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Abstract Background Rockfalls pose a serious threat along the main road network, representing a major hazard in mountainous territory and causing damage and victims. Currently, susceptibility mapping represents a starting point to identify areas more susceptible to rockfall occurrence, a key approach in land use planning and risk management. Despite the extensive use of these maps by decision makers and administrators, the usability of such maps over time and their reliability represent a poorly discussed and examined feature. Methods Here, we proposed a-posteriori analysis of a three-year-old rockfall susceptibility map, generated along the main road network of the Aosta Valley, an alpine region of north-western Italy. To verify map consistency over time, we implemented a dual-analysis in GIS-environment and by text mining, to respectively analyse the geocoded data and textual information derivable from the regional landslide inventory. The first one allowed us to extract rockfall events occurred after the susceptibility map generation. By this way, we operated to spatially and temporally verify the map consistency. Jointly, the textual information reported in the Event Description Form, linked to each geocoded event, are being exploited. This allowed us to derive relevant information about occurred damage and their degree, presence of protective measures or secondary roads, i.e. involvement of, farm or forestry, road. Results The implemented approach allowed us to prove the quality of the previous map in terms of reliability, robustness and degree of fitting respect to the succession of rockfall occurrence over time. After only three years as many as 198 rockfall events have been occurred and collected since the map was generated. Particularly, 80% of rockfall fit with “high” and “very high” susceptibility classes, and pointed out large involvement of main roads in rockfall occurrence, representing the most affected target with damage to road pavement and vehicles, as well as a relevant involvement of existing rockfall barriers and of the dense network of forestry roads and footpaths that characterize this alpine region. Results The proposed approach representing a starting point in landslide susceptibility map verification and usability as valid instrument for a reliable land planning.

Abstract Background Liquid biopsy based on cell-free DNA (cfDNA) analysis holds significant promise as a minimally invasive approach for the diagnosis, genotyping, and monitoring of solid malignancies. Human tumors release cfDNA in the bloodstream through a combination of events, including cell death, active and passive release. However, the precise mechanisms leading to cfDNA shedding remain to be characterized. Addressing this question in patients is confounded by several factors, such as tumor burden extent, anatomical and vasculature barriers, and release of nucleic acids from normal cells. In this work, we exploited cancer models to dissect basic mechanisms of DNA release. Methods We measured cell loss ratio, doubling time, and cfDNA release in the supernatant of a colorectal cancer (CRC) cell line collection (N = 76) representative of the molecular subtypes previously identified in cancer patients. Association analyses between quantitative parameters of cfDNA release, cell proliferation, and molecular features were evaluated. Functional experiments were performed to test the impact of modulating DNA methylation on cfDNA release. Results Higher levels of supernatant cfDNA were significantly associated with slower cell cycling and increased cell death. In addition, a higher cfDNA shedding was found in non-CpG Island Methylator Phenotype (CIMP) models. These results indicate a positive correlation between lower methylation and increased cfDNA levels. To explore this further, we exploited methylation microarrays to identify a subset of probes significantly associated with cfDNA shedding and derive a methylation signature capable of discriminating high from low cfDNA releasers. We applied this signature to an independent set of 176 CRC cell lines and patient derived organoids to select 14 models predicted to be low or high releasers. The methylation profile successfully predicted the amount of cfDNA released in the supernatant. At the functional level, genetic ablation of DNA methyl-transferases increased chromatin accessibility and DNA fragmentation, leading to increased cfDNA release in isogenic CRC cell lines. Furthermore, in vitro treatment of five low releaser CRC cells with a demethylating agent was able to induce a significant increase in cfDNA shedding. Conclusions Methylation status of cancer cell lines contributes to the variability of cfDNA shedding in vitro. Changes in methylation pattern are associated with cfDNA release levels and might be exploited to increase sensitivity of liquid biopsy assays.

Abstract Background Aggressive malignancies, such as pancreatic cancer, are increasingly impacting young, female populations. Our investigation centered on whether the observed trends in cancer incidence were unique to pancreatic cancer or indicative of a broader trend across various cancer types. To delve deeper into this phenomenon, we analyzed cancer incidence trends across different age and sex groups. Furthermore, we explored differences in cancer incidence within specific young subgroups aged 18 to 26 and 27 to 34, to better understand the emerging incidence trend among young individuals. Methods This study collected cancer incidence data from one of the Surveillance, Epidemiology, and End Results cancer registry databases (SEER22), with 10,183,928 total cases from 2000 to 2020. Data were analyzed through Joinpoint trend analysis approach to evaluate sex- and age-specific trends in cancer incidence. Exposure rates were reported as Average Annual Percentage Changes (AAPCs). Results The analysis revealed significant age and sex-specific disparities, particularly among individuals aged 18–26 and 27–34. Pancreatic cancer incidence rates increased more in females aged 18–26 (AAPC, 9.37% [95% CI, 7.36–11.41%]; p

Abstract Aim Functional Management and Recovery is a standardized Psychoeducational Intervention, derived from “Integro”, an effective salutogenic-psychoeducational intervention for people in recovery journey, designed to improve recovery and functioning of individuals with psychotic disorders in Psychiatric Residential Facilities (PRFs). The aim of this study is to evaluate the primary and secondary outcomes of this intervention elaborated specifically for PRFs where evidence based structured interventions seem rare and desirable. Methods 66 individuals with psychotic disorders were recruited in 9 PRFs dislocated in the North, Center and South Italy and 63 underwent a multicenter follow-up study with a two time-point evaluation (t0, pre-treatment and t1, 6 months; ). At each time point, social functioning was assessed as primary outcome by the Personal and Social Performance scale (PSP); furthermore, psychopathological status was assessed by Brief Psychiatric Rating Scale (BPRS), Recovery by Recovery Assessment Scale (RAS), Cognitive Functioning by Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Stress management by Stress-Scale, Cognitive Flexibility by Modified Five-Point Test (M-FPT), Emotional Intelligence by Emotional Intelligence Index (EI-I), the PRF Atmosphere and the Opinion of users about the PFR by an ad hoc questionnaire. The Abilities Knowledge, the Utility and Pleasantness of sessions were measured by an ad hoc list of items. Results 63 individuals out of 66, 52 (82,5%) affected by schizophrenia and 11 (17,5%) by bipolar I disorder with psychotic symptoms according to DSM-5-TR completed the study. At the end of the study, 43 (68,3%) were male, 57 (90.5%) were single, 5 (7.9%) engaged, 1 (1.6%) married; 45 (71.4%) unemployed. The total scores of PSP, RAS, BPRS, BANS, Stress management, Abilities Knowledge, Utility and Pleasantness of sessions showed a statistically significant improvement at t1 vs. t0. Two sub-scales out of 5 of M-FPT showed a statistically significant improvement. The Emotional Intelligence, the Unit Atmosphere and the Opinion of Users about PFR improved without statistical significance. Six months after the end of the follow-up study 22 individuals of the sample were dismissed with a very high turnover. Conclusions After a six-month follow-up (a short period of time), these results showed improvement in functioning, the primary outcome, as well as in the following secondary outcome variables: RAS, BPRS, BANS, Stress management, Abilities Knowledge, two sub-scales out of 5 of M-FPT, Utility and Pleasantness of sessions. Overall, a remarkable impact of psychoeducational structured intervention on the key Recovery variables is observed. Further studies are needed to address extent and duration of these improvements.

Sleep quality (SQ) is a crucial aspect of overall health. Poor sleep quality may cause cognitive impairment, mood disturbances, and an increased risk of chronic diseases. Therefore, assessing sleep quality helps identify individuals at risk and develop effective interventions. SQ has been demonstrated to affect heart rate variability (HRV) and skin temperature even during wakefulness. In this perspective, using wearables and contactless technologies to continuously monitor HR and skin temperature is highly suited for assessing objective SQ. However, studies modeling the relationship linking HRV and skin temperature metrics evaluated during wakefulness to predict SQ are lacking. This study aims to develop machine learning models based on HRV and skin temperature that estimate SQ as assessed by the Pittsburgh Sleep Quality Index (PSQI). HRV was measured with a wearable sensor, and facial skin temperature was measured by infrared thermal imaging. Classification models based on unimodal and multimodal HRV and skin temperature were developed. A Support Vector Machine applied to multimodal HRV and skin temperature delivered the best classification accuracy, 83.4%. This study can pave the way for the employment of wearable and contactless technologies to monitor SQ for ergonomic applications. The proposed method significantly advances the field by achieving a higher classification accuracy than existing state-of-the-art methods. Our multimodal approach leverages the synergistic effects of HRV and skin temperature metrics, thus providing a more comprehensive assessment of SQ. Quantitative performance indicators, such as the 83.4% classification accuracy, underscore the robustness and potential of our method in accurately predicting sleep quality using non-intrusive measurements taken during wakefulness.

