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Frequent User in Pronto Soccorso e Bed Blocker nei reparti di degenza: analisi del profilo e strategie preventive sul territorio attraverso le nuove piattaforme digitali e le COT distrettuali
No full textBackground
In recent decades, the progressive aging of the population and the higher levels of urbanisation and pollution are increasing the number of patients suffering from chronic diseases, which has a significant impact on the use of health care services, in particular Emergency Departments (EDs). In Italy, despite significant improvements in the emergency care system, the cuts in numbers of hospital beds over the last 30 years and the increase in numbers of fragile patients (adults and children) have led to a rise in ED attendances. Published evidence from many countries shows that frequent ED use increases the risk of adverse effects such as hospitalisation, functional decline, and complications related to treatment and procedures. A significant proportion of hospital attendances are inappropriate and the respective ailments could be managed by non-acute health care services outside the hospital setting; such inappropriate attendances, therefore, drive up costs and increase inefficiency. The causes of frequent ED use are multifactorial: although many patients have chronic medical problems, these are often combined with marked psychosocial morbidity.
Against this backdrop, the Covid-19 pandemic caused a significant fall in overall ED utilisation, with reduced volumes of up to 50% in some countries. The largest proportional reduction in ED users was in preventable ED attendance, including accident and traumatic injuries, probably as a result of a reduction in motor vehicle travel and fewer work activities, but also to time-dependent illnesses such as stroke or cardiac complaints among the oldest age groups, possibly due to concerns about Covid-19 acquisition in hospital. In Italy and in other countries, the Covid-19 pandemic also influenced the usage of Emergency Medical Services (EMSs).
Despite a copious international literature on the frequent use of EDs, there is no single definition of a Frequent User (FU). The choice of threshold values is often subjective, generally based on previous literature or the distribution of ED attendances in a given period. More often a FU is considered a user with ≥4 or 5 attendances at the hospital, with both physical and mental issues, but various alternatives, from 2 to 12 attendances per year or six-month period, have also been chosen.
Similar studies have also been conducted in Italy and the Netherlands showing that FUs represent a small percentage of hospital attendances, but nevertheless form a high proportion of the total ED costs. Among children, available studies conducted in Italy report that non-urgent attendances account for 27.6% of ED users and 58.2% of total paediatric attendance episodes. Non-urgent attendances have been negatively associated with crowding and costs, causing longer waiting times and greater dissatisfaction among both parents and health workers.
The Italian National Health Service (NHS) is structured on three levels: the first includes the Central Government and the Ministry of Health, the second comprises the twenty Regional Governments and the third consists of the Local Health Authorities (LHAs) together with independent hospitals. The NHS is primarily funded through public taxation and is guided by the principles of universal coverage, solidarity, and human dignity. Each LHA includes at least one non-independent hospital and one or more Local Health Districts (LHDs), which provide primary care services (vaccination and screening, specialist consultations, family planning counselling, home care) and coordinates General Practitioners (GPs) and Primary Care Paediatricians (PCPs). Primary care physicians may work individually or in operational and multidisciplinary associations to ensure full ac-cess to care, 24 hours a day, 7 days a week.
The availability of beds in hospital for acute patients and outside hospital for post-acute assistance is a major issue for the Italian NHS, especially in metropolitan areas like Rome, the most populous municipality in Italy, where three large LHAs administer health care services. Various Italian studies have explored the problem by analysing some of the characteristics of the adults and children FU but there is still insufficient consideration in the literature of the following points: number of attendances, usage of EMS, level of urgency, and appropriateness of attendance, geographical distribution and social-clinical characteristics. Covid-19 diagnosis was also investigated for a possible influence on ED attendances.
The first study of this project investigates ED attendances in Rome; it describes the characteristic of the FU population and defines a FU profile (for adults and children), which highlights the differences between FUs and non-FUs, and identifies factors linked to FU status and appropriate ED attendance. The second analysis was aimed to identify the clinical and social characteristics of FUs and to quantify and compare the variation in the probability of being FU attributable to GPs and LHDs. The third part of the study described an example of strategic interventions of FU case management in a pilot phase carried out between 2023 and 2024.
