78%) cases in the persistent and new lesion, respectively (p = 0.34). No systemic adverse events were noted. The main side effects were mild: erythema, scales, and crusts, itching, or pain. Conclusions Topical imiquimod represents a viable and safe option in this category of patients. The response to imiquimod in subjects who have had more than one cycle is not related to the response to previous treatments but rather to the intrinsic characteristics of the lesion.

Societal Impact Statement Arbuscular mycorrhizal fungi (AMF) impact the relationships between plants, aphids (insects that feed on plant phloem), and their natural enemies (insects that prey on or parasitize aphids). The presence of AMF influences the growth and population of different aphid species and affects the development of aphid‐killing wasps and their attraction to plants. This research has been conducted also considering the insects' feeding strategy and their feeding specialization. This study provides novel perspectives on how these fungi shape interactions in the natural world, offering potential insights for the development of sustainable pest management strategies in agriculture. Summary Arbuscular mycorrhizal fungi (AMF) are major root symbionts regulating plant physiology. Their presence affects the performance of aboveground insect herbivores in relation to their feeding strategy and their feeding specialization. For example, the effect of the arbuscular mycorrhizal (AM) symbiosis on chewing insects, positive for specialists and negative for generalists, has been previously demonstrated. Conversely, the impact of AMF on phloem‐suckers with relatively different levels of specialization remains unexplored. We tested the influence of the AM Funneliformis mosseae on the fitness of the specialist aphid Acyrthosiphon pisum and the generalist aphid Myzus persicae on Vicia faba plants. Further, we investigated the effects of AMF on the higher trophic level, the aphid parasitoids Aphidius ervi (specialist) and Aphidius colemani (generalist), by evaluating plant attractiveness and parasitoid fitness. To support the results of behavioral and biological bioassays we characterized the photosynthetic parameters, the volatilome and the transcriptome of tested plants. Mycorrhizal plants proved unsuitable for the generalist M. persicae but enhanced the fitness of the specialist A. pisum. The AM symbiosis had no effects on the behavioral response of A. colemani and enhanced the attraction and fitness of A. ervi. Volatilome and transcriptome profiling corroborated the results of bioassay highlighting a bottom‐up effect of the AMF across a plant–aphid–parasitoid system.

Abstract Background Cardiogenic shock (CS) is associated with high in‐hospital mortality. Objective assessment of its severity and prognosis is paramount for timely therapeutic interventions. This study aimed to evaluate the efficacy of the shock index (SI) and its variants as prognostic indicators for in‐hospital mortality. Methods A retrospective study involving 1282 CS patients were evaluated. Baseline patient characteristics, clinical trajectory, hospital outcomes, and shock indices were collected and analysed. Receiver operating characteristic (ROC) curves were employed to determine the predictive accuracy of shock indices in predicting in‐hospital mortality. Results Of those evaluated, 866 (67.6%) survived until discharge. Non‐survivors were older (66.0 ± 13.7 vs. 57.4 ± 16.2, P

Abstract The seismic‐electromagnetic phenomenon entails the generation of transient electromagnetic signals, which can be observed both simultaneously (co‐seismic) and preceding (pre‐seismic) a seismic wave arrival. Following the most accredited hypothesis, these signals are mainly due to electrokinetic effects, generated on microscopic scale in porous media containing electrolytic fluids. Thus, the seismic‐electromagnetic signals are expected to be suitable for the detection and tracking of crustal fluids. Despite the growing interest in this phenomenon, there is a lack of freely available observational database of earthquake‐related electromagnetic signals recorded at co‐located seismic and magnetotelluric stations. To fill this gap, we set up two multicomponent monitoring stations in two seismically active areas of Southern Italy: the Gargano Promontory and the High Agri Valley. This work is both aimed to systematically analyse earthquake‐generated seismic‐electromagnetic recordings and to make the collected database accessible to the scientific community.

Abstract Clinical bleeding events are reported here from 773 patients with B‐cell malignancies receiving pirtobrutinib monotherapy from the phase 1/2 BRUIN study (ClinicalTrials.gov identifier: NCT03740529), either in the presence or absence of antithrombotic therapy (antithrombotic exposed [AT‐E], n = 216; antithrombotic nonexposed [AT‐NE], n = 557). Among the AT‐E cohort, 51.9% received platelet aggregation inhibitors, 36.6% received direct factor Xa inhibitors, 18.5% received heparins, 5.6% received salicylic acid for indications other than platelet aggregation inhibition, and 2.3% received thrombolytics. Warfarin was not permitted. Any‐grade bleeding/bruising events occurred in 97 patients (44.9%; 95% confidence interval [CI], 38.3–51.5) in the AT‐E cohort and 181 patients (32.5%; 95% CI, 28.6–36.4) in the AT‐NE cohort. Most bleeding/bruising events in both cohorts began within the first 6 months of treatment (AT‐E: 65.4%; AT‐NE: 72.5%). Contusion was the most common bleeding/bruising event in both cohorts (AT‐E: 22.7%; AT‐NE: 18.1%). Grade ≥3 bleeding/bruising events were reported in six patients (2.8%) in the AT‐E cohort and 11 patients (2.0%) in the AT‐NE cohort. Bleeding/bruising events requiring or prolonging hospitalization were reported in 2.3% and 1.6% of patients in the AT‐E and AT‐NE cohorts, respectively. No bleeding/bruising events led to pirtobrutinib dose reduction or permanent discontinuation in the AT‐E cohort, and one patient (0.2%) in the AT‐NE cohort experienced an event requiring dose reduction. These data support the safety of pirtobrutinib in patients requiring antithrombotic therapies.

Abstract Objectives To analyse and compare the functionality of extraluminal and intraluminal artificial urinary sphincters (AUSs), an in silico procedure has been defined and applied. Design and reliability assessments of the AUS are typically performed using a clinical approach, which does not provide data on mechanical stimulation of urethral tissues. Mechanical stimulation may determine tissue degeneration, such as urethral atrophy or erosion, the main causes of AUS failure. In silico techniques can provide a quantitative description of stress and strain fields due to the interaction between tissues and AUS and allow investigating an extremely large number of situations, considering different configurations of AUS and urethra. Materials and Methods Computational investigations were carried out to evaluate the mechanical reliability of the main extraluminal and intraluminal AUS, AMS 800 and Relief. The lower urinary tract was modelled based on previous experiments. The AUS models took into account the main components that interact with biological tissues. Urethra and AUS models were coupled and used to investigate mechanical stimulation of urethral tissues. Results In silico simulations provide quantitative information about the mechanical stimulation of urethral tissue, such as compressive strain and stress and hydrostatic pressure, due to interaction with the AUS. Such mechanical quantities allow a comparison of reliability between extraluminal and intraluminal devices. Conclusions The activities define and demonstrate the effectiveness of a novel in silico approach to the design and reliability assessment of AUS devices, increasing the investigative possibilities and reducing the time, ethical and economic costs.