Abstract Background The European Regulation on Health Technology Assessment (EU HTA R), effective since January 2022, aims to harmonize and improve the efficiency of common HTA across Member States (MS), with a phased implementation from January 2025. At “midterms” of the preparation phase for the implementation of the Regulation our aim was to identify and prioritize tangible action points to move forward. Methods During the 2023 Spring Convention of the European Access Academy (EAA), participants from different nationalities and stakeholder backgrounds discussed readiness and remaining challenges for the Regulation’s implementation and identified and prioritized action points. For this purpose, participants were assigned to four working groups: (i) Health Policy Challenges, (ii) Stakeholder Readiness, (iii) Approach to Uncertainty and (iv) Challenges regarding Methodology. Top four action points for each working group were identified and subsequently ranked by all participants during the final plenary session. Results Overall “readiness” for the Regulation was perceived as neutral. Prioritized action points included the following: Health Policy, i.e. assess adjustability of MS laws and health policy processes; Stakeholders, i.e. capacity building; Uncertainty, i.e. implement HTA guidelines as living documents; Methodology, i.e. clarify the Population, Intervention, Comparator(s), Outcomes (PICO) identification process. Conclusions At “midterms” of the preparation phase, the focus for the months to come is on executing the tangible action points identified at EAA’s Spring Convention. All action points centre around three overarching themes: harmonization and standardization, capacity building and collaboration, uncertainty management and robust data. These themes will ultimately determine the success of the EU HTA R in the long run.

Background: Human-Machine Interaction (HMI) has been an important field of research in recent years, since machines will continue to be embedded in many human actvities in several contexts, such as industry and healthcare. Monitoring in an ecological mannerthe cognitive workload (CW) of users, who interact with machines, is crucial to assess their level of engagement in activities and the required effort, with the goal of preventing stressful circumstances. This study provides a comprehensive analysis of the assessment of CW using wearable sensors in HMI. Methods: this narrative review explores several techniques and procedures for collecting physiological data through wearable sensors with the possibility to integrate these multiple physiological signals, providing a multimodal monitoring of the individuals’CW. Finally, it focuses on the impact of artificial intelligence methods in the physiological signals data analysis to provide models of the CW to be exploited in HMI. Results: the review provided a comprehensive evaluation of the wearables, physiological signals, and methods of data analysis for CW evaluation in HMI. Conclusion: the literature highlighted the feasibility of employing wearable sensors to collect physiological signals for an ecological CW monitoring in HMI scenarios. However, challenges remain in standardizing these measures across different populations and contexts.

Introducción: La metatarsalgia central es una causa frecuente de dolor de antepié. La osteotomía de Weil es el tratamiento quirúrgico más popular y la osteotomía metatarsiana distal percutánea (OMDP) es la técnica percutánea más utilizada. La principal desventaja de estas técnicas es la aparición de dedo flotante que es aún mayor cuando se la asocia a artrodesis interfalángica proximal (AIFP). En esta serie de casos, se combinó la OMDP y la osteosíntesis con clavija de Kirschner para elevar el centro de rotación de la cabeza del metatarsiano con el objetivo de disminuir la presencia de dedos flotantes. Nuestra principal hipótesis fue que esta técnica generará menos dedos flotantes en los pacientes con diagnóstico de metatarsalgia mecánica y dedo en martillo rígido, comparada con la osteotomía de Weil. Materiales y Métodos: Se realizó un estudio retrospectivo en pacientes adultos con diagnóstico de metatarsalgia mecánica y dedo en martillo rígido. Se los sometió a una OMDP más fijación con clavija de Kirschner en combinación con AIFP. Finalmente, se comparó la presencia de dedos flotantes con un grupo de pacientes operados con la técnica de Weil y AIFP. Resultados: Se realizaron 39 OMDP más AIFP. La tasa de dedos flotantes fue del 31%. No hubo una diferencia estadísticamente significativa comparada con la técnica de Weil (36%, p = 0,634). Conclusión: La OMDP con elevación del centro de rotación asociada con AIFP no proporcionó una menor incidencia de dedos flotantes en comparación con la osteotomía de Weil.

Introducción: Las osteotomías supramaleolares son una opción terapéutica para la artrosis asimétrica de tobillo. El objetivo de este artículo es describir los resultados clínicos, radiográficos y subjetivos obtenidos en pacientes con artrosis de tobillo sometidos a una osteotomía supramaleolar. Materiales y Métodos: Estudio observacional descriptivo retrospectivo de pacientes sometidos a una osteotomía supramaleolar por artrosis de tobillo entre enero de 2010 y julio de 2017. Se analizaron las historias clínicas para recabar datos clínicos y radiográficos preoperatorios y posoperatorios. Resultados: Se incluyó a 13 pacientes: 8 con una desalineación del tobillo y retropié en valgo (61,5%) y 5 (38,5%) en varo. El puntaje medio posoperatorio de la escala analógica visual del grupo con deformidad en varo disminuyó de 9 ± 0,45 a 3 ± 1 (p

Objectives: Stakeholder involvement has long been considered a success factor for a joint European health technology assessment (HTA) process, and its relevance is now anchored in the EU HTA Regulation’s (EU HTAR) legislative wording. Therefore, we aimed to explore the roles, challenges, and most important activities to increase the level of involvement per stakeholder group. Methods: At the 2022 Fall Convention of the European Access Academy (EAA), working groups addressed the involvement of patients, clinicians, regulators, health technology developers (HTD), and national HTA bodies and payers within the EU HTA process. Each working group revisited the pre-convention survey results, determined key role characteristics for each stakeholder, and agreed on the most important activities to fulfill the role profile. Finally, the activities suggested per group were prioritized by plenary group. Results: The prioritized actions for patients included training and capacity building, the establishment of a patient involvement committee, and the establishment of a patient unit at the EC secretariat. For clinicians, it included alignment on evidence assessment from a clinical vs. HTA point of view, capacity building, and standardization of processes. The most important actions for regulators are to develop joint regulatory-HTA guidance documents, align processes and interfaces under the regulation, and share discussions on post-licensing evidence generation. HTDs prioritized scientific advice capacity and the review of the scoping process, and further development of the scope of the assessment report fact checks. The top three actions for national HTA bodies and payers included clarification on the early HTD dialogue process, political support and commitment, and clarification on financial support. Conclusions: Addressing the activities identified as the most important for stakeholders/collaborators in the EU HTA process (e.g., in the implementation of the EU HTA Stakeholder Network and of the guidance documents developed by the EUnetHTA 21 consortium) will be key to starting an “inclusive civil society dialogue”, as suggested by the European Commission’s Pharmaceutical Strategy.

Abstract Allopregnanolone (ALLO) is a known neurosteroid and a progesterone metabolite synthesized in the ovary, CNS, PNS, adrenals and placenta. Its role in the neuroendocrine control of ovarian physiology has been studied, but its in situ ovarian effects are still largely unknown. The aims of this work were to characterize the effects of intrabursal ALLO administration on different ovarian parameters, and the probable mechanism of action. ALLO administration increased serum progesterone concentration and ovarian 3β-HSD2 while decreasing 20α-HSD mRNA expression. ALLO increased the number of atretic follicles and the number of positive TUNEL granulosa and theca cells, while decreasing positive PCNA immunostaining. On the other hand, there was an increase in corpora lutea diameter and PCNA immunostaining, whereas the count of TUNEL-positive luteal cells decreased. Ovarian angiogenesis and the immunohistochemical expression of GABAA receptor increased after ALLO treatment. To evaluate if the ovarian GABAA receptor was involved in these effects, we conducted a functional experiment with a specific antagonist, bicuculline. The administration of bicuculline restored the number of atretic follicles and the diameter of corpora lutea to normal values. These results show the actions of ALLO on the ovarian physiology of the female rat during the follicular phase, some of them through the GABAA receptor. Intrabursal ALLO administration alters several processes of the ovarian morpho-physiology of the female rat, related to fertility and oocyte quality.