Materials and methods
Study design and data collection
A retrospective cohort study was carried out during 2022 of the ED attendances in 2021 for adults and the ED attendances in 2022 for children. The LHA Roma 1 geographical area in Rome was chosen for the analysis as it is one of the most populous areas in Italy, containing 13 EDs (of 22 in the Rome metropolitan area), including 8 paediatric EDs, with an aging index (number of population aged >64 years per 100 individuals aged <14 years) of 192 (the Italian mean is 183.3).
The study population consisted of all patients with residency in the LHA Roma 1 geographical area who were admitted to any of its 13 local EDs. Records of the attendances at two other EDs close to the LHA Roma 1 area were added to the total to include potential ED attendances of LHA Roma 1 residents outside the main metropolitan area. A digital platform was used to extract the ED data from the Lazio Region official data flows for emergency attendances. The data are pseudo-anonymised: although the ID code of each patient is represented by an encrypted string, it is still possible to connect health events attributable to the same individual. Using this pseudo-anonymised ID, subsequent attendances of the same individual in 2021 were counted and classified according to the number of attendances made.
In the first analysis, records included information on the following variables for each patient:
- Number of attendances: a FU is defined as having ≥4 attendances per year, according to the literature;
- Demographic characteristics: age, gender;
- Arrival mode: by EMS or not by EMS;
- Triage code: in 2001, a 24-h nurse-led triage system was introduced by the Italian Ministry of Health to evaluate a patient’s level of urgency, with assessment resulting in the assignment of a priority code. Since 2019, a transition from colour codes to numerical codes (1, 2, 3, 4, 5) has gradually been introduced;
- Appropriateness of attendance: according to a visiting physician evaluation, all patients who were admitted to a hospital ward, had refused admission to a hospital ward or died in ED, were considered as appropriate;
- Diagnosis of Covid-19: defined by any positive swab during ED attendance.
All variables are mandatory in each patient’s attendance record, so there were no missing data.
Single-specialism EDs (ophthalmology and obstetrics) were excluded from the study as they could affect the appropriateness of the results. The analysis was performed separately between individuals <18 years old and adults.
Among children demographic characteristics the gender was classified as binary (male or female) according to the LHA registry; age was classified according to the age stages of the National Institute of Child Health and Human Development: 'infancy' (birth to 12 months); “toddler” (13 to 24 months); “early childhood” (25 months to 5 years), “middle childhood” (6 to 12 years), and “adolescent” (12 to 15 years).
In the second analysis for each patient in the cohort the following potential risk factors were assessed: gender, age, socioeconomic status (high, middle-high, medium, middle-low, low) and the presence of chronic or multiple-chronic conditions. The socioeconomic level was calculated at the census tract level, based on the methodology developed by Nicola Caranci et al. This index integrates multiple socio-economic indicators de-rived from national census data, including educational attainment, employment status, home ownership versus rental, household overcrowding, and family structure. It provides a composite measure of socio-economic disadvantage within small geographic areas. Among patients with multiple chronic conditions, high clinical complexity was defined as a five-year mortality risk higher than 10%, based on the number and type of chronic dis-eases.
The cohort was derived from the Healthcare Emergency Information System, which collects all attendances to emergency services and patient data. The cohort was linked to the automated databases of Lazio Region residents who receive NHS assistance, thus allowing researchers to obtain information related to chronic or multiple chronic diseases, GP and LHD of each patient, and socioeconomic status based on the residence address. A deterministic record linkage procedure with anonymous identification codes was used to merge the data from different information systems. To preserve privacy, each individual identification code was subsequently and automatically deidentified, and the conversion table was deleted, leaving only fully anonymized data available to researchers.
Regarding the geographical analysis, the administrative-territorial division of the LHA Roma 1 was used to examine the association between FU prevalence and urban settings, as previously described. Each of the six LHDs of LHA Roma 1 is divided into Geographical Units (GUs, in Italy called “Zone Urbanistiche”), as defined by the Municipality of Rome. This represent the smallest territorial unit for which population data are available in Italy and many other countries.