ABSTRACT This study investigates climate change impacts on spontaneous vegetation, focusing on the Mediterranean basin, a hotspot for climatic changes. Two case study areas, Monti Sibillini (central Italy, temperate) and Sidi Makhlouf (Southern Tunisia, arid), were selected for their contrasting climates and vegetation. Using WorldClim's CMCC‐ESM2 climate model, future vegetation distribution was predicted for 2050 and 2080 under SSP 245 (optimistic) and 585 (pessimistic) scenarios. Two spectral indices, NDVI (temperate area) and SAVI (arid area), served as vegetation proxies, classified into three classes using K‐means (NDVI: high = mainly associated with woodlands, medium = shrublands, continuous grasslands and crops, low = discontinuous grasslands, bare soil, and rocks; SAVI: high = mainly associated with woods, olive trees, and crops, medium = shrublands and sparse olive trees, low = bare soil and saline areas). Classes validated with ESA WorldCover 2020 data and sampled via 1390 presence‐only points. A set of 33 environmental variables (topography, soil, and bioclimatic) was screened using Pearson correlation matrices, and predictive models were built using four algorithms: MaxEnt, Random Forest, XG Boost, and Neural Network. Results revealed increasing temperatures and declining precipitation in both regions, confirming Mediterranean climate trends. Vegetation changes varied by area: in the temperate area, woodlands and shrublands were stable, but discontinuous grasslands expanded. In the arid area, woodlands gained suitable habitat, while bare soil declined under the pessimistic SSP 585 scenario. Both areas showed an upward shift for shrublands and grasslands. The models indicated significant shifts in areal distribution and environmental conditions, affecting habitat suitability and ecosystem dynamics. MaxEnt emerged as the most reliable algorithm for small presence‐only datasets, effectively predicting habitat suitability. The findings highlight significant vegetation redistribution and altered ecosystem dynamics due to climate change, underscoring the importance of these models in planning for future ecological challenges.

Conclusion: Ethnicity and SES may be associated with differential risk of development and progression of DN and DR. The available evidence was limited by the number of studies and small samples for certain ethnic/socioeconomic groups.

Abstract The achievement of a carbon‐neutral energy economy is nowadays mandatory to face global warming and the current energy crisis. To mitigate the present and future environmental issues, replacing fossil feedstocks with renewable sources is of primary importance, aiming to meet future generations' demands for energy and commodities. In light of this, the revamp of the ammonia synthesis, which today consumes almost 2% of the energy globally produced, gained increasing interest. The ammonia generation by reacting air and water and using sunlight as an inexhaustible source of energy is the closest approach to the ideal situation for zero‐carbon energy and chemical production. To promote solar‐to‐ammonia production, the photocatalyst plays a crucial role. However, for large‐scale implementation and long‐term utilization, the selection of noncritical raw materials in catalyst preparation is central aiming at resource security. In this context, herein are reviewed different strategies developed to improve the photocatalytic performances of carbon‐based materials. The introduction of vacancies and surface doping are discussed as valuable approaches to enhance the photocatalytic activity in the nitrogen fixation reactions, as well as the construction of heterojunctions to finely tune the electronic properties of carbon‐based materials.

Abstract This project, titled ‘Listeria Control,’ aimed to advance expertise across Europe in applying predictive microbiology to shelf‐life studies of Listeria monocytogenes in ready‐to‐eat (RTE) products. By increasing the capacity of the two participating organisations in predictive microbiology, this initiative strengthens Europe's overall ability to manage and mitigate the risk of L. monocytogenes in RTE foods. The project's first experimental phase involved experimental trials that examined the growth of L. monocytogenes under both constant and dynamic temperature conditions. Subsequent analysis fitted existing primary growth models to the constant temperature growth data. The resulting models were then employed to predict L. monocytogenes growth under fluctuating temperature scenarios. Given the limited reported research on modelling L. monocytogenes growth in dynamic environments, this work represents a significant contribution to this emerging field. Furthermore, this fellowship facilitated collaboration between IZS‐Teramo and UCD, leading to enhanced and harmonised expertise in experimental and predictive techniques for L. monocytogenes shelf‐life studies – a partnership that both organisations are committed to continuing beyond the fellowship's duration.

Abstract Myocardial revascularization in patients presenting with an anterior mediastinal mass poses considerable challenges. In this report, we outline two cases involving patients with anterior mediastinal masses who underwent surgical resection alongside concurrent myocardial revascularization. One patient underwent coronary artery bypass graft surgery, while the other was treated by percutaneous coronary intervention with drug‐eluting stent placement. Both patients fully recovered from the relative procedures and were discharged within two weeks post‐surgery, ultimately diagnosed with thymoma. The concomitant intervention offered the advantage of promptly addressing both conditions, and it was performed safely through a collaborative multidisciplinary effort.

Patterned hair loss (PHL) or androgenetic alopecia is a condition affecting about 50% of people worldwide. Several pharmacological medications have been developed over the years, but few studies have investigated their effectiveness. Therefore, new, safer and more effective strategies are required. Recent investigations showed that Annurca apple extract application could induce keratin production and promote hair growth thanks to the high amount of procyanidin B2 contained in. Hence, this study aimed to investigate the role of an Annurca apple extract in preventing PHL by testing it on human follicle dermal papilla cells (HFDPCs) for the first time. Treatment of HFDPCs with Annurca apple extract counteracted intracellular reactive oxygen species accumulation by increasing the activity of antioxidant enzymes such as superoxide dismutase 2 and catalase. Furthermore, treatment with Annurca apple extract increased β‐catenin and fibroblast growth factor 2, which are involved in hair growth stimulation. These data suggest that Annurca apple extract may be a potential therapeutically useful nutraceutical product for preventing or treating hair loss by reducing oxidative stress and inducing the expression of hair growth‐related factors.

Abstract Objective Alzheimer's disease (AD) and cerebral small vessel disease (cSVD), the two most common causes of dementia, are characterized by white matter (WM) alterations diverging from the physiological changes occurring in healthy aging. Diffusion tensor imaging (DTI) is a valuable tool to quantify WM integrity non‐invasively and identify the determinants of such alterations. Here, we investigated main effects and interactions of AD pathology, APOE‐ε4, cSVD, and cardiovascular risk on spatial patterns of WM alterations in non‐demented older adults. Methods Within the prospective European Prevention of Alzheimer's Dementia study, we selected 606 participants (64.9 ± 7.2 years, 376 females) with baseline cerebrospinal fluid samples of amyloid β1‐42 and p‐Tau181 and MRI scans, including DTI scans. Longitudinal scans (mean follow‐up time = 1.3 ± 0.5 years) were obtained in a subset (n = 223). WM integrity was assessed by extracting fractional anisotropy and mean diffusivity in relevant tracts. To identify the determinants of WM disruption, we performed a multimodel inference to identify the best linear mixed‐effects model for each tract. Results AD pathology, APOE‐ε4, cSVD burden, and cardiovascular risk were all associated with WM integrity within several tracts. While limbic tracts were mainly impacted by AD pathology and APOE‐ε4, commissural, associative, and projection tract integrity was more related to cSVD burden and cardiovascular risk. AD pathology and cSVD did not show any significant interaction effect. Interpretation Our results suggest that AD pathology and cSVD exert independent and spatially different effects on WM microstructure, supporting the role of DTI in disease monitoring and suggesting independent targets for preventive medicine approaches.