BackgroundInterest in the application of predictive risk models (PRMs) in health care to identify people most likely to experience disease and treatment-related complications is increasing. In cancer care, these techniques are focused primarily on the prediction of survival or life-threatening toxicities (eg, febrile neutropenia). Fewer studies focus on the use of PRMs for symptoms or supportive care needs. The application of PRMs to chemotherapy-related symptoms (CRS) would enable earlier identification and initiation of prompt, personalized, and tailored interventions. While some PRMs exist for CRS, few were translated into clinical practice, and human factors associated with their use were not reported. ObjectiveWe aim to explore patients’ and clinicians’ perspectives of the utility and real-world application of PRMs to improve the management of CRS. MethodsFocus groups (N=10) and interviews (N=5) were conducted with patients (N=28) and clinicians (N=26) across 5 European countries. Interactions were audio-recorded, transcribed verbatim, and analyzed thematically. ResultsBoth clinicians and patients recognized the value of having individualized risk predictions for CRS and appreciated how this type of information would facilitate the provision of tailored preventative treatments or supportive care interactions. However, cautious and skeptical attitudes toward the use of PRMs in clinical care were noted by both groups, particularly in relationship to the uncertainty regarding how the information would be generated. Visualization and presentation of PRM information in a usable and useful format for both patients and clinicians was identified as a challenge to their successful implementation in clinical care. ConclusionsFindings from this study provide information on clinicians’ and patients’ perspectives on the clinical use of PRMs for the management of CRS. These international perspectives are important because they provide insight into the risks and benefits of using PRMs to evaluate CRS. In addition, they highlight the need to find ways to more effectively present and use this information in clinical practice. Further research that explores the best ways to incorporate this type of information while maintaining the human side of care is warranted. Trial RegistrationClinicalTrials.gov NCT02356081; https://clinicaltrials.gov/study/NCT02356081

Background: The integration of edge computing into smart healthcare systems requires the development of computationally efficient models and methodologies for monitoring and detecting patients’ healthcare statuses. In this context, mobile devices, such as smartphones, are increasingly employed for the purpose of aiding diagnosis, treatment, and monitoring. Notably, smartphones are widely pervasive and readily accessible to a significant portion of the population. These devices empower individuals to conveniently record and submit voice samples, thereby potentially facilitating the early detection of vocal irregularities or changes. This research focuses on the creation of diverse machine learning frameworks based on vocal samples captured by smartphones to distinguish between pathological and healthy voices. Methods: The investigation leverages the publicly available VOICED dataset, comprising 58 healthy voice samples and 150 samples from voices exhibiting pathological conditions, and machine learning techniques for the classification of healthy and diseased patients through the employment of Mel-frequency cepstral coefficients. Results: Through cross-validated two-class classification, the fine k-nearest neighbor exhibited the highest performance, achieving an accuracy rate of 98.3% in identifying healthy and pathological voices. Conclusions: This study holds promise for enabling smartphones to effectively identify vocal disorders, offering a multitude of advantages for both individuals and healthcare systems, encompassing heightened accessibility, early detection, and continuous monitoring.

Abstract Mounting evidence recognizes structural variations (SVs) and repetitive DNA sequences as crucial players in shaping the existing grape phenotypic diversity at intra- and inter-species levels. To deepen our understanding on the abundance, diversity, and distribution of SVs and repetitive DNAs, including transposable elements (TEs) and tandemly repeated satellite DNA (satDNAs), we re-sequenced the genomes of the ancient grapes Aglianico and Falanghina. The analysis of large copy number variants (CNVs) detected candidate polymorphic genes that are involved in the enological features of these varieties. In a comparative analysis of Aglianico and Falanghina sequences with 21 publicly available genomes of cultivated grapes, we provided a genome-wide annotation of grape TEs at the lineage level. We disclosed that at least two main clusters of grape cultivars could be identified based on the TEs content. Multiple TEs families appeared either significantly enriched or depleted. In addition, in silico and cytological analyses provided evidence for a diverse chromosomal distribution of several satellite repeats between Aglianico, Falanghina, and other grapes. Overall, our data further improved our understanding of the intricate grape diversity held by two Italian traditional varieties, unveiling a pool of unique candidate genes never so far exploited in breeding for improved fruit quality.

The use of alternative renewable sources to totally or partially replace bitumen is one of the most current challenges in the road pavement sector. The growing energy cost and environmental concerns lead to the necessity to find alternative solutions, by supporting at the same time sustainability and circular economy principles. Within this framework, this paper presents the application of a powder lignin, a natural bio-polymer deriving from by-products of wood pulp and paper industry, to replace part of bitumen. The bituminous blend consisting in 70% of bitumen and 30% of powder lignin (by weight) was made in laboratory through the use of a high shear stirring mixer, and a reference plain bitumen characterized by a similar consistency (i.e., same penetration grade) was used as comparison. Then, an extensive investigation on chemical and rheological properties of the bio-binder is presented. Fourier transform infrared spectroscopy (FTIR), saturates, aromatics, resins and asphaltenes (SARA), bending beam rheometer (BBR), frequency sweep tests and multiple stress creep recovery tests (MSCR) with a dynamic shear rheometer (DSR) were performed. Moreover, unaged, short- and long-term aging conditions were considered. Results indicated that powder lignin dominates the rheological behavior of the bio-binder and, from chemical analysis, it seems that it partially acts as a filler and partially as a binder. This would result in improved performances at both low and high temperatures, leading to a wider temperature range of performance grade (PG). Moreover, despite a stiffening effect is recognized, lignin also offers an antioxidant potentiality, reducing the aging susceptibility of the investigated bio-binder.

Abstract Angiopoietin-like 4 (ANGPTL4) is known to regulate various cellular and systemic functions. However, its cell-specific role in endothelial cells (ECs) function and metabolic homeostasis remains to be elucidated. Here, using endothelial-specific Angptl4 knock-out mice (Angptl4 iΔEC ), and transcriptomics and metabolic flux analysis, we demonstrate that ANGPTL4 is required for maintaining EC metabolic function vital for vascular permeability and angiogenesis. Knockdown of ANGPTL4 in ECs promotes lipase-mediated lipoprotein lipolysis, which results in increased fatty acid (FA) uptake and oxidation. This is also paralleled by a decrease in proper glucose utilization for angiogenic activation of ECs. Mice with endothelial-specific deletion of Angptl4 showed decreased pathological neovascularization with stable vessel structures characterized by increased pericyte coverage and reduced permeability. Together, our study denotes the role of endothelial-ANGPTL4 in regulating cellular metabolism and angiogenic functions of EC.

Analyzing the uncertainty of outcomes based on estimates of the data’s membership degrees to fuzzy sets is essential for making decisions. These fuzzy sets are often designated by experts as strong fuzzy partitions of the data domain with trapezoidal fuzzy numbers. Some indices of the fuzzy set’s fuzziness provide an assessment of the degree of uncertainty of the results. It is feasible to bring the fuzzy sets’ fuzziness below a tolerable level by suitably redefining the strong fuzzy partition. Significant differences in the original fuzzy partition, however, result in disparities concerning the decision maker’s approximative reasoning and the interpretability of the results. In light of this, we provide in this study a technique applied to trapezoidal strong fuzzy partitions that, while not appreciably altering the original fuzzy partition, reduces the fuzziness of its fuzzy sets. The fuzziness of the fuzzy sets is assessed using the De Luca and Termini fuzzy entropy. An iterative process is then executed, with the aim of modifying the cores of the trapezoidal fuzzy partitions to decrease their fuzziness. This technique is tested on datasets containing average daily temperatures measured in various cities. The findings demonstrate that this approach strikes a great balance between the goal of lessening the fuzziness of the fuzzy sets and the goal of not appreciably altering the original fuzzy partition.