The third analysis is a prospective cohort study conducted between January 2024 and January 2025. The FU selection criteria are the same of previous analyses. Initial patient contact was mediated by GPs who acted as facilitators. In this first phase, the number of patients recruited was opportunistic, based on the availability of participating GPs (participation in the project was voluntary).
Information regarding FU health problems was also collected, allowing the attendances to be divided by main health issue. Only data regarding ED attendances made between 2023 and 2024 were collected; single-specialty attendances were not considered, and patients <16 years of age were excluded to avoid confounding the results. A descriptive analysis of the overall sample and a sub-analysis of the care group were performed, analyzing variables such as ED attendances and reasons of attendances, both as absolute numbers and as percentages. Due to the large sample size, it was not deemed useful to perform a univariate or multivariate analysis.
Statistical analysis
Microsoft® Excel® v.2016 MSO and STATA v. 17.0 were used for data analysis. The cumulative number of ED attendances was computed for each patient ID, and patients with ≥4 attendances were classified as FUs.
Descriptive analysis for adults and children was performed on all variables recorded. Descriptive statistics, such as mean, SD, frequency and percentage, were used to describe the demographics and ED attendance characteristics of the sample. For inferential analysis, both for adults and children, given the large sample size, statistical significance was determined at a level of p=0.001. Welch’s t-test was used to test differences in mean age among FUs and non-FUs. Pearson’s χ2-test was used to investigate differences in categorical variables among FUs and non-FUs. Univariate analysis was performed for any potentially associated factor. Multivariable logistic regression was performed for all factors identified with the significance level set at p<0.001.
The second analysis included a multilevel logistic model (patient < GP < District) to quantify the variability in FU behaviour attributable to LHDs and primary care physicians and to identify the role of social and clinical determinants (gender, age, socioeconomic level and chronic conditions). Age was considered as a continuous variable. The effect of individual variables was expressed as Odds Ratios (OR); variance components estimated by multilevel models were expressed as Median Odds Ratios (MORs). The MOR quantifies between-cluster variation by comparing two patients from two randomly chosen, different clusters. Consider two persons with the same covariates, chosen randomly from two different clusters. The MOR represents the median odds ratio between the person of higher propensity and the person of lower propensity. MOR values are always ≥1.00; if MOR = 1.00, there is no variation between clusters, while larger values indicate greater variation. MORs were estimated for both the “empty” model, which includes a random intercept only, and the full model, which includes all patient risk factors. Statistical analyses were conducted using SAS software (SAS Institute Inc., North Carolina).
In the analysis for children, a four-level model was performed, with observations clustered as follows: attendance15 (MOR < 1 year old: 3.05 and MOR > 15 years old: 3.32), EMS usage (MOR EMS: 5.65).
Pilot study
Regarding the case management pilot study, 745 FUs were identified in the population and 62 patients agreed to participate in the project and be contacted by our staff. The FUs have an average of 5.6 attendances in 2023, while in 2024 it decreased to 2.6. The patients were divided in different groups based on the main clinical diagnosis. In 38.7%, the attendances were caused by cardiovascular problem, followed by respiratory and kidney/urinary tract problems, both at 16.1%. Psychiatric problems were the main reason for 7 patients (11.3%), while the remaining 17.7% of patients had an issue belonging to a different macro-category. Among them, 20 had 4 attendances in 2023, 21 patients had 5 attendances, 9 had >5 attendances in a year, 12 patients had more than 7 attendances. The highest number of attendances was 14; overall the average number of attendances was 5.7. However, in 2024 51 patients (82.2% of the sample), had <4 attendances, while the remaining 11 reported from a minimum of 4 to a maximum of 11 attendances, and the average was 2.3. Moving on to the univariate analysis, no significant differences were found in the reduction of attendances between 2023 and 2024, although the FU group decreased from the average 3.4 to 3.
