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This comprehensive Review delves into the chemical principles governing RNA-mediated crowding events, commonly referred to as granules or biological condensates. We explore the pivotal role played by RNA sequence, structure, and chemical modifications in these processes, uncovering their correlation with crowding phenomena under physiological conditions. Additionally, we investigate instances where crowding deviates from its intended function, leading to pathological consequences. By deepening our understanding of the delicate balance that governs molecular crowding driven by RNA and its implications for cellular homeostasis, we aim to shed light on this intriguing area of research. Our exploration extends to the methodologies employed to decipher the composition and structural intricacies of RNA granules, offering a comprehensive overview of the techniques used to characterize them, including relevant computational approaches. Through two detailed examples highlighting the significance of noncoding RNAs, NEAT1 and XIST, in the formation of phase-separated assemblies and their influence on the cellular landscape, we emphasize their crucial role in cellular organization and function. By elucidating the chemical underpinnings of RNA-mediated molecular crowding, investigating the role of modifications, structures, and composition of RNA granules, and exploring both physiological and aberrant phase separation phenomena, this Review provides a multifaceted understanding of the intriguing world of RNA-mediated biological condensates.

Objective This study described older patients receiving hospitalisation-at-home (HaH) services and identified factors associated with 30-day hospital readmission.Design 3-year retrospective study in 2017–2019 in France.Participants 75 108 patients aged 75 years and older who were discharged from hospital medical wards (internal medicine and geriatric units) and admitted to HaH.Primary outcome measure 30-day hospital readmission.Results The mean age of patients was 83.4 years (SD 5.7), 52.3% were male and 88.4% lived in a private household. Patients were primarily discharged from the internal medicine unit (85.3%). The top four areas of care in the HaH were palliative care, complex dressing, intravenous therapy and complex nursing care. Overall, 23.5% of patients died during their HaH stay and 27.8% were readmitted to the hospital at 30 days. In the multivariate model, male (OR 1.19, 95% CI 1.16 to 1.23), supportive cancer HaH care (OR 1.78, 95% CI 1.51 to 2.11) and very high intensity care during the previous in-person hospitalisation (OR 1.45, 95% CI 1.34 to 1.57) increased the risk of hospital readmission at 30 days. Older age (OR 0.97, 95% CI 0.97 to 0.98), living in a nursing home (OR 0.51, 95% CI 0.48 to 0.54), postsurgery HaH care (OR 0.49, 95% CI 0.41 to 0.58) and having been previously hospitalised in a geriatric unit (OR 0.81, 95% CI 0.77 to 0.85) decreased the risk of hospital readmission at 30 days.Conclusions HaH provides complex care to very old patients, which is associated with high mortality. Several factors are associated with rehospitalisation within 30 days that could be avoided with better integration of different services with higher geriatric skills.Trial registration number CNIL:2228861.

BackgroundRett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the X-linked methyl-CpG binding protein 2 (MeCP2) gene. While MeCP2 mutations are lethal in most males, females survive birth but show severe neurological defects. Because X-chromosome inactivation (XCI) is a random process, approximately 50% of the cells silence the wild-type (WT) copy of the MeCP2 gene. Thus, reactivating the silent WT copy of MeCP2 could provide therapeutic intervention for RTT.MethodsToward this goal, we screened ~ 28,000 small-molecule compounds from several libraries using a MeCP2-luciferase reporter cell line and cortical neurons from a MeCP2-EGFP mouse model. We used gain/increase of luminescence or fluorescence as a readout of MeCP2 reactivation and tested the efficacy of these drugs under different drug regimens, conditions, and cellular contexts.ResultsWe identified inhibitors of the JAK/STAT pathway as XCI-reactivating agents, both by in vitro and ex vivo assays. In particular, we show that AG-490, a Janus Kinase 2 (JAK2) kinase inhibitor, and Jaki, a pan JAK/STAT inhibitor, are capable of reactivating MeCP2 from the inactive X chromosome, in different cellular contexts.ConclusionsOur results suggest that inhibition of the JAK/STAT pathway is a new potential pathway to reinstate MeCP2 gene expression as an efficient RTT treatment.