Vitis vinifera is an important fruit crop which is mainly consumed fresh or used for the production of wine. Genetic improvement programs through New Genomic Techniques (NGTs) aim to develop grapevine varieties resistant to biotic and abiotic stresses or enhancing nutraceutical properties. In order to apply NGTs, maintaining embryogenic calluses from flower tissues is critical. Optimizing culture conditions—pH, gelling agents, temperature, light, growth regulators, and gas composition—is essential for inducing efficient embryogenic responses tailored to each genotype/explant. Ethylene, a pivotal gaseous plant hormone, significantly influences tissue culture by affecting organogenesis and embryogenesis processes in several plants. Modulating ethylene levels shows promise for improving tissue culture vitality. This study evaluates in Vitis vinifera the effects of silver thiosulfate (STS) and salicylic acid (SA) on embryogenic callus growth, specifically investigating their roles in maintaining and inducing embryogenic competence. STS, particularly at 40 µM and 60 µM concentrations, effectively preserved embryogenic competence in Italia and Red Globe calluses, while high SA concentrations showed varied and occasionally adverse effects. At the same time, STS markedly suppressed the non-embryogenic callus growth in recalcitrant variety Italia, potentially increasing the ratio between embryogenic to non-embryogenic calluses development.

mTOR plays a crucial role in cell growth by controlling ribosome biogenesis, metabolism, autophagy, mRNA translation, and cytoskeleton organization. It is a serine/threonine kinase that is part of two distinct extensively described protein complexes, mTORC1 and mTORC2. We have identified a rapamycin-resistant mTOR complex, called mTORC3, which is different from the canonical mTORC1 and mTORC2 complexes in that it does not contain the Raptor, Rictor, or mLST8 mTORC1/2 components. mTORC3 phosphorylates mTORC1 and mTORC2 targets and contains the ETS transcription factor ETV7, which binds to mTOR and is essential for mTORC3 assembly in the cytoplasm. Tumor cells that assemble mTORC3 have a proliferative advantage and become resistant to rapamycin, indicating that inhibiting mTORC3 may have a therapeutic impact on cancer. Here, we investigate which domains or amino acid residues of ETV7 and mTOR are involved in their mutual binding. We found that the mTOR FRB and LBE sequences in the kinase domain interact with the pointed (PNT) and ETS domains of ETV7, respectively. We also found that forced expression of the mTOR FRB domain in the mTORC3-expressing, rapamycin-resistant cell line Karpas-299 out-competes mTOR for ETV7 binding and renders these cells rapamycin-sensitive in vivo. Our data provide useful information for the development of molecules that prevent the assembly of mTORC3, which may have therapeutic value in the treatment of mTORC3-positive cancer.

Shallow landslides, frequently triggered by extreme events such as heavy rainfall, snowmelt, or earthquakes, affect vast areas with remarkable density. In the immediate aftermath of such events, it becomes crucial to rapidly assess landslides distribution and pinpoint the most severely affected areas to prioritize damage assessments and guide field survey operations effectively. Once the emergency phase subsides, the attention can shift to enhancing the accuracy of landslide inventory. In this work, we introduce the two-phase methodology “PANDA”, the unsuPervised shAllow laNdslide rapiD mApping, for the low-cost mapping of the potential landslides, firstly in the emergency phase and then, with an improved version, in the post-emergency one. This approach utilizes variations in NDVI derived from Sentinel-2 satellite imagery and geomorphological filters. We applied PANDA to rainfall events in the northeastern Apennine range, Italy, occurred in May 2023, causing dramatic social and economic consequences for this mountain territory. Within just five days of obtaining Sentinel-2 post-event imagery, we produced a reliable, ready-to-use map covering a vast area (∼4000 km2). The map tested during emergency field mapping shows positive feedback. In the post-emergency phase, accuracy was enhanced using completely cloud-free imagery, a filter to identify false positives associated with land use changes, a higher resolution digital terrain model (DTM), and an iterative approach to optimize NDVI and slope thresholds. Potential landslide density related with rainfall, indicating that the most severely affected region attained a density of approximately 50 landslides/km2. Validation against an independent manual inventory based on high-resolution imagery demonstrated encouraging accuracy results from both inventories, with a noticeable increase in the F1 score for the post-emergency version.

Abstract Duchenne muscular dystrophy (DMD) is a devastating X-linked muscular disease, caused by mutations in the DMD gene encoding Dystrophin and affecting 1:5000 boys worldwide. Lack of Dystrophin leads to progressive muscle wasting and degeneration resulting in cardiorespiratory failure. Despite the absence of a definitive cure, innovative therapeutic avenues are emerging. Myopathologic studies are important to further understand the biological mechanisms of the disease and to identify histopathologic benchmarks for clinical evaluations. We conducted a myopathologic analysis on twenty-four muscle biopsies from DMD patients, with particular emphasis on regeneration, fibro-adipogenic progenitors and muscle stem cells behavior. We describe an increase in content of fibro-adipogenic progenitors, central orchestrators of fibrotic progression and lipid deposition, concurrently with a decline in muscle regenerative capacity. This regenerative impairment strongly correlates with compromised activation and expansion of muscle stem cells. Furthermore, our study uncovers an early acquisition of a senescence phenotype by DMD-afflicted muscle stem cells. Here we describe the myopathologic trajectory intrinsic to DMD and establish muscle stem cell senescence as a pivotal readout for future therapeutic interventions.

Hepatocellular carcinoma (HCC) represents the most common primary liver cancer and is considered a major global health problem as one of the leading causes of cancer-related death in the world. Due to the increase in life expectancy and the epidemiological growth of specific risk factors, such as metabolic dysfunction-associated steatotic liver disease (MASLD), the incidence of HCC is growing globally, and mortality rates are still high. Moreover, patients frequently present at an intermediate or advanced tumor stage, when curative treatments, such as surgical resection, liver transplantation or ablation are no longer applicable. In these cases, trans-arterial chemoembolization (TACE), trans-arterial radioembolization (TARE), and systemic therapy are the only suitable options to achieve disease control. The multi-kinase inhibitor Sorafenib has been the only systemic treatment available for unresectable advanced HCC for almost a decade, but in the last couple of years new therapeutic options have emerged. Recent advances in understanding the interactions between the tumor and its microenvironment, especially cancer immune escape, led to the advent of immunotherapy. Currently, first-line systemic treatment for HCC is represented by the combination of the immune checkpoint inhibitor (ICI) Atezolizumab plus Bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, but many other ICIs have been investigated, such as Nivolumab, Pembrolizumab, Durvalumab and Ipilimumab. However, the problem of second- and third-line therapies, and the correct sequence of treatments remains open and is not addressed in most studies. This explains the urge to find new systemic treatments that can improve the survival and quality of life in patients that can go beyond the first line of treatment. The aim of this paper is to offer a complete overview of the most recent innovations in systemic treatments for unresectable locally advanced and metastatic HCC, including emerging therapies, with a particular focus on treatment sequences. Moreover, we will provide an outlook on possible future approaches to patients who progress beyond first-line therapies.

This research presents a GIS-based framework used to detect urban heat islands and determine which urban settlement elements are most critical when heatwave risks exist. The proposed method uses the Iterative Self-Organizing Data Analysis (ISODATA) clustering algorithm applied to the satellite land surface temperature distribution recorded during heatwaves for the detection of urban heat islands. A pixel classification confidence level maximization approach, obtained by running a maximum likelihood classification algorithm, is performed to determine the optimal number of clusters. The areas labeled as hotspots constitute the detected urban heat islands (UHIs). This method was tested on an urban settlement set up by the municipality of Naples (Italy). Comparison tests were performed with other urban heat island detection methods such as standard deviation thresholding and Getis-Ord Gi* hotspot detection; indices measuring the density of buildings, the percentage of permeable open spaces, and vegetation cover are taken into consideration to evaluate the accuracy of the urban heat islands detected. These tests highlight that the proposed method provides the most accurate results. It could be an effective tool to support the decision maker in evaluating which urban areas are the most critical during heatwave scenarios.