Discussion
Adults
FUs represented 2.7% of the overall population but were accounted for 11.3% of attendances in 2021, in line with the literature, most frequently in the 50-59 age group. The risk of being FU increased with the patient's clinical complexity and with low and medium-low socioeconomic status. Generally, patients with higher socioeconomic status were less likely to attend the ED. This is consistent with other studies, where the odds of avoidable hospital admissions were higher among patients with lower socioeconomic status compared with other groups. Prior studies suggest that patients with low socioeconomic level perceive ED assistance to be cheaper and more accessible than ambulatory care and are often more likely to use EDs for non-urgent conditions. Non-urgent triage codes were more frequent among FUs (from 8.1% in the FU≥4 group to 14.4% in the FU≥10 group), and mental disorders were common in a substantial proportion of FUs (to 15.9% in the FU≥10 group). Psychomotor agitation and social issues were important diagnoses associated with FUs, but the results of “symptoms, signs and ill-defined conditions” and “external causes of injury and supplemental classification” diagnosis groups, as well as the main issues on admission, such as fever, chest pain or dyspnea, may have been influenced by the COVID-19 pandemic. This may also have affected time-dependent conditions such as stroke or cardiac complaints, possibly due to concerns about acquiring COVID-19 in hospital. However, all patients included in the analysis were equally exposed to the pandemic waves, and no systematic differences were expected between subgroups that could have introduced bias. Furthermore, other studies in the Lazio Region comparing ED attendances during the COVID-19 waves found a sharp reduction in ED attendances, except for pneumonia. The increase of physical and mental morbidities was associated with higher ED attendance rates, supporting previous evidence that individuals with chronic diseases and psychiatric disorders are more likely to attend EDs. This also applies to individuals with socioeconomic deprivation. Some authors have investigated the importance of social support for older adults in the ED, although in a systematic review there was no significant association be-tween ED attendance and social support. Regarding the geographical analysis, this study characterized variation using more granular geographic unit of analysis. This may be considered a first step toward developing specific public health strategies aimed at improving appropriate healthcare utilization for specific populations and communities, as implemented in Paris by the Île-de-France Regional Health Agency. Further researches are needed to analyze the association among FUs, population density, income and medical services or GP offices in the same area.
Children
In our study, pediatric FUs are more likely to be two years younger than non-FUs (7.7 and 5.3, p=0.001), while there are no other differences in demographic data analysis regarding access condition. These findings are in line with other Italian studies in which patients who visited the ED for non-urgent attendances are more likely to be younger and male. Our study shows that up to 62% of pediatric ED attendances were inappropriate for FUs and non-FUs. This result is consistent with other studies results, which reported up to 80% inappropriate attendances for FUs and non-FUs. These rates of inappropriate access to EDs are even much higher than in adults and indicate a great opportunity to improve the appropriateness of care and patient safety. Finally, in our study, a higher rate of appropriateness for access was observed in FUs compared to non-FUs in EDs, this is likely due to the higher prevalence of serious urgent codes (code 1) compared to non-FU patients. The nested logistic regression and variance analysis show both PCP/GP and District factors seem to play a small role in determining a greater number of ED attendances.
Pilot study
As recommended in the literature, the care process for FUs is based on a multi-professional approach, allowing different strategies and professional skills to work synergistically. For example, throughout their journey, patients can interact with various professionals who contribute in various capacities to their care, such as doctors, nurses, social workers, physiotherapists, etc. This organization is also supported by a case management strategy through the active call of patients by nursing staff (IFeC-Institutional Health and Care Professional) specifically trained to manage community and home care. While the results cannot be extended to the entire sample, the subpopulation characterized by neurological and psychiatric conditions may benefit more from a humanized care and case management process due to the IFeC support. To our knowledge, this pilot study is the first to have systematically described a FU managing strategy in the Italian context through the new IFeC skills, and in synergy between hospitals and non-hospital community facilities.
These studies have some limitations. The retrospective design allowed investigation of the predictors of ED attendance only at a single point in time and exclusively among LHA residents, thereby excluding homeless individuals without residency, foreigners, and people formally resident in LHA Roma 1 but whose healthcare services were provided by other LHAs in Rome. Only the main diagnosis was considered, and inaccuracies in the clinical dataset may have led to underreporting of some morbidities. The potential influence of proximity to EDs and primary care services on ED attendance was not evaluated. The sample evaluated in this pilot phase is small and not generalizable.