The Tsunami Alert Centre of the National Institute of Geophysics and Volcanology (CAT-INGV) has been promoting, since 2018, the study of tsunami risk perception in Italy. Between 2018 and 2021 a semi-structured questionnaire on the perception of tsunami risk was administered to a sample of 5842 citizens residing in 450 Italian coastal municipalities, representative of more than 12 million people. The survey was conducted with the computer-assisted telephone interviewing (CATI) methodology, described in Cerase et al. (2019), who published the results of the first pilot survey (about 1000 interviews). The large sample and the socio-demographic stratification give an excellent representation of the resident population in the surveyed Italian coastal municipalities. Moreover, in 2021 an optimized version of the questionnaire was also administered via Telepanel (a tool for collecting proportional and representative opinions of citizens) that was representative of the Italian population and included 1500 people distributed throughout the country. In this work we present the main results of the three survey phases, with a comparison among the eight surveyed regions and between the coastal regions and some coastal metropolitan cities involved in the investigations (Rome, Naples, Bari, Reggio Calabria, and Catania). Data analysis reveals heterogeneous and generally low tsunami risk perception. Some seaside populations, in fact, show a good perception of tsunami risk, while others, such as in Apulia and Molise, reveal a lower perception, most likely due to the long time elapsed since the last event and lack of memory. We do not find relevant differences related to the socio-demographic characteristics (age, gender) of the sample, whereas the education degree appears to affect people's perception. The survey shows that the respondents' predominant source of information on tsunamis is the television and other media sources (such as newspapers, books, films, internet), while the official sources (e.g., civil protection, local authorities, universities and research institutes) do not contribute significantly. Also, we find an interesting difference in people's understanding of the words tsunami and maremoto, the local term commonly used in Italy until the 2004 Sumatra–Andaman event, which should be taken into account in scientific and risk communication. The Telepanel survey, based on a nationwide sample, highlights a lower level of tsunami risk perception in comparison to average risk perception levels found in the coastal-municipality sample. Our results are being used to drive our communication strategy aimed at reducing tsunami risk in Italy, to activate dissemination and educational programs (data driven), to fill the data gap on tsunami risk perception in the North-Eastern Atlantic, Mediterranean and connected seas (NEAM) area, and to implement multilevel civil protection actions (national and local, top-down and bottom-up). Not least, outputs can address a better development of the UNESCO Tsunami Ready program in Italy.

The chromodomain helicase DNA-binding protein 8 (CHD8) is a chromatin remodeler whose mutation is associated, with high penetrance, with autism. Individuals with CHD8 mutations share common symptoms such as autistic behaviour, cognitive impairment, schizophrenia comorbidity, and phenotypic features such as macrocephaly and facial defects. Chd8-deficient mouse models recapitulate most of the phenotypes seen in the brain and other organs of humans. It is known that CHD8 regulates - directly and indirectly - neuronal, autism spectrum disorder (ASDs)-associated genes and long non-coding RNAs (lncRNAs) genes, which, in turn, regulate fundamental aspects of neuronal differentiation and brain development and function. A major characteristic of CHD8 regulation of gene expression is its non-linear and dosage-sensitive nature. CHD8 mutations appear to affect males predominantly, although the reasons for this observed sex bias remain- unknown. We have recently reported that CHD8 directly regulates X chromosome inactivation (XCI) through the transcriptional control of the Xist long non-coding RNA (lncRNA), the master regulator of mammalian XCI. We identified a role for CHD8 in regulating accessibility at the Xist promoter through competitive binding with transcription factors (TFs) at Xist regulatory regions. We speculate here that CHD8 might also regulate accessibility at neuronal/ASD targets through a similar competitive binding mechanism during neurogenesis and brain development. However, whilst such a model can reconcile the phenotypic differences observed in Chd8 knock-down (KD) vs knock-out (KO) mouse models, explaining the observed CHD8 non-linear dosage-dependent activity, it cannot on its own explain the observed disease sex bias.