Motor impairment is a common issue in stroke patients, often affecting the upper limbs. To this standpoint, robotic neurorehabilitation has shown to be highly effective for motor function recovery. Notably, Machine learning (ML) may be a powerful technique able to identify the optimal kind and intensity of rehabilitation treatments to maximize the outcomes. This retrospective observational research aims to assess the efficacy of robotic devices in facilitating the functional rehabilitation of upper limbs in stroke patients through ML models. Specifically, clinical scales, such as the Fugl-Meyer Assessment (A-D) (FMA), the Frenchay Arm Test (FAT), and the Barthel Index (BI), were used to assess the patients’ condition before and after robotic therapy. The values of these scales were predicted based on the patients’ clinical and demographic data obtained before the treatment. The findings showed that ML models have high accuracy in predicting the FMA, FAT, and BI, with R-squared (R2) values of 0.79, 0.57, and 0.74, respectively. The findings of this study suggest that integrating ML into robotic therapy may have the capacity to establish a personalized and streamlined clinical practice, leading to significant improvements in patients’ quality of life and the long-term sustainability of the healthcare system.

A stroke represents a significant medical condition characterized by the sudden interruption of blood flow to the brain, leading to cellular damage or death. The impact of stroke on individuals can vary from mild impairments to severe disability. Treatment for stroke often focuses on gait rehabilitation. Notably, assessing muscle activation and kinematics patterns using electromyography (EMG) and stereophotogrammetry, respectively, during walking can provide information regarding pathological gait conditions. The concurrent measurement of EMG and kinematics can help in understanding disfunction in the contribution of specific muscles to different phases of gait. To this aim, complexity metrics (e.g., sample entropy; approximate entropy; spectral entropy) applied to EMG and kinematics have been demonstrated to be effective in identifying abnormal conditions. Moreover, the conditional entropy between EMG and kinematics can identify the relationship between gait data and muscle activation patterns. This study aims to utilize several machine learning classifiers to distinguish individuals with stroke from healthy controls based on kinematics and EMG complexity measures. The cubic support vector machine applied to EMG metrics delivered the best classification results reaching 99.85% of accuracy. This method could assist clinicians in monitoring the recovery of motor impairments for stroke patients.

This research presents a new method for detecting urban areas critical for the presence of air pollutants during periods of heatwaves. The proposed method uses a geospatial model based on the construction of Thiessen polygons and a fuzzy model based on assessing, starting from air quality control unit measurement data, how concentrations of air pollutants are distributed in the urban study area during periods of heatwaves and determine the most critical areas as hotspots. The proposed method represents an optimal trade-off between the accuracy of the detection of critical areas and the computational speed; the use of fuzzy techniques for assessing the intensity of concentrations of air pollutants allows evaluators to model the assessments of critical areas more naturally. The method is implemented in a GIS-based platform and has been tested in the city of Bologna, Italy. The resulting criticality maps of PM10, NO2, and PM2.5 pollutants during a heatwave period that occurred from 10 to 14 July 2023 revealed highly critical hotspots with high pollutant concentrations in densely populated areas. This framework provides a portable and easily interpretable decision support tool which allows you to evaluate which urban areas are most affected by air pollution during heatwaves, potentially posing health risks to the exposed population.

Esta Nota Técnica tem por objetivo apresentar o Sistema de Informações (SI) de Recursos Hídricos do Estado do Rio Grande do Sul (SIRH/RS). As fontes de dados consultadas foram disponibilizadas no próprio site da Secretaria do Meio Ambiente e Infraestrutura do Rio Grande do Sul (SEMA/RS) ou nos sites que hospedam dados de interesse para a gestão de recursos hídricos no Estado. O SI foi organizado segundo os principais temas de interesse em recursos hídricos (ex.: usos da água -superficial e subterrânea, saneamento, etc.), com o foco na reunião, integração e disponibilização dos dados. Além disso, cada tema teve uma descrição básica para facilitar ao usuário o acesso e a compreensão sobre os temas. Espera-se que a unificação do sistema de recursos hídricos forneça o acesso a dados e informações com celeridade aos usuários e forneça um novo marco na gestão de recursos hídricos do RS baseada na governança de dados, tornando-a mais interativa e participativa. Recomendações de manutenção e atualizações para os gestores e usuários são indicadas para que o Sistema de Informações (SI) possa ter melhorias periódicas.

Neuroimaging studies have suggested an important role for the default mode network (DMN) in disorders of consciousness (DoC). However, the extent to which DMN connectivity can discriminate DoC states-unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS)-is less evident. Particularly, it is unclear whether effective DMN connectivity, as measured indirectly with dynamic causal modelling (DCM) of resting EEG can disentangle UWS from healthy controls and from patients considered conscious (MCS+). Crucially, this extends to UWS patients with potentially "covert" awareness (minimally conscious star, MCS*) indexed by voluntary brain activity in conjunction with partially preserved frontoparietal metabolism as measured with positron emission tomography (PET+ diagnosis; in contrast to PET- diagnosis with complete frontoparietal hypometabolism). Here, we address this gap by using DCM of EEG data acquired from patients with traumatic brain injury in 11 UWS (6 PET- and 5 PET+) and in 12 MCS+ (11 PET+ and 1 PET-), alongside with 11 healthy controls. We provide evidence for a key difference in left frontoparietal connectivity when contrasting UWS PET- with MCS+ patients and healthy controls. Next, in a leave-one-subject-out cross-validation, we tested the classification performance of the DCM models demonstrating that connectivity between medial prefrontal and left parietal sources reliably discriminates UWS PET- from MCS+ patients and controls. Finally, we illustrate that these models generalize to an unseen dataset: models trained to discriminate UWS PET- from MCS+ and controls, classify MCS* patients as conscious subjects with high posterior probability (pp > .92). These results identify specific alterations in the DMN after severe brain injury and highlight the clinical utility of EEG-based effective connectivity for identifying patients with potential covert awareness.

O enquadramento de corpos hídricos é um importante instrumento para o acompanhamento da situação da qualidade da água. Avaliar e informar a distância na qual os principais cursos d’água se encontram em relação às metas pretendidas pelo enquadramento constitui-se em uma forma de avaliação profícua, mas normalmente pouco realizada. Esse estudo se propõe a aplicar a metodologia do Índice de Conformidade ao Enquadramento (ICE), desenvolvida pelo Canadian Council of Ministers of the Environment, em 172 estações em 19 bacias hidrográficas no Rio Grande do Sul, no período de 2015 a 2022. O estudo considerou 13 parâmetros definidos na resolução CONAMA Nº 357/2005. Os resultados indicaram que 45% das estações observadas ficaram com índice “razoável”, seguido de 41% com índice “marginal”, com resultados comprometidos principalmente pelos parâmetros cádmio, E. coli, ferro, fósforo, manganês e OD. O ICE se mostrou uma ferramenta adequada para informar de forma eficaz aos gestores e atores envolvidos a condição dos corpos hídricos de forma geral e realizar comparações entre bacias distintas.

Category: Arthroscopy; Ankle Introduction/Purpose: During the last decade, arthroscopic procedures have been replacing open techniques in Haglund's disease treatment due to their considerable advantages. Endoscopic calcaneoplasty is a technique that allows resection of posterosuperior calcaneal exostosis and retrocalcaneal bursitis. The objective of this article is to describe this technique and report its clinical and subjective outcome. Methods: A retrospective cohort study was carried out in patients who underwent endoscopic surgery between July 2014 and March 2020. The patients were clinically and radiologically evaluated. All cases included were studied prior to the intervention and postoperative. All patients who did not show any clinical improvement after 6 months of conservative treatment were surgically treated with endoscopic treatment in the prone position through two posterior arthroscopic portals. Results: In this study, 14 endoscopic calcaneoplasties were performed in 14 patients, with an average follow-up of 40 months. The visual analog scale improved from a preoperative average value of 9.07 to 1.79 after surgery (p> 0.0001). The AOFAS scale rose from 38.71 before surgery to 94.57 postoperative (p> 0.0001). Good subjective results were observed in twelve patients ( 85.71%) and all of them would have surgery again. There were no wound complications or infections. No patient required reoperation. Conclusion: Endoscopic treatment is a useful technique, with good clinical and subjective results and few complications, being a good alternative to open techniques.