Abstract The paper explores the use of the magnetic control strategy for the output power regulation of an LCC‐S compensated inductive wireless power transfer system. The magnetic control is implemented through a controlled variable inductor whose magnetization state is actively regulated by an auxiliary DC–DC converter. The principles for the design and regulation of the system are discussed, and the experimental setup for the validation of the regulation method is implemented. Several measurement results highlight the effectiveness and potential improvements of the magnetic control strategy for inductive wireless power transfer systems.

Abstract Global environmental change will cause shifts in species communities, with non‐native species likely replacing native ones at an unprecedented rate. This will have consequences for biodiversity and ecosystem services, in addition to the ecological and economic damage caused by those non‐native species that are invasive. Understanding general patterns driving distributions of native and non‐native species is therefore vital, but no study has compared yet whether environmental variables that correlate with a species' presence differ between the two groups other than at local scale and often with very limited sample size. In this study, we focus on 141 native and non‐native congeneric plant species pairs at the scale of Switzerland. In the framework of correlative species distribution models, we used newly developed methods for efficient automated selection of a parsimonious number of predictor environmental variables to determine which ones, out of a large candidate set in eight classes, have the strongest explanatory power for both species groups. Our results indicated that variables influence the two groups in significantly different ways. Climate was by far the strongest determinant of both native and non‐native species distributions, although it had significantly more explanatory power in native species models. Models for non‐native species were significantly more influenced by anthropogenic factors, land use variables and forest cover. The presence of non‐native species was also associated with habitats with a significantly lower mean naturality value than native species. These findings provide novel empirical evidence for the different environmental factors driving native and non‐native plants' distributions and guidance for non‐native species management. Practical implications: species distribution models are an increasingly frequently advised tool for conservation management and our results provide guidelines on which covariates should be specifically considered to assess the habitat suitability of non‐native versus native species. The distributions of the former group of species are particularly important to research, as, in time, they may turn invasive. In addition, areas close to infrastructure should be scanned regularly for incipient colonizations by non‐native species, especially in as yet uninvaded areas, such as high mountains.

ABSTRACT Introduction Strong indications support the notion that idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) acts as a precursor to multiple α‐synucleinopathies, including Parkinson's disease and dementia with Lewy bodies. Despite numerous investigations into the alterations in cortical thickness and the volume of subcortical areas associated with this condition, comprehensive studies on the cortical surface morphology, focusing on gyrification and sulcal depth changes, are scarce. The purpose of this research was to explore the cortical surface morphology in individuals with probable iRBD (piRBD), to pinpoint early‐phase diagnostic markers. Methods This study included 30 piRBD patients confirmed using the RBD Screening Questionnaire (RBDSQ) and 33 control individuals selected from the Parkinson's Progression Markers Initiative (PPMI) database. They underwent neurophysiological tests and MRI scans. The FreeSurfer software was utilized to estimate cortical thickness (CTH), cortical and subcortical volumetry, local gyrification index (LGI), and sulcus depth (SD). Subsequently, these parameters were compared between the two groups. Additionally, linear correlation analysis was employed to estimate the relationship between brain morphological parameters and clinical parameters. Results Compared to the healthy control (HC), piRBD patients exhibited a significant reduction in CTH, LGI, and cortical volume in the bilateral superior parietal, lateral occipital, orbitofrontal, temporo‐occipital, bilateral rostral middle frontal, inferior parietal, and precentral brain regions. Moreover, a significant and notable correlation was observed between CTH and Geriatric Depression Scale (GDS), letter–number sequencing (LTNS), the Benton Judgment of Line Orientation (BJLO) test, and the symbol digit modalities test (SDMT) in several brain regions encompassing the motor cortex. Conclusion Patients with piRBD displayed widespread atrophy in various brain regions, predominantly covering the motor and sensory cortex. Furthermore, LGI could serve as a prognostic biomarker of disease's progression in piRBD.

Abstract Interspecific interactions among species of the same guild play a critical role in shaping their realized niches, and their understanding may disclose mechanisms of coexistence. Investigating interactions among apex predators is of ecological and management interest, especially in human‐dominated landscapes where type and intensity of their interspecific competition may be affected by human interference. During 2005–2010, we investigated, by means of GPS‐telemetry, interactions between brown bears (n = 19) and wolves (n = 7) in a long‐established national park in the central Apennines, Italy, where bears and wolves have always coexisted close to humans. Based on a K‐select analysis and a randomization approach, we assessed the extent of overlap between the species' niches on a seasonal basis. Bears and wolves clearly segregated in fall but not during summer when overlap between their realized niches suggests a convergent adaptation to a seasonal peak of anthropogenic pressure. However, using multi‐species resource selection functions (RSFs) at the home range level (i.e., third‐order selection), we revealed that habitat selection by bears and wolves was reciprocally affected also when their niches overlapped, possibly disclosing mechanisms of fine‐scale resource partitioning. In early summer, bears selected areas with a high probability of resource selection by wolves, but in late summer avoided areas positively selected by wolves. On the contrary, wolves avoided areas where the probability of resource selection by bears was high, both in late summer and fall. These results indicate that bears and wolves do interact in our study area and, although the actual behavioral mechanisms are unknown, they reciprocally and asymmetrically affect their realized niche and habitat selection patterns. Further research is needed to better understand how anthropogenic factors impact intraguild interactions and what are the effects at the population and community levels.

There is limited evidence on the outcomes and safety of mechanical thrombectomy (MT) among patients with acute ischemic stroke (AIS) in the context of cardiac diseases. Our study reviews MT in AIS within the context of cardiac diseases, aiming to identify existing and emerging needs and gaps. PubMed and Scopus were searched until December 31, 2023, using a combination of cardiological diseases and “mechanical thrombectomy” or “endovascular treatment” as keywords. Study design included case reports/series, observational studies, randomized clinical trials, and meta‐analyses/systematic reviews. We identified 943 articles, of which 130 were included in the review. Results were categorized according to the cardiac conditions. MT shows significant benefits in patients with atrial fibrillation (n=139) but lacks data for stroke occurring after percutaneous coronary intervention (n=2) or transcatheter aortic valve implantation (n=5). MT is beneficial in AIS attributable to infective endocarditis (n=34), although functional benefit may be limited. Controversy surrounds the functional outcomes and mortality of patients with AIS with heart failure undergoing MT (n=11). Despite technical challenges, MT appears feasible in aortic dissection cases (n=4), and in patients with left ventricular assist device or total artificial heart (n=10). Data on AIS attributable to congenital heart disease (n=4) primarily focus on pediatric cases requiring technical modifications. Treatment outcomes of MT in patients with cardiac tumors (n=8) vary because of clot consistency differences. After cardiac surgery stroke, MT may improve outcomes with early intervention (n=13). Available data outline the feasibility of MT in patients with AIS attributable to large‐vessel occlusion in the context of cardiac diseases.

Abstract The physical processes governing a tropical cyclone's lifecycle are largely understood, but key processes occur at scales below those resolved by global climate models. Increased resolution may help simulate realistic tropical cyclone intensification. We examined fully coupled, global storm‐resolving models run at resolutions in the range 28–2.8 km in the atmosphere and 28–5 km in the ocean. Simulated tropical cyclone activity, peak intensity, intensification rate, and horizontal wind structure are all more realistic at a resolution of ∼5 km compared with coarser resolutions. Rapid intensification, which is absent at typical climate model resolutions, is also captured, and exhibits sensitivity to how, and if, deep convection is parameterized. Additionally, the observed decrease in inner‐core horizontal size with increasing intensification rate is captured at storm‐resolving resolution. These findings highlight the importance of global storm‐resolving models for quantifying risk and understanding the role of intense tropical cyclones in the climate system.