Large-scale coastal urban sprawl, development of tourist accommodations and industrial maritime poles have highly increased the tsunami risk to people living and/or traveling along the coasts of our planet. The disastrous tsunamis in the Indian Ocean (2004) and in the Pacific Ocean (2011), as well as a suite of other damaging events worldwide, have encouraged International Institutions, first of all UNESCO Intergovernmental Oceanographic Commission, National Governments and Local Communities to implement Tsunami Warning Systems (TWS), to raise awareness on tsunami risk, and to create a multilevel risk governance. In this framework, research on tsunami risk perception plays a key role. The results of these studies should be taken into account in designing risk mitigation programs and tools (such as drills, activities with local communities, emergency plans, etc.). This paper presents a review of such studies, carried out in several countries worldwide through many thousands of interviews performed with different techniques. Most tsunami risk perception studies were carried out in the regions where the Indian Ocean Tsunami Warning System and the Pacific Ocean one (PTWS) operate. In the NEAMTWS (North-East Atlantic, Mediterranean and connected seas Tsunami Warning Systems) region, only few specific studies were conducted, mostly within the EU-funded ASTARTE project (2013–2017) and more recently in a few extensive surveys on tsunami risk perception conducted in Italy between 2019 and 2021. Although the twenty-three studies analyzed in our review show a strong heterogeneity of methodological approaches and population samples, they allow us to outline some general considerations on tsunami risk as perceived by people in the different regions of the world. With the help of a table, we schematically summarized the emerging strengths, weaknesses and lessons learned in the twenty-three papers, noting an increase in the number of such studies in the last 5 years. The surveys were mostly concentrated in high-risk areas and focused on local residents. Some differences emerged depending on the memory of past tsunamis, education level, and local cultures. This provides useful hints for sound citizen-based tsunami risk reduction actions, including improved risk communication aimed at increasing the resilience of tsunami-prone populations. The need for increasing the assessment of tourists’ tsunami risk perception, and for a more homogeneous survey strategy also emerge from our analysis.

Central nervous system localization of multiple myeloma (CNS-MM) accounts for about 1% of all MM during disease course or even rarer at diagnosis. A difference in the origin, i.e., osteodural or primary dural vs leptomeningeal/intraparenchymal, seems to define two distinct types of intracranial myeloma, with different clinical behavior. CNS-MM may occur also as a presentation of MM. Treatment is still unsatisfactory and many treatments have been reported: chemotherapy, intrathecal therapy, and radiotherapy, with dismal prognosis. Other sites of myeloma localization could be also of interest and deserve description. Because of the rarity and aggressiveness of the disease clinicians are often doubtful on how to treat it since there is no general agreement. Moreover, recent drugs such as the anti CD38 monoclonal antibody, immunomodulatory drugs, and proteasome inhibitors have changed the treatment of patients with MM with a significant improvement in overall response and survival. The role of novel agents in CNS MM management and unusual presentations will be discussed as well as the potential role of other new immunomodulatory drugs and proteasome inhibitors that seem to cross the blood-brain barrier. The purpose of this review is to increase awareness of the clinical unusual presentation and neuroradiological findings, give practical diagnostic advice and treatment options algorithm.

Andrea Cerase et al. report that the chromatin remodeler Chd8 is a key regulator of mammalian Xist expression and therefore X chromosome inactivation. They find that Chd8 activates Xist expression in embryonic stem cells, while in differentiating cells it acts to prevent spurious Xist expression through blocking transcription factor binding to the Xist promoter.

Young et al. report a new mouse model for Pelger-Huet anomaly, a genetic disorder caused by mutations in the Lamin B receptor gene (Lbr) that leads to abnormal neutrophil differentiation and skeletal defects. Using CRISPR/Cas-9 editing of Lbr, which has also been associated with X chromosome inactivation (XCI), they generate a mouse model that recapitulates the major phenotypes of the disease without majorly affecting XCI.