Neuroscientists agree on the value of locating the source of consciousness within the brain. Anaesthesiologists are no exception, and have their own operational definition of consciousness based on phenomenological observations during anaesthesia. The full functional correlates of consciousness are yet to be precisely identified, however rapidly evolving progress in this scientific domain has yielded several theories that attempt to model the generation of consciousness. They have received variable support from experimental observations, including those involving anaesthesia and its ability to reversibly modulate different aspects of consciousness. Aside from the interest in a better understanding of the mechanisms of consciousness, exploring the functional tenets of the phenomenological consciousness states of general anaesthesia has the potential to ultimately improve patient management. It could facilitate the design of specific monitoring devices and approaches, aiming at reliably detecting each of the possible states of consciousness during an anaesthetic procedure, including total absence of mental content (unconsciousness), and internal awareness (sensation of self and internal thoughts) with or without conscious perception of the environment (connected or disconnected consciousness, respectively). Indeed, it must be noted that unresponsiveness is not sufficient to infer absence of connectedness or even absence of consciousness. This narrative review presents the current knowledge in this field from a system-level, underlining the contribution of anaesthesia studies in supporting theories of consciousness, and proposing directions for future research.

ABSTRACTInvolvement of all relevant stakeholders will be of utmost importance for the success of the developing EU HTA harmonization process.A multi-step procedure was applied to develop a survey across stakeholders/collaborators within the EU HTA framework to assess their current level of involvement, determine their suggested future role, identify challenges to contribution, and highlight efficient ways to fulfilling their role. The ‘key’ stakeholder groups identified and covered by this research included: patients‘, clinicians‘, regulatory, and Health Technology Developer representatives. The survey was circulated to a wide expert audience including all relevant stakeholder groups in order to determine self-perception by the ‘key’ stakeholders regarding involvement in the HTA process (self-rating), and in a second, slightly modified version of the questionnaire, to determine the perception of ‘key’ stakeholder involvement by HTA bodies, payers, and policymakers (external rating). Predefined analyses were conducted on the submitted responses.Fifty-four responses were received (patients 9; clinicians: 8; regulators: 4; HTDs 14; HTA bodies: 7; Payers: 5; policymakers 3; others 4). The mean self-perceived involvement score was consistently lower for each of the ‘key’ stakeholder groups than the respective external ratings. Based on the qualitative insights generated in the survey, a RACI Chart (Responsible/Accountable/Consulted/Informed) was developed for each of the stakeholder groups to determine their roles and involvement in the current EU HTA process.Our findings suggest extensive effort and a distinct research agenda are required to ensure adequate involvement of the key stakeholder groups in the evolving EU HTA process.

Abstract Congenital titinopathies are an emerging group of a potentially severe form of congenital myopathies caused by biallelic mutations in titin, encoding the largest existing human protein involved in the formation and stability of sarcomeres. In this study we describe a patient with a congenital myopathy characterized by multiple contractures, a rigid spine, non progressive muscular weakness, and a novel homozygous TTN pathogenic variant in a metatranscript-only exon: the c.36400A > T, p.Lys12134*. Muscle biopsies showed increased internalized nuclei, variability in fiber size, mild fibrosis, type 1 fiber predominance, and a slight increase in the number of satellite cells. RNA studies revealed the retention of intron 170 and 171 in the open reading frame, and immunoflourescence and western blot studies, a normal titin content. Single fiber functional studies showed a slight decrease in absolute maximal force and a cross-sectional area with no decreases in tension, suggesting that weakness is not sarcomere-based but due to hypotrophy. Passive properties of single fibers were not affected, but the observed increased calcium sensitivity of force generation might contribute to the contractural phenotype and rigid spine of the patient. Our findings provide evidence for a pathogenic, causative role of a metatranscript-only titin variant in a long survivor congenital titinopathy patient with distal arthrogryposis and rigid spine.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with high mortality due to early metastatic dissemination and high chemoresistance. All these factors are favored by its extracellular matrix (ECM)-rich microenvironment, which is also highly hypoxic and acidic. Gemcitabine (GEM) is still the first-line therapy in PDAC. However, it is quickly deaminated to its inactive metabolite. Several GEM prodrugs have emerged to improve its cytotoxicity. Here, we analyzed how the acidic/hypoxic tumor microenvironment (TME) affects the response of PDAC cell death and invadopodia-mediated ECM proteolysis to both GEM and its C18 prodrug. Methods: For this, two PDAC cell lines, PANC-1 and Mia PaCa-2 were adapted to pHe 6.6 or not for 1 month, grown as 3D organotypic cultures and exposed to either GEM or C18 in the presence and absence of acidosis and the hypoxia inducer, deferoxamine. Results: We found that C18 has higher cytotoxic and anti-invadopodia activity than GEM in all culture conditions and especially in acid and hypoxic environments. Conclusions: We propose C18 as a more effective approach to conventional GEM in developing new therapeutic strategies overcoming PDAC chemoresistance.

Alterations in cellular signaling, chronic inflammation, and tissue remodeling contribute to hepatocellular carcinoma (HCC) development. The release of damage-associated molecular patterns (DAMPs) upon tissue injury and the ensuing sterile inflammation have also been attributed a role in HCC pathogenesis. Cargoes of extracellular vesicles (EVs) and/or EVs themselves have been listed among circulating DAMPs but only partially investigated in HCC. Mitochondria-derived vesicles (MDVs), a subpopulation of EVs, are another missing link in the comprehension of the molecular mechanisms underlying the onset and progression of HCC biology. EVs have been involved in HCC growth, dissemination, angiogenesis, and immunosurveillance escape. The contribution of MDVs to these processes is presently unclear. Pyroptosis triggers systemic inflammation through caspase-dependent apoptotic cell death and is implicated in tumor immunity. The analysis of this process, together with MDV characterization, may help capture the relationship among HCC development, mitochondrial quality control, and inflammation. The combination of immune checkpoint inhibitors (i.e., atezolizumab and bevacizumab) has been approved as a synergistic first-line systemic treatment for unresectable or advanced HCC. The lack of biomarkers that may allow prediction of treatment response and, therefore, patient selection, is a major unmet need. Herein, we overview the molecular mechanisms linking mitochondrial dysfunction, inflammation, and pyroptosis, and discuss how immunotherapy targets, at least partly, these routes.

Parkinson’s disease (PD) is a prevalent neurodegenerative disorder, primarily associated with dopaminergic neuron depletion in the Substantia Nigra. Current treatment focuses on compensating for dopamine (DA) deficiency, but the blood–brain barrier (BBB) poses challenges for effective drug delivery. Using differentiated SH-SY5Y cells, we investigated the co-administration of DA and the antioxidant Grape Seed Extract (GSE) to study the cytobiocompability, the cytoprotection against the neurotoxin Rotenone, and their antioxidant effects. For this purpose, two solid lipid nanoparticle (SLN) formulations, DA-co-GSE-SLNs and GSE-ads-DA-SLNs, were synthesized. Such SLNs showed mean particle sizes in the range of 187–297 nm, zeta potential values in the range of −4.1–−9.7 mV, and DA association efficiencies ranging from 35 to 82%, according to the formulation examined. The results showed that DA/GSE-SLNs did not alter cell viability and had a cytoprotective effect against Rotenone-induced toxicity and oxidative stress. In addition, this study also focused on the evaluation of Alpha-synuclein (aS) levels; SLNs showed the potential to modulate the Rotenone-mediated increase in aS levels. In conclusion, our study investigated the potential of SLNs as a delivery system for addressing PD, also representing a promising approach for enhanced delivery of pharmaceutical and antioxidant molecules across the BBB.

The reproduction of Crocus sativus L., a sterile triploid plant, is carried out exclusively through corms, whose size determines the saffron yield. The development of daughter corms (DC) is supported by photoassimilates supplied by the leaves as well as by the mother corms (MC). While biomass partitioning during DC development is well studied, growth dynamics in terms of cell number and size, the involved meristems, as well as carbohydrate partition and allocation, are not yet fully understood. We conducted a comprehensive study into saffron corm growth dynamics at the macroscopic and microscopic levels. Variations in carbohydrate content and enzymatic activities related to sucrose metabolism in sources and sinks were measured. Two key meristems were identified. One is involved in vascular connections between DC and MC. The other is a thickening meristem responsible for DC enlargement. This research explains how the previously described phases of corm growth correlate with variations in cell division, enlargement dynamics, and carbohydrate partitioning among organs. Results also elucidated that the end of DC growth relates to a significant drop in MC root biomass, limiting the water supply for the DC growth, and establishing the onset of leaf wilting. The lack of starch accumulation in aged leaf cells is noteworthy, as is the accumulation of lipids. We hypothesize a signaling role of sugars in DC growth initiation, stop, and leaf aging. Finally, we established a predominant role of sucrose synthase as a sucrolytic enzyme in the maintenance of the high flux of carbon for starch synthesis in DC. Together, the obtained results pave the way for the definition of strategies leading to better control of saffron corm development.