Conclusion
Frequent ED use represents a major challenge for healthcare system management. Analysis of ED attendances and the socioeconomic and geographical characteristics of FUs highlights the need for new approaches to address key issues such as socioeconomic inequalities, improvement of housing and employment conditions, and structural factors including the strategic placement of primary care services and improved transportation. This project identified the potential risk factors predictive of disproportionate ED use in order to support policymakers in anticipating the needs of specific patient groups or categories. The FU phenomenon requires a systematic approach that utilizes all available professional skills. While it is not yet possible to draw any generalizable conclusions from the pilot study, the preliminary results appear encouraging, and lays the foundation for expanding the project to collect more data in order to have a more representative sample
Host-pathogen interactions: dissecting the multifactorial virulence of Enteroaggregative Escherichia coli and exploring epithelial responses to bacterial infections
No full textEnteroaggregative Escherichia coli (EAEC) is an emerging enteric pathogen increasingly associated with persistent diarrhoea, especially in children and vulnerable populations. Its pathogenicity is multifactorial, involving strong adhesion to the intestinal mucosa, robust biofilm formation, and the secretion of toxins and modulators that trigger inflammation and epithelial responses. Its ability to persist in the intestinal niche, combined with the rise of antimicrobial resistance, highlights the urgent need for new therapeutic approaches beyond conventional antibiotics. This thesis investigates EAEC pathogenesis by identifying key bacterial determinants involved in colonisation and persistence, and it explores host epithelial responses to bacterial infections using advanced cellular models. First, we characterised the AcrAB-TolC efflux pump, traditionally known for its role in multidrug resistance, demonstrating its key contribution to EAEC virulence. Loss of AcrB compromised key virulence-associated traits, including biofilm formation, extracellular DNA production, and the characteristic aggregative adherence phenotype, and led to attenuated virulence in vivo in Caenorhabditis elegans. Second, we analysed AggR, an AraC/XylS-family transcriptional regulator that orchestrates multiple virulence pathways, including the expression of aggA, which encodes the major structural subunit of aggregative adherence fimbriae (AAF). We demonstrate that medium-chain fatty acids (caprylic, lauric and decenoic) strongly inhibit EAEC pathogenicity by downregulating aggR and aggA expression and interfering with AggR activity, resulting in reduced biofilm formation and epithelial adhesion. Finally, we established a human colon organoid model to examine epithelial responses to infection. Using an ExPEC strain as proof-of-concept, we showed that different bacterial loads induce distinct epithelial outcomes: low infection levels promote adaptive transcriptional reprogramming, including metaplastic gene expression, whereas high loads trigger strong inflammatory responses. Altogether, these findings clarify key aspects of EAEC virulence and its modulation by host and environmental factors, suggesting new avenues to limit colonisation and persistence through novel therapeutic interventions
Beyond the Capitalist/Alternative Economic Binary. Diverse Economies in Urban Planning
No full textCapitalism’s dominance in economic discourse has rendered alternative economic practices invisible, narrowing the scope of what is considered viable within planning and economic development. Drawing on Gibson-Graham’s work and the Community Economies Research Network, this chapter challenges binary framings of the economy—such as capitalist versus alternative—and calls for a fundamental ontological and ethical reframing. By rejecting pre-given categories rooted in Western capitalist logics, diverse economies thinking expands the terrain of economic possibility, offering planning a framework to recognize and cultivate collective, interdependent, and community-driven forms of economic life.
This theoretical lens is applied to the case of the Vance Avenue Collaborative (VAC), a community/university partnership in Memphis, Tennessee, that resisted neoliberal housing policies and co-produced a long-term development vision grounded in stewardship, commoning, and economic co-production. Through projects such as a resident-led land use plan and the Green Machine Mobile Market, the VAC exemplified how planning can activate and sustain diverse economies. The case illustrates how planning practices, when informed by economic reframing, can empower marginalized communities, disrupt capitalist dependencies, and enable more just and sustainable futures
Design and synthesis of new indolyl derivatives as SARS-CoV-2 non-structural protein 13 inhibitors
No full textThe severe and acute respiratory syndrome coronavirus 2 has caused to pandemic with considerably great socioeconomical impact worldwide. Throughout the global pandemic, vaccine development has been prioritized. Despite the outstanding job done in the development of vaccines, there are various downsides when it comes to lacking antiviral drugs active on SARS-CoV-2: first and foremost, the short-term vaccine-induced immunity, and obscurity of vaccines among new variants. Furthermore, the clinical efficacy of antivirals used throughout the pandemic also remains limited in spite of variety of the therapeutic agents. Taken together, these reasons rightfully highlight the pivotal importance of having broad spectrum antiviral inhibitors.