Abstract Background The therapeutic role and prognostic relevance of lymphadenectomy in mast cell tumor (MCT) has historically been evaluated on regional rather than sentinel lymph nodes. Hypothesis/Objectives To update information about the association of histological nodal (HN) classes with clinical outcome in dogs with MCT after tumor excision and extirpation of normal‐sized sentinel nodes (SLN) guided by radiopharmaceutical. Animals Ninety‐four dogs with histologically‐confirmed treatment‐naïve MCT (71 cutaneous, 22 subcutaneous and 1 conjunctival MCT) were included if without: distant metastases, lymphadenomegaly, concurrent mixed cutaneous, and subcutaneous MCT. Methods This was a monoistitutional cohort study. Tumors characteristics were retrieved and SLNs were classified according to Weishaar's system. Incidence of MCT‐related events (local, nodal, distant relapse), de novo MCT or other tumors and death (MCT‐related and non‐MCT‐related), were recorded. Incidence curves were compared among the HN classes. Results Twenty‐seven dogs had HN0, 19 HN1, 37 HN2, and 11 HN3 SLN. Thirteen (2 HN0, 4 HN2, and 7 HN3) received adjuvant chemotherapies. Kiupel high grade, increasing number of SLN and lymphocentrums were associated with higher HN classes. Five dogs died for MCT‐related causes: 1 low‐grade (HN0) and 1 subcutaneous (HN3) had a local relapse, 2 high‐grade had distant relapse (HN3‐HN0) and 1 dog developed disease progression from a de novo subcutaneous MCT. No nodal relapse was registered. Fourteen dogs developed de novo MCTs. Conclusion/Discussion Low grade/low‐risk MCT with nonpalpable and normal sized SLN have a favorable outcome independently from the HN. Result should be considered strictly related to the successful SLN detection guided pre‐ and intraoperative by radiopharmaceutical markers.

Abstract Background Reports describing sciatic nerve injuries (SNI) and their outcome are scarce in veterinary medicine. Hypothesis Describe the causes of traumatic and iatrogenic SNI and evaluate which clinical and electrodiagnostic findings predict outcome. Animals Thirty‐eight dogs and 10 cats with confirmed SNI referred for neurologic and electrodiagnostic evaluation. Methods Clinical and electrodiagnostic examination results, including electromyography (EMG), motor nerve conduction studies, muscle‐evoked potential (MEP), F‐waves, sensory nerve conduction studies, and cord dorsum potential (CDP), were retrospectively evaluated. Quality of life (QoL) was assessed based on owner interviews. Results Surgery (42%) and trauma (33%) were the most common causes of SNI; in dogs, 24% were caused by bites from wild boars. Ability to flex and extend the tarsus was significantly associated with positive outcome in dogs. Mean time from onset of clinical signs until electrodiagnostic evaluation was 67 ± 65 (range, 7‐300) days and 65 ± 108 (range, 7‐365) days for dogs and cats, respectively. A cut‐off amplitude of 1.45 mV for compound motor action potentials (CMAP) was predictive of positive outcome in dogs (P = .01), with sensitivity of 58% and specificity of 100%. Conclusions and Clinical Importance Clinical motor function predicts recovery better than sensory function. Electrodiagnostic findings also may play a role in predicting the outcome of SNI. Application of the proposed CMAP cut‐off amplitude may assist clinicians in shortening the time to reassessment or for earlier suggestion of salvage procedures. Owners perceived a good quality of life (QoL), even in cases of hindlimb amputation.

Abstract Background Muscle and bone are physiologically interconnected, but joint changes of muscle and bone with aging, and whether the muscle‐bone changes are different by sex and by country has been little studied. We examined longitudinal associations of bone mineral density (BMD) and muscle mass or muscle strength in community‐dwelling 65 years or older in the United States and Japan. Methods The present analytic sample included 1129 women and men from the Baltimore Longitudinal Study of Aging (BLSA) (mean age, 74.5 ± 7.5 years; women, 49.8%) and 1998 women and men from the National Institute for Longevity Sciences‐Longitudinal Study of Aging (NILS‐LSA) (mean age, 70.0 ± 4.5 years; women, 51.4%). Median follow‐up was 4.6 (min‐max, 0–15.4) years in the BLSA and 4.0 (min‐max, 0–13.4) years in the NILS‐LSA. We selected visits at which participants had BMD (whole body, pelvic, femoral neck, trochanter, and Ward's triangle BMDs) and muscle mass [appendicular lean mass, (ALM)] measured by DXA scan. In each bone site, we ran cohort‐specific bivariate linear mixed‐effects models adjusted for baseline age, sex, body height, body weight, fat mass, education year, and smoking status. Race was an additional adjustment in the BLSA. Additionally, we performed sex‐specific analyses. Results In the BLSA, the rate of change in ALM positively correlated with the rate of change in the whole body (rho = 0.30, P 0.05). In the NILS‐LSA, ALM positively correlated with the rate of change in all bone sites (rho ranged from 0.20 to 0.71, P

Abstract Synucleinopathies‐related disorders such as Lewy body dementia (LBD) and isolated/idiopathic REM sleep behavior disorder (iRBD) have been associated with neuroinflammation. In this study, we examined whether the human leukocyte antigen (HLA) locus plays a role in iRBD and LBD. In iRBD, HLA‐DRB1*11:01 was the only allele passing FDR correction (OR = 1.57, 95% CI = 1.27–1.93, p = 2.70e‐05). We also discovered associations between iRBD and HLA‐DRB1 70D (OR = 1.26, 95%CI = 1.12–1.41, p = 8.76e‐05), 70Q (OR = 0.81, 95%CI = 0.72–0.91, p = 3.65e‐04) and 71R (OR = 1.21, 95%CI = 1.08–1.35, p = 1.35e‐03). Position 71 (pomnibus = 0.00102) and 70 (pomnibus = 0.00125) were associated with iRBD. Our results suggest that the HLA locus may have different roles across synucleinopathies.