One of the issues of greatest interest in urban planning today concerns the evaluation of the most vulnerable urban areas in the presence of different types of climate hazards. In this research, a hierarchical fuzzy MCDA model is implemented on a GIS-based platform aimed at detecting the urban areas most at risk in the presence of heatwave and pluvial flooding scenarios. The proposed model aims to detect the urban areas most vulnerable to both the two climatic phenomena and the two types of hazards as independent events; it partitions the physical component of an urban settlement into two subsystems: buildings and open spaces, and it determines the criticality of a subzone of the urban area of study by evaluating the vulnerabilities of the two subsystems to the two phenomena. The use of a hierarchical fuzzy MCDA model facilitates the modeling of the two subsystems and the assessment of their vulnerability to the two phenomena, and it provides a computationally fast tool for detecting critical urban areas. The model was tested on a study area made up of the districts of the central-eastern area of the city of Naples (Italy); it was divided into subzones made up of individual census areas. The most critical areas are represented by the subzones with criticality values higher than a specific threshold.

Pancreatic cancer is a highly lethal disease with a 5-year survival rate of around 11–12%. Surgery, being the treatment of choice, is only possible in 20% of symptomatic patients. The main reason is that when it becomes symptomatic, IT IS the tumor is usually locally advanced and/or has metastasized to distant organs; thus, early diagnosis is infrequent. The lack of specific early symptoms is an important cause of late diagnosis. Unfortunately, diagnostic tumor markers become positive at a late stage, and there is a lack of early-stage markers. Surgical and non-surgical cases are treated with neoadjuvant and/or adjuvant chemotherapy, and the results are usually poor. However, personalized targeted therapy directed against tumor drivers may improve this situation. Until recently, many pancreatic tumor driver genes/proteins were considered untargetable. Chemical and physical characteristics of mutated KRAS are a formidable challenge to overcome. This situation is slowly changing. For the first time, there are candidate drugs that can target the main driver gene of pancreatic cancer: KRAS. Indeed, KRAS inhibition has been clinically achieved in lung cancer and, at the pre-clinical level, in pancreatic cancer as well. This will probably change the very poor outlook for this disease. This paper reviews the genetic characteristics of sporadic and hereditary predisposition to pancreatic cancer and the possibilities of a personalized treatment according to the genetic signature.

Marine bioconstructions are complex habitats that represent a hotspot of biodiversity. Among Mediterranean bioconstructions, those thriving on mesophotic bottoms on southeastern Italian coasts are of particular interest due to their horizontal and vertical extension. In general, the communities that develop in the Mediterranean twilight zone encompassed within the first 30 m of depth are better known, while relatively few data are available on those at greater depths. By further investigating the diversity and structure of mesophotic bioconstructions in the southern Adriatic, we can improve our understanding of Mediterranean biodiversity while developing effective conservation strategies to preserve these habitats of particular interest. The dataset reported here comprises records of benthic marine taxa from algae and invertebrate mesophotic bioconstructions investigated at six sites along the southern Adriatic coast of Italy, at depths between approximately 25 and 65 m. The dataset contains a total of 1718 records, covering 11 phyla and 648 benthic taxa, of which 580 were recognized at the species level. These data could provide a reference point for further investigations with descriptive or management purposes, including the possible assessment of mesophotic bioconstructions as refuges for shallow-water species.

Objective: Analyze the postoperative complications after repairing acute Achilles tendon rupture and compare them according to the surgical approach (open surgery (OS) or minimally invasive surgery (MIS)) and the patient’s comorbidities. Methods: A retrospective analytical study including 154 consecutive patients with an acute Achilles tendon rupture submitted to surgery and divided into OS and MIS cohorts. The following relevant comorbidities were analyzed: obesity, diabetes mellitus, smoking, dyslipidemia, gout, chronic corticosteroid use, connective tissue pathologies, transplant history, cancer treatment patients, and postoperative complications. Results: Seventy-eight patients (50.6%) were treated surgically with an OS technique and 76 (49.4%) with an MIS approach. Twenty patients (13%) had postoperative complications between the two cohorts (OS 11.5%; MIS 14.5%; p = 0.588). No statistically significant difference was found in the logistic regression of the risk of the surgical approaches and complications. Obesity had a significant statistical difference when complications and comorbidities were compared. Conclusions: Patients with obesity have a higher risk of developing postoperative complications with both OS and MIS techniques. No relationship was found between the type of surgical approach and a higher percentage of postoperative complications in treating acute Achilles tendon rupture.

Since 2000, the Moderate Resolution Imaging Spectroradiometer (MODIS) has acquired infrared images of the Earth’s surface daily. These data have made it possible to measure the thermal energy radiated by the world’s most famous volcanoes and also to discover and track eruptions in remote and poorly monitored regions. In this work, we present the database of Volcanic Radiative Power (VRP, in W) time series, recorded by the MIROVA (Middle Infrared Observation of Volcanic Activity) system over 2 decades of MODIS observations (2000–2019) at 111 active volcanoes. The database reveals that globally, the number of thermally active volcanoes each year varies between 60 and 80, almost equally partitioned between volcanoes with a basic (50%) and intermediate (45%) composition, while only 5% is represented by volcanoes erupting acidic lavas. Within the investigated period, the global-scale heat flux was almost stationary, and occasionally punctuated by peaks associated with the largest effusive eruptions (e.g., Bardarbunga and Kilauea). The Volcanic Radiative Energy (VRE, in J) emitted by basic volcanoes (∼1.8 × 1018 J) in 20 years constitutes 91% of the total, while intermediates and acids contribute only 8% (∼1.8 × 1017 J) and 1% (∼1.7 × 1016 J), respectively. A comparison with the volume of lava erupted effusively by the same volcanoes reveals that this difference is attributed to the lower efficiency in radiating thermal energy of increasingly acidic (viscous) lava bodies. Each compositional group is associated with a specific relationship between VRE and erupted volume which characterises most of the effusive volcanoes. On the other hand, some open-vent volcanoes reveal that much more heat is released than that theoretically radiated by the erupted lava. This imbalance (hereby called excess radiation) is attributed to an additional heat source, likely associated with an underlying convective magma column and/or to outgassing through a permeable conduit. We are convinced that the database presented in this work will be useful to support new emerging studies on global-scale volcanism and will contribute to a better understanding of each volcanic system.

Many modern applications are modeled using graphs of some kind. Given a graph, assigning labels (usually called colors) to vertices is called graph coloring. Colors must be assigned so that no two vertices connected by an edge share the same color. Graph coloring has essential applications in many different fields, and many scalable algorithms have been proposed to solve it efficiently, such that researchers have recently started experimenting with coloring, even on many-core GPU devices. In our work, we selected, analyzed, implemented, and compared state-of-the-art algorithms suited for multi-core CPU and many-core GPU architectures. Our analysis allowed us to discover the advantages and disadvantages of each algorithm, and enabled us to implement new strategies for those algorithms running on CPU and GPU devices. We propose a new technique based on “value permutation” and “index shifting” that, once applied to the Jones-Plassmann-Luby algorithm can reduce both the runtime and the number of colors. We compare our code on standard graph benchmarks with the two most used state-of-the-art applications, cuSparse’s csrColor and Gunrock’s implementations, and one innovative approach named Atos. We present extensive results in terms of computation time and quality of the solution. We show that our fastest implementation is able to achieve high average speedups on mesh-like graphs, with a geometric mean (harmonic mean) of 3.16x (3.05x) against Gunrock, 4.09x (3.06x) against cuSparse, and 4.45x (2.21x) against Atos. Nonetheless it proves to be significantly less effective on scale-free graphs, winning consistently only against Gunrock, with geometric mean (harmonic mean) speedups of 2.76x (2.71x) against Gunrock, 0.13x (0.11x) against cuSparse, and 0.03x (0.01x) against Atos. Moreover, it produces 47% fewer colors than cuSparse, 7% fewer colors than Gunrock, and 63% more colors than Atos.