Non-structural protein 13 was reported with 99.8% conservation ratio among variants with two druggable pockets the binding site occupied by AMP PNP, and 5′ end of the RNA substrate as well as potential allosteric hotspots. Targeting them with small molecule inhibitors could be advantageous considering the pace of evolution of variants.
In this content, there are literature data suggesting the potential use indolyl diketo acids have as inhibitors of nsp13 for SARS-CoV-2. This class of compounds are particularly interesting since they were reported to have dual inhibitory activity, unwinding and ATPase activity with an allosteric mechanism of inhibition. Inspired by these outcomes, the main objective of the thesis is to focus at deepening the structure activity relationship of this novel class compounds with various strategies in addition to unveil a bioisosteric replacement analogue of indolyl diketo acids with pyrazole moiety placement. To state deeper, firstly the chemical space is assessed by systematically modifying the substituent patterns on the core scaffolds, which results in the design of new series of small molecules. The strategies that are employed within this include the removing of vinyl group that links the indolyl core to diketo acid moiety, the use of spacer with different chemical features in between indolyl core and phenyl ring as well as the placement of a Cl atom on position 5 of indolyl core and R-group substitutions of benzyl ring with a diverse set of functional groups with differing electronic, steric, and lipophilic designed, synthesized, characterised and their inhibitory profile were examined with in vitro studies asides from cellular antiviral activity assessment in addition to the assessment of inhibition type. The results indicate that almost all the newly obtained analogues were active in low micromolar range and displayed a non-covalent, reversible inhibition mechanism of action. Followingly, the binding pose was also examined. The results demonstrate a similar binding pattern with previously reported allosteric fragments in literature. Another strategy that was employed within the thesis is the bioisosteric replacement of diketo acid moiety. In order to improve the pharmacokinetic and pharmacodynamics profile, this is essential due to the ionized presence of diketo moiety at physiological pH, which could result in high metabolic turnover and poor cell membrane penetration. In this sense, the replacement of the DKA chain with a pyrazole ring – a Lewis base that could mimic the DKA functionality through number of heteroatoms and bonds was employed. Followingly, various analogues of this new class were also designed with a similar fashion with previously mentioned substituent patterns in a way that the comparison of diketo acid and pyrazole analogues can be done. Having synthesized and characterized these analogues, their inhibitory profile was assessed with in vitro studies. The results indicate that the pyrazole analogues are also active in the low micromolar range as it is with diketo acid analogues. Furthermore, the binding pose prediction was also done by in silico studies. There is a correlation with the binding modes of pyrazole analogues and diketo acids analogues as it would be expected. Lastly, the comparison of pyrazole and diketo acid analogues were assessed by SAR report option of Molecular Operating Environment to clearly illustrate the correlation between the analogues as well as assessment of contribution of each varying substitutes both individually and combination strategies.