Background REST (Repressor‐Element 1 [RE1]‐silencing transcription factor) inhibits Na+/Ca2+exchanger‐1 (Ncx1) transcription in neurons through the binding of RE1 site on brain promoter (Br) after stroke. We identified a new putative RE1 site in Ncx1 heart promoter (Ht) sequence (Ht‐RE1) that participates in neuronal Ncx1 transcription. Because REST recruits DNA‐methyltransferase‐1 (DNMT1) and MeCP2 (methyl‐CpG binding protein 2) on different neuronal genes, we investigated the role of this complex in Ncx1 transcriptional regulation after stroke. Methods and Results Luciferase experiments performed in SH‐SY5Y cells demonstrated that Br activity was selectively decreased by REST, whereas Ht activity was reduced by DNMT1, MeCP2, and REST. Notably, site‐direct mutagenesis of Ht‐RE1 prevented REST‐dependent downregulation of Ncx1. Furthermore, in temporoparietal cortex of 8‐week‐old male wild‐type mice (C57BL/6) subjected to transient middle cerebral artery occlusion, DNMT1, MeCP2, and REST binding to Ht promoter was increased, with a consequent DNA promoter hypermethylation. Intracerebroventricular injection of siREST prevented DNMT1/MeCP2 binding to Ht and Ncx1 downregulation, thus causing a reduction in stroke‐induced damage. Consistently, in cortical neurons subjected to oxygen and glucose deprivation plus reoxygenation Ncx1 knockdown counteracted neuronal protection induced by the demethylating agent 5‐azacytidine. For comparisons between 2 experimental groups, Student's t test was used, whereas for more than 2 experimental groups, 1‐way ANOVA was used, followed by Tukey or Newman Keuls. Statistical significance was set at P

Abstract The potential of real‐world data to inform clinical trial design and supplement control arms has gained much interest in recent years. The most common approach relies on reproducing control arm outcomes by matching real‐world patient cohorts to clinical trial baseline populations. However, recent studies pointed out that there is a lack of replicability, generalisability, and consensus. In this article, we propose a novel approach that aims to explore and examine these discrepancies by concomitantly investigating the impact of selection criteria and operations on the measurements of outcomes from the patient data. We tested the approach on a dataset consisting of small‐cell lung cancer patients receiving platinum‐based chemotherapy regimens from a real‐world data cohort (n = 223) and six clinical trial control arms (n = 1224). The results showed that the discrepancy between real‐world and clinical trial data potentially depends on differences in both patient populations and operational conditions (e.g., frequency of assessments, and censoring), for which further investigation is required. Discovering and accounting for confounders, including hidden effects of differences in operations related to the treatment process and clinical trial study protocol, would potentially allow for improved translation between clinical trials and real‐world data. Continued development of the method presented here to systematically explore and account for these differences could pave the way for transferring learning across clinical studies and developing mutual translation between the real‐world and clinical trials to inform clinical study design.

Background The optimal treatment for acute minor ischemic stroke is still undefined. and options include dual antiplatelet treatment (DAPT), intravenous thrombolysis (IVT), or their combination. We aimed to investigate benefits and risks of combining IVT and DAPT versus DAPT alone in patients with MIS. Methods and Results This is a prespecified propensity score‐matched analysis from a prospective multicentric real‐world study (READAPT [Real‐Life Study on Short‐Term Dual Antiplatelet Treatment in Patients With Ischemic Stroke or Transient Ischemic Attack]). We included patients with MIS (National Institutes of Health Stroke Scale score at admission ≤5), without prestroke disability (modified Rankin scale [mRS] score ≤2). The primary outcomes were 90‐day mRS score of 0 to 2 and ordinal mRS distribution. The secondary outcomes included 90‐day risk of stroke and other vascular events and 24‐hour early neurological improvement or deterioration (≥2‐point National Institutes of Health Stroke Scale score decrease or increase from the baseline, respectively). From 1373 patients with MIS, 240 patients treated with IVT plus DAPT were matched with 427 patients treated with DAPT alone. At 90 days, IVT plus DAPT versus DAPT alone showed similar frequency of mRS 0 to 2 (risk difference, 2.3% [95% CI −2.0% to 6.7%]; P=0.295; risk ratio, 1.03 [95% CI 0.98–1.08]; P=0.312) but more favorable ordinal mRS scores distribution (odds ratio, 0.57 [95% CI 0.41–0.79]; P

Background Currently, no clear impact of sex on short‐ and long‐term survival following transcatheter edge‐to‐edge mitral valve repair (TEER) is evident, although no data are available on postprocedural life expectancy. Our aim was to assess sex‐specific differences in outcomes of patients with mitral regurgitation (MR) treated by TEER. Methods and Results Short‐term and 5‐year outcomes in men and women undergoing TEER between 2011 and 2018 who were included in the large, multicenter, real‐world MitraSwiss registry were analyzed. Outcomes were compared stratified by sex and according to MR cause (primary versus secondary). The impact of TEER on postprocedural life expectancy was estimated by relative survival analysis. Among 1142 patients aged 60 to 89 years, 39.8% were women. They were older, with fewer cardiovascular risk factors and lower functional capacity compared with men. Thirty‐day mortality was higher in men than in women (3.3% versus 1.1%; odds ratio, 3.16 [95% CI, 1.16–10.7]; P=0.020). Five‐year survival was comparable in both sexes (adjusted hazard ratio for 5‐year mortality in men, 1.14 [95% CI, 0.90–1.44], P=0.275). Both men and women with either primary or secondary MR showed similar clinical efficacy over time. TEER provided high relative survival estimates among all groups, and fully restored predicted life expectancy in women with primary MR (5‐year relative survival estimate, 97.4% [95% CI, 85.5–107.0]). Conclusions TEER is not associated with increased short‐term mortality in women, whereas 5‐year outcomes are comparable between sexes. Moreover, TEER completely restored normal life expectancy in women with primary MR. A residual excess mortality persists in secondary MR, independently of sex.

Abstract Background Pancreatic cancer (PC) first‐line therapy often consists of polychemotherapy regimens, but choosing a second‐line therapy after disease progression, especially following first‐line FOLFIRINOX, remains a clinical challenge. This study presents results from a large, multicenter, retrospective analysis of Italian patients with metastatic PC (mPC) treated with Nab‐paclitaxel/Gemcitabine (AG) as second or later line of treatment. Main objective of the study is to identify prognostic factors that could inform treatment decisions. Methods The study included 160 mPC patients treated with AG in 17 Italian institutions. AG was administered according to labelling dose, until disease progression, unacceptable toxicity or patient refusal. Variations in schedules, dose modifications, supportive measures, and response evaluation were determined by individual clinicians' practice. Results AG was well‐tolerated and exhibited promising clinical activity. The overall response rate (ORR) and the disease control rate (DCR) were 22.5% and 45.6%, respectively. Median progression‐free survival (PFS) and overall survival (OS) were 3.9 and 6.8 months, respectively. Among the patients who received AG as a second‐line therapy (n = 111, 66.9%), median PFS and OS were 4.2 and 7.4 months, respectively. Notably, in the 76 patients (68%) receiving AG after first‐line FOLFIRINOX, an ORR of 19.7% and a DCR of 46.0% were observed, resulting in a median PFS of 3.5 and median OS of 5.7 months. The study identified specific clinical or laboratory parameters (LDH, NLR, fasting serum glucose, liver metastases, ECOG PS, and first‐line PFS) as independent prognostic factors at multivariate level. These factors were used to create a prognostic nomogram that divided patients into three risk classes, helping to predict second‐line OS and PFS. Conclusions This study represents the largest real‐world population of mPC patients treated with AG as a second or later line of therapy. It supports the feasibility of this regimen following first‐line FOLFIRINOX, particularly in patients with specific clinical and laboratory characteristics who derived prolonged benefit from first‐line therapy.