Simple Summary: Glioblastoma is a highly aggressive type of brain tumor that is very difficult to treat, and surgery is crucial for improving patient survival. However, there are significant differences in access to brain tumor surgery based on factors like income, location, and available healthcare resources. People in low- and middle-income countries often struggle to receive the surgery they need due to a lack of specialized doctors, inadequate healthcare facilities, and financial challenges. As a result, patients in these regions are often diagnosed later, receive less effective treatment, and have lower survival rates compared to those in wealthier countries. This not only affects the patients but also adds economic and social burdens to their communities. The study calls for urgent actions to address these inequalities through international cooperation, better healthcare policies, and fair distribution of resources, with the goal of improving access to brain tumor surgeries for everyone, no matter where they live. Glioblastoma: a highly aggressive brain tumor, presents substantial challenges in treatment and management, with surgical intervention playing a pivotal role in improving patient outcomes. Disparities in access to brain tumor surgery arise from a multitude of factors, including socioeconomic status, geographical location, and healthcare resource allocation. Low- and middle-income countries (LMICs) often face significant barriers to accessing surgical services, such as shortages of specialized neurosurgical expertise, limited healthcare infrastructure, and financial constraints. Consequently, glioblastoma patients in LMICs experience delays in diagnosis, suboptimal treatment, and poorer clinical outcomes compared to patients in high-income countries (HICs). The clinical impact of these disparities is profound. Patients in LMICs are more likely to be diagnosed at advanced disease stages, receive less effective treatment, and have lower survival rates than their counterparts in HICs. Additionally, disparities in access to surgical care exacerbate economic and societal burdens, emphasizing the urgent need for targeted interventions and health policy reforms to address healthcare inequities. This review highlights the importance of addressing global disparities in access to brain tumor surgery for glioblastoma through collaborative efforts, policy advocacy, and resource allocation, aiming to improve outcomes and promote equity in surgical care delivery for all glioblastoma patients worldwide. [ABSTRACT FROM AUTHOR]

Abstract Background Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the X-linked methyl-CpG binding protein 2 (MeCP2) gene. While MeCP2 mutations are lethal in most males, females survive birth but show severe neurological defects. Because X-chromosome inactivation (XCI) is a random process, approximately 50% of the cells silence the wild-type (WT) copy of the MeCP2 gene. Thus, reactivating the silent WT copy of MeCP2 could provide therapeutic intervention for RTT. Methods Toward this goal, we screened ~ 28,000 small-molecule compounds from several libraries using a MeCP2-luciferase reporter cell line and cortical neurons from a MeCP2-EGFP mouse model. We used gain/increase of luminescence or fluorescence as a readout of MeCP2 reactivation and tested the efficacy of these drugs under different drug regimens, conditions, and cellular contexts. Results We identified inhibitors of the JAK/STAT pathway as XCI-reactivating agents, both by in vitro and ex vivo assays. In particular, we show that AG-490, a Janus Kinase 2 (JAK2) kinase inhibitor, and Jaki, a pan JAK/STAT inhibitor, are capable of reactivating MeCP2 from the inactive X chromosome, in different cellular contexts. Conclusions Our results suggest that inhibition of the JAK/STAT pathway is a new potential pathway to reinstate MeCP2 gene expression as an efficient RTT treatment.

SUMMARY Checkpoint inhibitors have substantially improved the prognosis for patients with advanced malignancy. Treatment with immunomodulants has the ability to reactivate the immune system against tumor cells, but can also trigger the development of immune-related adverse events that reflects a loss of tolerance of the immune system for self-antigens. Regarding the endocrine system, thyroid and pituitary are the most frequent glands involved; in particular hypophysitis is commonly observed with anti-CTLA4 with a variable impaired anterior pituitary dysfunction (mainly ACTH and TSH dysregulation) while a posterior pituitary dysfunction has been rarely described. A 68-year-old man with a diagnosis of metastatic mesothelioma started in September 2016 first-line treatment with tremelimumab and durvalumab. After 3 cycles he presented sudden onset of polydipsia and polyuria without other symptoms. Diagnostic work-up, including a water deprivation test, established a diagnosis of central diabetes insipidus. Patient started sublingual desmopressin 60 mcg three times a day, that was subsequently increased up to 480 mcg/die. At magnetic resonance imaging the posterior lobe of pituitary gland did not show high signal intensity on T1-weighted images. After regression of diabetes insipidus symptoms under desmopressin, patient restarted cancer treatment and received additional 10 doses without worsening of endocrinological toxicity or further treatment-related toxicities, maintaining the same desmopressin dosage. Posterior pituitary dysfunction has been rarely observed in patients treated with immunomodulants. To our knowledge, this is the first observation of permanent central diabetes insipidus in patients treated with combined immune checkpoint inhibitors (tremelimumab and durvalumab).