Taken together, lessons learned from the development of these analogues reveals promising insights and can accelerate the development of hit-to-led stage
Measuring jealousy in intimate relationships: A systematic review of instruments and their psychometric qualities
No full textJealousy may constitute a risk factor for intimate partner violence (IPV). Several authors have validated instruments based on different theoretical models to measure jealousy. However, studies have yet to compare existing questionnaires to evaluate their psychometric properties and understand which instrument best helps to prevent IPV. The objective of the systematic review was to evaluate the psychometric properties of instruments for studying jealousy in intimate relationships. We focus on the reliability, validity, and overall effectiveness of self-report questionnaires used to measure this construct, identifying the most suitable tools for different populations and contexts. A search was conducted on the electronic databases of PubMed, Scopus, Web of Science, and Eric. Using inclusion and exclusion criteria, 32 studies were included, representing 21 instruments, with sample ages ranging from 13 to 65 years. Results revealed the presence of various scales for measuring jealousy: some focused on different triggers and relational consequences of jealousy, while others differed in their purpose and content. These instruments also differ in their psychometric properties, with most demonstrating adequate reliability and validity. However, there are limitations in the way this construct is conceptualized and measured, leading to difficulties in identifying the psychological mechanisms that contribute to pathological forms of jealousy. In conclusion, validated self-report measures of jealousy are crucial for advancing research and clinical practice, helping to identify maladaptive jealousy patterns and inform effective interventions. This work also underscores the need for future research to develop more comprehensive tools that capture the complex individual and relational factors involved in jealousy, particularly as a risk factor for IPV
Exploring rapid non-genomic glucocorticoid signaling in hepatic cells through FRET-based biosensors
No full textGlucocorticoids (GCs) are steroid hormones produced from cholesterol under the control of
the hypothalamic–pituitary–adrenal axis. They play essential roles in metabolism, immune
regulation, and stress adaptation, and synthetic analogs are widely used therapeutically. While
the classical genomic actions of GCs are mediated by the glucocorticoid receptor (GR) acting
as a transcription factor, increasing evidence indicates that GCs can also trigger rapid, non-
genomic effects independent of direct DNA binding. These non-genomic pathways often
involve membrane-associated or cytoplasmic GR pools that activate kinase signaling cascades
such as cAMP/PKA.
This study investigated compartment-specific, non-genomic GC signaling in hepatocyte-
derived cells using FRET-based A-kinase activity reporter (AKAR) biosensors targeted to the
plasma membrane, mitochondria, and nucleus. Treatment with hydrocortisone,
dexamethasone, and the membrane-impermeable BSA-conjugated cortisol induced dose-
dependent activation of PKA, with distinct spatial patterns. Notably, BSA-cortisol produced a
rapid increase in PKA activity at the plasma membrane, demonstrating the presence of a
membrane-initiated, GR-dependent signaling route. Pharmacological inhibition with
mifepristone and the selective GR modulator relacorilant confirmed GR involvement.
Mitochondrial and nuclear PKA activation were also detected at higher hormone
concentrations, suggesting signal propagation across subcellular compartments. Nuclear PKA
likely phosphorylates CREB and histone H3, linking acute non-genomic signaling to chromatin
remodeling and transcriptional regulation. Immunofluorescence confirmed a membrane-
associated GR population consistent with functional data.
Overall, these findings demonstrate that glucocorticoids can activate PKA in distinct
intracellular microdomains via GR-dependent, non-genomic mechanisms. This spatially
i
organized signaling integrates rapid metabolic regulation with long-term genomic effects and
highlights new opportunities to pharmacologically target specific GR pools to reduce adverse
outcomes of glucocorticoid therapy
Linguaggi e narrazioni: analizzare i "film della melodia principale"