Abstract Ferromanganese (FeMn) crusts are Fe and Mn oxides that typically form on deep‐sea elevations by deposition of colloids from seawater. These mineral deposits are considered a source of critical metals and rare earth elements. Besides their potential economic value, FeMn crusts are extremely relevant in ocean science, since their very slow growth rates result in long‐term paleoenvironmental and paleoceanographic records. In this study, we applied geochemical, mineralogical, and magnetic analyses to unravel paleoenvironmental changes at two locations on opposite sides of the Atlantic Ocean, the Rio Grande Rise in the SW Atlantic and the Tropic Seamount in the NE Atlantic. Our results show that the occurrence of amorphous (non‐crystalline) Fe oxyhydroxides and the absence of Fe oxides in hydrogenetic, non‐phosphatized FeMn crusts prevented the development of primary remanent magnetization. In contrast, phosphatized FeMn crusts may have contained a remanent magnetic signal. Phosphatization resulted from increased primary productivity and occurred at different stages during the growth of the FeMn crusts, leading to suboxic conditions and partial dissolution of pre‐existing, remanence‐carrying magnetic minerals. Carbonate Fluorapatite (CFA) accumulation in the phosphatized layers of FeMn crusts replaced Fe and Mn, decreasing their magnetic content. Thus, magnetic variations do not reflect a primary magnetization but rather result from geochemical alterations. The loss of primary magnetization may hamper the use of FeMn deposits for magnetostratigraphic purposes.

Abstract Background Mitochondrial dysfunction may contribute to brain and muscle health through inflammation or fat infiltration in the muscle, both of which are associated with cognitive function and mobility. We aimed to examine the association between skeletal muscle mitochondrial function and cognitive and mobility outcomes and tested the mediation effect of inflammation or fat infiltration. Methods We analysed data from 596 Baltimore Longitudinal Study of Aging participants who had concurrent data on skeletal muscle oxidative capacity and cognitive and mobility measures of interest (mean age: 66.1, 55% women, 24% Black). Skeletal muscle oxidative capacity was assessed as post‐exercise recovery rate (kPCr) via P31 MR spectroscopy. Fat infiltration was measured as intermuscular fat (IMF) via CT scan and was available for 541 participants. Inflammation markers [IL‐6, C‐reactive protein (CRP), total white blood cell (WBC), neutrophil count, erythrocyte sedimentation rate (ESR), or albumin] were available in 594 participants. We examined the association of kPCr and cognitive and mobility measures using linear regression and tested the mediation effect of IMF or inflammation using the mediation package in R. Models were adjusted for demographics and PCr depletion. Results kPCr and IMF were both significantly associated with specific cognitive domains (DSST, TMA‐A, and pegboard dominant hand performance) and mobility (usual gait speed, HABCPPB, 400 m walk time) (all P

Abstract Background Standard surgical treatment for lower urinary tract symptoms (LUTS) due to benign prostatic obstruction (BPO) requires anaesthesia and hospitalization. Transperineal laser ablation (TPLA) is a novel minimally invasive treatment for BPO, which has been performed using local anaesthetics and conscious sedation. Objectives The aim of this study is to assess safety, feasibility and functional outcomes of TPLA for the treatment of LUTS in men fit also for standard surgery. Methods This prospective, multicentre, interventional pilot study included 20 patients. Eligible patients were men ≥40 years of age, with urodynamically proven bladder outlet obstruction, a peak urinary flow of 5–15 mL/s and a prostate volume of 30–120 cc. All subjects underwent Soractelite™ TPLA using the Echolaser® X4 system. Two to four fibres were placed in the prostate, whereafter laser light induced coagulative necrosis. Twelve months of follow‐up included uroflowmetry, an ultrasound of the prostate and PROMs (IPSS and IIEF). Results Twenty patients were treated with TPLA using local anaesthetics and optional sedation. Sixteen patients were treated in an outpatient setting, using only local anaesthetics in 12 of them; four were treated in the operating room, whereof two under general anaesthesia. No device related adverse events occurred, nor did any grade ≥3 adverse events during follow‐up. Post‐TPLA, 10 men continued spontaneous voiding, and 10 men developed a urinary retention treated by a temporary indwelling catheter for 15.2 ± 3.5 days. At 12 months, Qmax improved from 9.7 ± 3.5 to 14.9 ± 6.0 (p = 0.015), IPSS improved from 21.3 ± 5.2 to 10.9 ± 5.5 (p

Alterations in glycosphingolipid metabolism have been linked to the pathophysiological mechanisms of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease affecting motor neurons. Accordingly, administration of GM1, a sialic acid‐containing glycosphingolipid, is protective against neuronal damage and supports neuronal homeostasis, with these effects mediated by its bioactive component, the oligosaccharide head (GM1‐OS). Here, we add new evidence to the therapeutic efficacy of GM1 in ALS: Its administration to WT and SOD1G93A motor neurons affected by glutamate‐induced excitotoxicity significantly increased neuronal survival and preserved neurite networks, counteracting intracellular protein accumulation and mitochondria impairment. Importantly, the GM1‐OS faithfully replicates GM1 activity, emphasizing that even in ALS the protective function of GM1 strictly depends on its pentasaccharide.

Abstract Copanlisib dose selection was established under the maximum tolerated dose paradigm, and no dedicated dose‐finding studies have investigated copanlisib dose selection when used in combination with rituximab. In CHRONOS‐3, copanlisib plus rituximab demonstrated significantly improved progression‐free survival versus placebo plus rituximab in patients with relapsed indolent non‐Hodgkin lymphoma (iNHL). We conducted a comprehensive investigation of copanlisib population pharmacokinetics (PopPK) from a pooled analysis of 712 patients across nine copanlisib phase I–III studies and exposure–response (ER) relationships for efficacy and safety from the 1‐year follow‐up of CHRONOS‐3. PopPK analyses examined the impact of demographic, laboratory, and comedication covariates on copanlisib between‐patient PK variability. Individual static and time‐varying exposure estimates were derived to investigate exposure–efficacy and exposure–safety relationships. Multivariate Cox proportional hazards and logistic regression analyses examined ER relationships with consideration of predefined potentially prognostic demographic‐, laboratory‐, and/or disease‐related baseline covariates. Copanlisib PK were best described by a three‐compartment model with first‐order elimination. Individual identified covariates had modest effects on copanlisib PK and were generally in line with known copanlisib disposition properties. In CHRONOS‐3, ER analyses showed a significant relationship between time‐varying exposure estimates and progression‐free survival, and no significant exposure–safety relationships. Thus, lower copanlisib doses may result in reduced efficacy but not necessarily improved safety or tolerability. These outcomes substantiate the current intermittent dosing regimen of copanlisib 60 mg on days 1, 8, and 15 of a 28‐day cycle and support the observed clinical results of copanlisib in combination with rituximab in the iNHL population.