The genomes of metazoans are organized at multiple spatial scales, ranging from the double helix of DNA to whole chromosomes. The intermediate genomic scale of kilobases to megabases, which corresponds to the 50–300 nm spatial scale, is particularly interesting, as the 3D arrangement of chromatin is implicated in multiple regulatory mechanisms. In this context, polycomb group (PcG) proteins stand as major epigenetic modulators of chromatin function, acting prevalently as repressors of gene transcription by combining chemical modifications of target histones with physical crosslinking of distal genomic regions and phase separation. The recent development of super-resolution microscopy (SRM) has strongly contributed to improving our comprehension of several aspects of nano-/mesoscale (10–200 nm) chromatin domains. Here, we review the current state-of-the-art SRM applied to PcG proteins, showing that the application of SRM to PcG activity and organization is still quite limited and mainly focused on the 3D assembly of PcG-controlled genomic loci. In this context, SRM approaches have mostly been applied to multilabel fluorescence in situ hybridization (FISH). However, SRM data have complemented the maps obtained from chromosome capture experiments and have opened a new window to observe how 3D chromatin topology is modulated by PcGs.

Introduction: In the past years, governments from several countries have shown interest in implementing integrated health information systems. The interRAI Suite of instruments fits this concept, as it is a set of standardised, evidence-based assessments, which have been validated for different care settings. The system allows the electronic transfer of information across care settings, enabling integration of care and providing support for care planning and quality monitoring. The main purpose of this research is to describe the recent implementation process of the interRAI instruments in seven countries: Belgium, Switzerland, France, Ireland, Iceland, Finland and New Zealand. Methods: The study applied a case study methodology with the focus on the implementation strategies in each country. Principal investigators gathered relevant information from multiple sources and summarised it according to specific aspects of the implementation process, comparing them across countries. The main implementation aspects are described, as well as the main advantages and barriers perceived by the users. Results: The seven case studies showed that adequate staffing, appropriate information technology, availability of hardware, professional collaboration and continuous training are perceived as important factors which can contribute to the implementation of the interRAI instruments. In addition, the use of electronic standardised assessment instruments such as the interRAI Suite provided evidence to improve decision-making and quality of care, enabling resource planning and benchmarking. Conclusion: In practice, the implementation of health information systems is a process that requires a cultural shift of policymakers and professional caregivers at all levels of health policy and service delivery. Information about the implementation process of the interRAI Suite in different countries can help investigators and policymakers to better plan this implementation. This research sheds light on the advantages and pitfalls of the implementation of the interRAI Suite of instruments and proposes approaches to overcome difficulties.

Genomic repeats have been intensely studied as regulatory elements controlling gene transcription, splicing and genome architecture. Our understanding of the role of the repetitive RNA such as the RNA coming from genomic repeats, or repetitive sequences embedded in mRNA/lncRNAs, in nuclear and cellular functions is instead still limited. In this review we discuss evidence supporting the multifaceted roles of repetitive RNA and RNA binding proteins in nuclear organization, gene regulation, and in the formation of dynamic membrane-less aggregates. We hope that our review will further stimulate research in the consolidating field of repetitive RNA biology.

The Italian Tsunami Alert Centre of the Istituto Nazionale di Geofisica e Vulcanologia (Centro di Allerta Tsunami, hereinafter CAT-INGV) supported a computer-assisted telephone interview (CATI) survey to investigate tsunami risk perception in two pilot regions of southern Italy. The survey was carried out on a stratified sample of 1021 interviewees representing about 3.2 million people living in 183 coastal municipalities of the two regions, namely Calabria and Apulia. The main goal of this research is to verify whether and how people's perception of tsunami hazard compares to the results of (PTHA) – probabilistic tsunami hazard assessment (TSUMAPS-NEAM project; Basili et al., 2018). As shown by the results of this project, both investigated regions are characterised by high tsunami hazard. Nonetheless, the long return time of such events could lead people to consider the occurrence of a tsunami in the Mediterranean Sea to be very unlikely. The survey results reveal that people's risk perception is low: for almost half of the whole sample the occurrence of a tsunami in the Mediterranean Sea is considered quite unlikely, with a clear difference between Apulia and Calabria. In the latter region the risk perception is much higher than in the former, probably due to the shorter time elapsed since the last event. Also, belonging to different coastal areas1 appears to have a significant influence on the way tsunami hazard is conceived, having a stronger effect on risk characterisation: the interviewees of Tyrrhenian Calabria are indeed more likely to associate tsunami risk with volcanoes than the Ionian citizens. This is coherent considering the presence of active volcanoes and related tsunami precedents in the Tyrrhenian. Television emerged as the most relevant source of knowledge for almost 90 % of the sample, and the influence of media also results in the way tsunami risk is characterised. In particular, the survey showed that people's perception and understanding of tsunamis are affected by media accounts of large events, such as the 2004 Sumatra and the 2011 Japan tsunamis. At the same time, it is evident that the risk posed by smaller events is underrated. Furthermore, the survey's results show that the word “tsunami” occupies a different semantic space in comparison to the Italian traditional headword maremoto, with differences among sample strata. In other words, the same physical phenomenon would be understood in two different ways by younger, educated people and elders with a low education level. The results of this study, although limited to two regions, provide a first assessment of tsunami risk perception in Italy, also entailing important consequences for both risk communication practice and mitigation policies.