Abstract Objectives Key challenges for a joint European Health Technology Assessment (HTA) include consolidated approaches towards the choice of adequate comparator(s), selection of endpoints that are relevant to patients with a given disease, dealing with remaining uncertainties as well as transparent and consistent management of related processes. We aimed to further crystallize related core domains within these four areas that warrant further research and scrutiny. Methods Building on the outcomes of a previously conducted questionnaire survey, four key areas, processes, uncertainty, comparator choice and endpoint selection, were identified. At the inaugural convention of the European Access Academy dedicated working groups were established defining and prioritizing core domains for each of the four areas. The working groups consisted of ~ 10 participants each, representing all relevant stakeholder groups (patients/ clinicians/ regulators/ HTA & payers/ academia/ industry). Story books identifying the work assignments were shared in advance. Two leads and one note taker per working group facilitated the process. All rankings were conducted on an ordinal Likert Response Scale scoring from 1 (low priority) to 7 (high priority). Results Identified key domains include for processes: i) address (resource-) challenge of multiple PICOs (Patient/ Intervention/ Comparator/ Outcomes), ii) time and capacity challenges, iii) integrating all involved stakeholders, iv) conflicts and aligning between different multi-national stakeholders, v) interaction with health technology developer; for uncertainty: i) early and inclusive collaboration, ii) agreement on feasibility of RCT and acceptance of uncertainty, iii) alignment on closing evidence gaps, iv) capacity gaps; for comparator choice: i) criteria for the choice of comparator in an increasingly fragmented treatment landscape, ii) reasonable number of comparators in PICOs, iii) shape Early Advice so that comparator fulfils both regulatory and HTA needs, iv) acceptability of Indirect Treatment Comparisons (ITC), v) ensure broad stakeholder involvement in comparator selection; for endpoint selection: i) approaching new endpoints; ii) patient preferences on endpoints; iii) position of HTA and other stakeholders; iv) long-term generation and secondary use of data; v) endpoint challenges in RCTs. Conclusions The implementation of a joint European HTA assessment is a unique opportunity for a stronger European Health Union. We identified 19 domains related to the four key areas, processes, uncertainty, comparator choice and endpoint selection that urgently need to be addressed for this regulation to become a success.

Introduction: Treatment advances for metastatic breast cancer (mBC) have improved overall survival (OS) in some mBC subtypes; however, there remains no cure for mBC. Considering the use of progression-free survival (PFS) and other surrogate endpoints in clinical trials, we must understand patient perspectives on measures used to assess treatment efficacy. Objective: To explore global patient perceptions of the concept of PFS and its potential relation to quality of life (QoL). Materials and methods: Virtual roundtables in Europe and the United States and interviews in Japan with breast cancer patients, patient advocates, and thought leaders. Discussions were recorded, transcribed, and analyzed thematically. Results: Lengthened OS combined with no worsening or improvement in QoL remain the most important endpoints for mBC patients. Time when the disease is not progressing is meaningful to patients when coupled with improvements in QoL and no added treatment toxicity. Clinical terminology such as “PFS” is not well understood, and participants underscored the need for patient-friendly terminology to better illustrate the concept. Facets of care that patients with mBC value and that may be related to PFS include relief from cancer-related symptoms and treatment-related toxicities as well as the ability to pursue personal goals. Improved communication between patients and providers on managing treatment-related toxicities and addressing psychosocial challenges to maintain desired QoL is needed. Conclusion: While OS and QoL are considered the most relevant endpoints, patients also value periods of time without disease progression. Incorporation of these considerations into the design and conduct of future clinical trials in mBC, as well as HTA and reimbursement decision-making, is needed to better capture the potential value of a therapeutic innovation.

BackgroundImproving the functional recovery of patients with DoC remains one of the greatest challenges of the field. Different theories exist about the role of the anterior (prefrontal areas) versus posterior (parietal areas) parts of the brain as hotspots for the recovery of consciousness. Repetitive transcranial magnetic stimulation (rTMS) is a powerful non-invasive brain stimulation technique for the treatment of DoC. However, a direct comparison of the effect of TMS treatment on the front versus the back of the brain has yet to be performed. In this study, we aim to assess the short- and long-term effects of frontal and parietal rTMS on DoC recovery and characterize responders phenotypically.Methods/designNinety patients with subacute and prolonged DoC will be included in a two-part multicenter prospective study. In the first phase (randomized controlled trial, RCT), patients will undergo four rTMS sessions in a crossover design over 10 days, targeting (i) the left dorsolateral prefrontal cortex (DLPFC) and (ii) the left angular gyrus (AG), as well as (iii & iv) their sham alternatives. In the second phase (longitudinal personalized trial), patients will receive personalized stimulations for 20 working days targeting the brain area that showed the best results in the RCT and will be randomly assigned to either active or sham intervention. The effects of rTMS on neurobehavioral and neurophysiological functioning in patients with DoC will be evaluated using clinical biomarkers of responsiveness (i.e., the Coma Recovery Scale-Revised; CRS-R), and electrophysiological biomarkers (e.g., power spectra, functional and effective connectivity, perturbational complexity index before and after intervention). Functional long-term outcomes will be assessed at 3 and 6 months post-intervention. Adverse events will be recorded during the treatment phase.DiscussionThis study seeks to identify which brain region (front or back) is best to stimulate for the treatment of patients with DoC using rTMS, and to characterize the neural correlates of its action regarding recovery of consciousness and functional outcome. In addition, we will define the responders’ profile based on patients’ characteristics and functional impairments; and develop biomarkers of responsiveness using EEG analysis according to the clinical responsiveness to the treatment.Clinical Trial Registrationhttps://clinicaltrials.gov/ct2/show/NCT04401319, Clinicaltrials.gov, n° NCT04401319.

Insulin secretion from pancreatic β cells is essential to the maintenance of glucose homeostasis. Defects in this process result in diabetes. Identifying genetic regulators that impair insulin secretion is crucial for the identification of novel therapeutic targets. Here, we show that reduction of ZNF148 in human islets, and its deletion in stem cell–derived β cells (SC–β cells), enhances insulin secretion. Transcriptomics of ZNF148-deficient SC–β cells identifies increased expression of annexin and S100 genes whose proteins form tetrameric complexes involved in regulation of insulin vesicle trafficking and exocytosis. ZNF148 in SC–β cells prevents translocation of annexin A2 from the nucleus to its functional place at the cell membrane via direct repression of S100A16 expression. These findings point to ZNF148 as a regulator of annexin-S100 complexes in human β cells and suggest that suppression of ZNF148 may provide a novel therapeutic strategy to enhance insulin secretion.

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by a range of motor and non-motor symptoms. One of the notable non-motor symptoms of PD is the presence of vocal disorders, attributed to the underlying pathophysiological changes in the neural control of the laryngeal and vocal tract musculature. From this perspective, the integration of machine learning (ML) techniques in the analysis of speech signals has significantly contributed to the detection and diagnosis of PD. Particularly, MEL Frequency Cepstral Coefficients (MFCCs) and Gammatone Frequency Cepstral Coefficients (GTCCs) are both feature extraction techniques commonly used in the field of speech and audio signal processing that could exhibit great potential for vocal disorder identification. This study presents a novel approach to the early detection of PD through ML applied to speech analysis, leveraging both MFCCs and GTCCs. The recordings contained in the Mobile Device Voice Recordings at King’s College London (MDVR-KCL) dataset were used. These recordings were collected from healthy individuals and PD patients while they read a passage and during a spontaneous conversation on the phone. Particularly, the speech data regarding the spontaneous dialogue task were processed through speaker diarization, a technique that partitions an audio stream into homogeneous segments according to speaker identity. The ML applied to MFCCS and GTCCs allowed us to classify PD patients with a test accuracy of 92.3%. This research further demonstrates the potential to employ mobile phones as a non-invasive, cost-effective tool for the early detection of PD, significantly improving patient prognosis and quality of life.