Abstract Aims Early start and patient profile‐oriented heart failure (HF) management has been recommended. In this post hoc analysis from the SHIFT trial, we analysed the treatment effects of ivabradine in HF patients with systolic blood pressure (SBP) 25% (HR 0.85, 95% CI 0.72–1.01 vs. HR 0.80, 95% CI 0.71–0.90, P interaction = 0.53), and NYHA III–IV and II (HR 0.83, 95% CI 0.74–0.94 vs. HR 0.81, 95% CI 0.69–0.94, P interaction = 0.79). The effect was more pronounced in patients with RHR ≥ 75 compared with

Abstract Aims This study aimed to determine whether any change occurred over time in level of evidence (LoE) of therapeutic interventions supporting heart failure (HF) and other European Society of Cardiology guideline recommendations. Methods and results We selected topics with at least three documents released between 2008 and April 2022. Classes of recommendations (CoR) and supporting LoE related to therapeutic interventions within each document were collected and compared over time. A total of 1822 recommendations from 18 documents on 6 topics [median number per document = 112, 867 (48%) CoR I] were included in the analysis. There was a trend towards a reduction over time in the percentage of CoR I in HF (46–36–34%), non‐ST elevation myocardial infarction (NSTEMI; 78–58–54%), and pulmonary embolism (PE; 65–50–39%) guidelines, with a decrease in the total number of recommendations for HF only. Percentage of CoR I was stable over time around 40% for valvular heart disease (VHD) and atrial fibrillation (AF), and around 60% for cardiovascular prevention (CVP), with an increase in the total number of recommendations for VHD and CVP and a decrease for AF. Among CoR I, 319 (37%) were supported by LoE A, with a decrease over time for HF (56–46–42%), an increase for NSTEMI (29–38–48%) and AF (28–31–36%), a bimodal distribution for PE and CVP, and a lack for VHD. Conclusions LoE supporting therapeutic recommendations in contemporary European guidelines is generally low. Physicians should be aware of these limitations, and scientific societies promote a greater understanding of their significance and drive future research directions.

Abstract Triple‐negative breast cancer (TNBC) is usually an aggressive disease with a poor prognosis and limited treatment options. The neurotrophic tyrosine receptor kinase (NTRK) gene fusions are cancer type‐agnostic emerging biomarkers approved by the Food and Drug Administration (FDA), USA, for the selection of patients for targeted therapy. The main aim of our study was to investigate the frequency of NTRK aberrations, i.e. fusions, gene copy number gain, and amplification, in a series of TNBC using different methods. A total of 83 TNBCs were analyzed using pan‐TRK immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), real‐time polymerase chain reaction (RT‐PCR), and RNA‐based next‐generation sequencing (NGS). Of 83 cases, 16 showed pan‐TRK positivity although no cases had NTRK‐fusions. Indeed, FISH showed four cases carrying an atypical NTRK1 pattern consisting of one fusion signal and one/more single green signals, but all cases were negative for fusion by NGS and RT‐PCR testing. In addition, FISH analysis showed six cases with NTRK1 amplification, one case with NTRK2 copy number gain, and five cases with NTRK3 copy number gain, all negative for pan‐TRK IHC. Our data demonstrate that IHC has a high false‐positive rate for the detection of fusions and molecular testing is mandatory; there is no need to perform additional molecular tests in cases negativity for NTRK by IHC. In conclusion, the NTRK genes are not involved in fusions in TNBC, but both copy number gain and amplification are frequent events, suggesting a possible predictive role for other NTRK aberrations.

Abstract There is currently no evidence to support the use of antiseizure medications to prevent unprovoked seizures following stroke. Experimental animal models suggested a potential antiepileptogenic effect for eslicarbazepine acetate (ESL), and a Phase II, multicenter, randomized, double‐blind, placebo‐controlled study was designed to test this hypothesis and assess whether ESL treatment for 1 month can prevent unprovoked seizures following stroke. We outline the design and status of this antiepileptogenesis study, and discuss the challenges encountered in its execution to date. Patients at high risk of developing unprovoked seizures after acute intracerebral hemorrhage or acute ischemic stroke were randomized to receive ESL 800 mg/d or placebo, initiated within 120 hours after primary stroke occurrence. Treatment continued until Day 30, then tapered off. Patients could receive all necessary therapies for stroke treatment according to clinical practice guidelines and standard of care, and are being followed up for 18 months. The primary efficacy endpoint is the occurrence of a first unprovoked seizure within 6 months after randomization (“failure rate”). Secondary efficacy assessments include the occurrence of a first unprovoked seizure during 12 months after randomization and during the entire study; functional outcomes (Barthel Index original 10‐item version; National Institutes of Health Stroke Scale); post‐stroke depression (Patient Health Questionnaire‐9; PHQ‐9); and overall survival. Safety assessments include the evaluation of treatment‐emergent adverse events; laboratory parameters; vital signs; electrocardiogram; suicidal ideation and behavior (PHQ‐9 question 9). The protocol aimed to randomize approximately 200 patients (1:1), recruited from 21 sites in seven European countries and Israel. Despite the challenges encountered, particularly during the COVID‐19 pandemic, the study progressed and included a remarkable number of patients, with 129 screened and 125 randomized. Recruitment was stopped after 30 months, the first patient entered in May 2019, and the study is ongoing and following up on patients according to the Clinical Trial Protocol.

Abstract Background Uterine leiomyosarcomas (uLMS) are aggressive tumours with poor prognosis and limited treatment options. Although immune checkpoint blockade (ICB) has proven effective in some ‘challenging‐to‐treat’ cancers, clinical trials showed that uLMS do not respond to ICB. Emerging evidence suggests that aberrant PI3K/mTOR signalling can drive resistance to ICB. We therefore explored the relevance of the PI3K/mTOR pathway for ICB treatment in uLMS and explored pharmacological inhibition of this pathway to sensitise these tumours to ICB. Methods We performed an integrated multiomics analysis based on TCGA data to explore the correlation between PI3K/mTOR dysregulation and immune infiltration in 101 LMS. We assessed response to PI3K/mTOR inhibitors in immunodeficient and humanized uLMS patient‐derived xenografts (PDXs) by evaluating tumour microenvironment modulation using multiplex immunofluorescence. We explored response to single‐agent and a combination of PI3K/mTOR inhibitors with PD‐1 blockade in humanized uLMS PDXs. We mapped intratumoural dynamics using single‐cell RNA/TCR sequencing of serially collected biopsies. Results PI3K/mTOR over‐activation (pS6high) associated with lymphocyte depletion and wound healing immune landscapes in (u)LMS, suggesting it contributes to immune evasion. In contrast, PI3K/mTOR inhibition induced profound tumour microenvironment remodelling in an ICB‐resistant humanized uLMS PDX model, fostering adaptive anti‐tumour immune responses. Indeed, PI3K/mTOR inhibition induced macrophage repolarisation towards an anti‐tumourigenic phenotype and increased antigen presentation on dendritic and tumour cells, but also promoted infiltration of PD‐1+ T cells displaying an exhausted phenotype. When combined with anti‐PD‐1, PI3K/mTOR inhibition led to partial or complete tumour responses, whereas no response to single‐agent anti‐PD‐1 was observed. Combination therapy reinvigorated exhausted T cells and induced clonal hyper‐expansion of a cytotoxic CD8+ T‐cell population supported by a CD4+ Th1 niche. Conclusions Our findings indicate that aberrant PI3K/mTOR pathway activation contributes to immune escape in uLMS and provides a rationale for combining PI3K/mTOR inhibition with ICB for the treatment of this patient population.