Abstract Until very few years ago, the oncology community dogmatically excluded any clinical potential for immunotherapy in controlling brain metastases. Therefore, despite the significant therapeutic efficacy of monoclonal antibodies to immune check-point(s) across a wide range of tumor types, patients with brain disease were invariably excluded from clinical trials with these agents. Recent insights on the immune landscape of the central nervous system, as well as of the brain tumor microenvironment, are shedding light on the immune-biology of brain metastases. Interestingly, retrospective analyses, case series, and initial prospective clinical trials have recently investigated the role of different immune check-point inhibitors in brain metastases, reporting a significant clinical activity also in this subset of patients. These findings, and their swift translation in the daily practice, are driving fundamental changes in the clinical management of patients with brain metastases, and raise important neuroradiologic challenges. Along this line, neuro-oncology undoubtedly represents an additional area of active investigation and of growing interest to support medical oncologists in the evaluation of clinical responses of brain metastases to ICI treatment, and in the management of neurologic immune-related adverse events. Aim of this review is to summarize the most recent findings on brain metastases immunobiology, on the evolving scenario of clinical efficacy of ICI therapy in patients with brain metastases, as well as on the increasing relevance of neuroradiology in this therapeutic setting.

The aim of the present study is to report the outcomes of round window reinforcement surgery performed with the application of a Vibrant Soundbridge middle ear implant (VSB; MED-EL) in a patient with superior semicircular canal dehiscence (SSCD) who presented with recurrent vertigo, Tullio phenomenon, Hennebert's sign, bone conduction hypersensitivity, and bilateral moderate to severe mixed hearing loss. Vestibular evoked myogenic potentials (VEMPs) and high-resolution computed tomography (HRCT) confirmed bilateral superior semicircular canal dehiscence while this was not seen in magnetic resonance imaging. The surgical procedure was performed in the right ear as it had worse vestibular and auditory symptoms, a poorer hearing threshold, and greatly altered HRCT and VEMPs findings. With local-assisted anesthesia, round window reinforcement surgery (plugging) with perichondrium was performed with simultaneous positioning of a VSB on the round window niche. At the one and 3 months follow-up after surgery, VSB-aided hearing threshold in the right ear improved to mild, and loud sounds did not elicit either dizziness or pain in the patient.

The interaction between polycomb-repressive complexes 1/2 (PRC1/2) and long non-coding RNA (lncRNA), such as the X inactive specific transcript Xist and the HOX transcript antisense RNA (HOTAIR), has been the subject of intense debate. While cross-linking, immuno-precipitation and super-resolution microscopy argue against direct interaction of Polycomb with some lncRNAs, there is increasing evidence supporting the ability of both PRC1 and PRC2 to functionally associate with RNA. Recent data indicate that these interactions are in most cases spurious, but nonetheless crucial for a number of cellular activities. In this review, we suggest that while PRC1/2 recruitment by HOTAIR might be direct, in the case of Xist, it might occur indirectly and, at least in part, through the process of liquid–liquid phase separation. We present recent models of lncRNA-mediated PRC1/2 recruitment to their targets and describe potential RNA-mediated roles in the three-dimensional organization of the nucleus.