No full textDall’avvio delle politiche di riforma e apertura, la presenza di un’alternativa al cinema di Stato, legata all’ingresso di investimenti privati nell’industria cinematografica, portò a un ripensamento delle modalità di gestione della propaganda. Su iniziativa dell’Ufficio cinema del ministero di Radio, Film e Televisione (Guangbo dianying dianshibu dianyingju 广播电影电视部电影局), in occasione della Conferenza nazionale dei direttori degli studi di film a soggetto (Quanguo gushipian changzhang huiyi 全国故事片厂长会议), tenutasi a Pechino tra il febbraio e il marzo , venne lanciato il cosiddetto “cinema della melodia principale” (zhuxuanlü dianying 主旋律电影) con l’obiettivo di trasmettere l’ideologia socialista e di creare un prodotto in grado di competere con il cinema commerciale nelle sale della RPC. Il progetto fu accompagnato dallo slogan: “Promuovere la melodia principale, sostenere la diversificazione”, che individuava nell’aggiornamento dei generi tradizionalmente associati alla propaganda (non più solo film di guerra e sulla storia della rivoluzione, sebbene rimasti filoni di punta) una soluzione per incontrare i gusti del grande pubblico. Dopo una prima fase di assestamento, prolungatasi fino ai primi anni Duemila, il “cinema della melodia principale” rappresenta un prodotto di enorme successo al botteghino della RPC. Obiettivo di questo capitolo è quello di indagare i linguaggi e le narrazioni mainstream della “melodia principale”, attraverso un caso studio sul film The Assembly (Jijiehao 集结号, ) di Feng Xiaogang 冯小刚 (1958-)
Flagellin recognition triggers zinc mobilization in Arabidopsis thaliana as a response to Salmonella Typhimurium invasion
No full text: Salmonella enterica serovar Typhimurium can enter and colonize the apoplast of plants, including the edible ones, making them a potential reservoir for the pathogen and a route for human contamination. We previously showed that in Arabidopsis thaliana shoot colonization, S. Typhimurium takes advantage of its ability to export zinc primarily through the P1B-type ATPase ZntA induced by zinc excess. Moreover, a plant line with reduced ability to translocate zinc from roots to shoots is more susceptible to S. Typhimurium shoot colonization. We, therefore, hypothesized that plants employ zinc intoxication as a defense strategy against invading bacteria. Here we show that, upon S. Typhimurium colonization, A. thaliana modulates the expression of zinc transporters, favoring the long-distance movement of the metal as well as lowering zinc storage into the plant vacuoles. Notably, we demonstrate that this strategy depends on the recognition of bacterial flagellin by the FLS2 receptor, a signal that triggers the PAMP-Triggered Immunity response in plants. Disrupting this interaction, either using an S. Typhimurium Δfla strain or an A. thaliana fls2 mutant line, reduces the zntA expression in shoot-colonizing bacteria. This observation is confirmed by a luminescent zinc biosensor assay, showing that the A. thaliana fls2 does not increase bioavailable zinc in the S. Typhimurium colonized shoots. Moreover, gene expression analyses in the colonized fls2 line revealed a downregulation of the root-to-shoot zinc translocation compared to Col-0. Overall, our results suggest that flagellin recognition by plants triggers zinc fluxes towards the invading bacteria as a facet of the PAMP-Triggered Immunity response, highlighting the importance of plant zinc homeostasis for the interaction with human pathogens
LETTURE CRITICHE. Emiliano Ippoliti, Crash Point. Un’analisi filosofica e pratica per capire le crisi finanziarie, Rubbettino Editore, Soveria Mannelli, 2024, pp. 286
No full textIl libro “Crash Point” di Emiliano Ippoliti propone un approccio filosofico alle crisi finanziarie, interpretandole come fenomeni complessi in cui teoria e pratica risultano strettamente interconnesse. Il volume si articola attorno a quattro dimensioni: ontologia, epistemologia, metodologia e modalità di gestione. Tra i temi centrali emergono il ruolo dei mercati come oggetti epistemici, capaci di aggregare conoscenze distribuite, e il rapporto tra teorie delle crisi e le crisi stesse, influenzate dalle prime nella loro interpretazione. Il testo si distingue per una prospettiva olistica e interdisciplinare, che integra filosofia della storia, teorie strutturaliste, agent-based e della complessità. La lettura critica include un’applicazione pratica al caso della rivalutazione del Bitcoin (novembre-dicembre 2024), mostrando come gli strumenti concettuali proposti consentano di interpretare fenomeni finanziari contemporanei. In conclusione, il libro rappresenta un ponte tra riflessione teorica e operatività, offrendo strumenti concettuali utili sia ai teorici sia agli operatori finanziari.The book “Crash Point” by Emiliano Ippoliti offers a philosophical approach to financial crises, interpreting them as complex phenomena in which theory and practice are closely intertwined. The volume is structured around four dimensions: ontology, epistemology, methodology, and management strategies. Among the central themes are the role of markets as epistemic objects, capable of aggregating distributed knowledge, and the relationship between crisis theories and crises themselves, the latter being influenced by the former in their interpretation. The text stands out for its holistic and interdisciplinary perspective, integrating philosophy of history, structuralist theories, agent-based models, and complexity theory. The critical reading includes a practical application to the case of Bitcoin’s revaluation (November–December 2024), illustrating how the proposed conceptual tools can be used to interpret contemporary financial phenomena. In conclusion, the book serves as a bridge between theoretical reflection and operational practice, providing conceptual instruments useful to both theorists and financial practitioners