Background Minimally invasive mitral valve repair has a favorable risk–benefit profile in patients with significant de novo mitral regurgitation. Its role in patients with prior mitral valve repair is uncertain. We aimed to appraise the outcome of patients undergoing transcatheter edge‐to‐edge repair (TEER) with prior transcatheter or surgical mitral valve repair (SMVR). Methods and Results We queried the Italian multicenter registry on TEER with MitraClip, distinguishing naïve patients from those with prior TEER or (SMVR). Inhospital and long‐term clinical/echocardiographic outcomes were appraised. The primary outcome was the occurrence of death or rehospitalization for heart failure. A total of 2238 patients were included, with 2169 (96.9%) who were naïve to any mitral intervention, 29 (1.3%) with prior TEER, and 40 (1.8%) with prior SMVR. Several significant differences were found in baseline clinical and imaging features. Respectively, device success was obtained in 2120 (97.7%), 28 (96.6%), and 38 (95.0%, P=0.261) patients; procedural success in 2080 (95.9%), 25 (86.2%), and 38 (95.0%; P=0.047); and inhospital death in 61 (2.8%), 1 (3.5%), and no (P=0.558) patients. Clinical follow‐up after a mean of 14 months showed similar rates of death, cardiac death, rehospitalization, rehospitalization for heart failure, and their composite (all P>0.05). Propensity score–adjusted analysis confirmed unadjusted analysis, with lower procedural success for the prior TEER group (odds ratio, 0.28 [95% CI, 0.09–0.81]; P=0.019) but similar odds ratios and hazard ratios for all other outcomes in the naïve, TEER, and SMVR groups (all P>0.05). Conclusions In carefully selected patients, TEER can be performed using the MitraClip device even after prior TEER or SMVR.

Background Brugada syndrome (BrS) has been associated with sudden cardiac death in otherwise healthy subjects, and drug‐induced BrS accounts for 55% to 70% of all patients with BrS. This study aims to develop a deep convolutional neural network and evaluate its performance in recognizing and predicting BrS diagnosis. Methods and Results Consecutive patients who underwent ajmaline testing for BrS following a standardized protocol were included. ECG tracings from baseline and during ajmaline were transformed using wavelet analysis and a deep convolutional neural network was separately trained to (1) recognize and (2) predict BrS type I pattern. The resultant networks are referred to as BrS‐Net. A total of 1188 patients were included, of which 361 (30.3%) patients developed BrS type I pattern during ajmaline infusion. When trained and evaluated on ECG tracings during ajmaline, BrS‐Net recognized a BrS type I pattern with an AUC‐ROC of 0.945 (0.921–0.969) and an AUC‐PR of 0.892 (0.815–0.939). When trained and evaluated on ECG tracings at baseline, BrS‐Net predicted a BrS type I pattern during ajmaline with an AUC‐ROC of 0.805 (0.845–0.736) and an AUC‐PR of 0.605 (0.460–0.664). Conclusions BrS‐Net, a deep convolutional neural network, can identify BrS type I pattern with high performance. BrS‐Net can predict from baseline ECG the development of a BrS type I pattern after ajmaline with good performance in an unselected population.

Background The limited ability of enzyme replacement therapy (ERT) in removing globotriaosylceramide from cardiomyocytes is recognized for advanced Fabry disease cardiomyopathy (FDCM). Prehypertrophic FDCM is believed to be cured or stabilized by ERT. However, no pathologic confirmation is available. We report here on the long‐term clinical–pathologic impact of ERT on prehypertrophic FDCM. Methods and Results Fifteen patients with Fabry disease with left ventricular maximal wall thickness ≤10.5 mm at cardiac magnetic resonance required endomyocardial biopsy because of angina and ventricular arrhythmias. Endomyocardial biopsy showed coronary small‐vessel disease in the angina cohort, and vacuoles in smooth muscle cells and cardiomyocytes ≈20% of the cell surface containing myelin bodies at electron microscopy. Patients received α‐agalsidase in 8 cases, and β‐agalsidase in 7 cases. Both groups experienced symptom improvement except 1 patients treated with α‐agalsidase and 1 treated with β‐agalsidase. After ERT administration ranging from 4 to 20 years, all patients had control cardiac magnetic resonance and left ventricular endomyocardial biopsy because of persistence of symptoms or patient inquiry on disease resolution. In 13 asymptomatic patients with FDCM, left ventricular maximal wall thickness and left ventricular mass, cardiomyocyte diameter, vacuole surface/cell surface ratio, and vessels remained unchanged or minimally increased (left ventricular mass increased by

Abstract Rapid eye movement behavior disorder (RBD) is a parasomnia characterized by the loss of skeletal muscle atonia during the rapid eye movement (REM) sleep phase. On the other hand, idiopathic RDB (iRBD) is considered the prelude of the various α‐synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies and multiple system atrophy. Consequently, over 40% of patients eventually develop PD. Recent neuroimaging studies utilizing structural magnetic resonance imaging (s‐MRI), diffusion‐weighted imaging (DWI), and functional magnetic resonance imaging (fMRI) with graph theoretical analysis have demonstrated that patients with iRBD and Parkinson's disease have extensive brain abnormalities. Thus, it is crucial to identify new biomarkers that aid in determining the underlying physiopathology of iRBD group. This review was conducted systematically on the included full‐text articles of s‐MRI, DWI, and fMRI studies using graph theoretical analysis on patients with iRBD, per the procedures recommended by Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA). The literature search was conducted through the PubMed and Google scholar databases concentrating on studies from September to January 2022. Based on the three perspectives of integration, segregation, and centrality, the reviewed articles demonstrated that iRBD is associated with segregation disorders in frontal and limbic brain regions. Moreover, this study highlighted the need for additional longitudinal and multicenter studies to better understand the potential of graph metrics as brain biomarkers for identifying the underlying physiopathology of iRBD group.

Abstract Aims The HFA‐PEFF algorithm (Heart Failure Association‐Pre‐test assessment, Echocardiography and natriuretic peptide score, Functional testing in cases of uncertainty, Final aetiology) is a three‐step algorithm to diagnose heart failure with preserved ejection fraction (HFpEF). It provides a three‐level likelihood of HFpEF: low (score 4). HFpEF may be confirmed in individuals with a score > 4 (rule‐in approach). The second step of the algorithm is based on echocardiographic features and natriuretic peptide levels. The third step implements diastolic stress echocardiography (DSE) for controversial diagnostic cases. We sought to validate the three‐step HFA‐PEFF algorithm against a haemodynamic diagnosis of HFpEF based on rest and exercise right heart catheterization (RHC). Methods and results Seventy‐three individuals with exertional dyspnoea underwent a full diagnostic work‐up following the HFA‐PEFF algorithm, including DSE and rest/exercise RHC. The association between the HFA‐PEFF score and a haemodynamic diagnosis of HFpEF, as well as the diagnostic performance of the HFA‐PEFF algorithm vs. RHC, was assessed. The diagnostic performance of left atrial (LA) strain 3. LA strain alone had a sensitivity and specificity of 39% and 14% for haemodynamic HFpEF, increasing to 55% and 22% when corrected for E/E′. Conclusions As compared with rest/exercise RHC, the HFA‐PEFF score lacks sensitivity: Half of the patients were wrongly classified as non‐cardiac dyspnoea after non‐invasive tests, with a minimal impact of DSE in modifying HFpEF likelihood.