WNT Oncogenic Transcription Requires MYC Suppression of Lysosomal Activity and EPCAM Stabilization in Gastric Tumours.

BACKGROUND AND AIMS: WNT signaling is central to spatial tissue arrangement, regulating stem cell activity, and represents the hallmark of gastrointestinal cancers. While its role in driving intestinal tumors is well characterized, WNT's role in gastric tumorigenesis remains elusive. METHODS: We have developed mouse models to control the specific expression of an oncogenic form of B-CATENIN in combination with MYC activation in Lgr5+ cells of the gastric antrum. We used multi-omics approaches applied in vivo and in organoid models to characterize their cooperation in driving gastric tumorigenesis. RESULTS: We report that constitutive B-CATENIN stabilization in the stomach has negligible oncogenic effects and requires MYC activation to induce gastric tumour formation. While physiologically low MYC levels in gastric glands limit B-CATENIN transcriptional activity, increased MYC expression unleashes the WNT oncogenic transcriptional program, promoting B-CATENIN enhancer invasion without a direct transcriptional cooperation. MYC activation induces a metabolic rewiring that suppresses lysosomal biogenesis through mTOR and ERK activation and MiT/TFE inhibition. This prevents EPCAM degradation by macropinocytosis, promoting B-CATENIN chromatin accumulation and activation of WNT oncogenic transcription. CONCLUSION: Our results uncovered a new signaling framework with important implications for the control of gastric epithelial architecture and WNT-dependent oncogenic transformation.

Healthcare Risk Management and Monitoring of patient falls in Italian National Service. The experience of a Local Health Authority.

Falls are a widespread concern in hospitals settings. In Italy, falls are the fourth frequent damage claim type after surgical, diagnostic and therapeutic error and 90% of falls are avoidable. The first necessary action for the prevention of falls consists in identifying the possible risk factors, in relation to the characteristics of the patient and those of the environment and the structure that hosts him, in terms of safety, organization and adequacy of the process welfare. In this work we wanted to evaluate the extent, frequency and characteristics of the phenomenon of falls in the population hospitalized at the Local Health Authority called "Roma 2", with the aim of analyzing the critical issues to allow the identification of possible preventive and improvement interventions as well as reducing the risk of falls.

Novel TLR4-Activating Vaccine Adjuvant Enhances the Production of Enterococcus faecium-binding Antibodies.

Vaccines are one of the greatest achievements of modern medicine. Due to their safer profile, the latest investigations usually focus on subunit vaccines. However, the active component often needs to be coupled with an adjuvant to be effective and properly trigger an immune response. We are developing a new synthetic monosaccharide-based TLR4 agonist, such as glucosamine-derived compounds FP18 and FP20, as a potential vaccine adjuvant. In this study, we present a new FP20 derivative, FP20Hmp, with a hydroxylated ester linked to the glucosamine core. We show that the modification introduced improves the activity of the adjuvant and its solubility. This study presents the synthesis of FP20Hmp, its in vitro characterization, and in vivo activity while coupled with the ovalbumin antigen or in formulation with an enterococcal antigen. We show that FP20Hmp enables increased production of antigen-specific antibodies that bind to the whole bacterium.

PCGF6 controls murine Tuft cell differentiation via H3K9me2 modification independently of Polycomb repression.

Cell fate is determined by specific transcription programs that are essential for tissue homeostasis and regeneration. The E3-ligases RING1A and B represent the core activity of the Polycomb repressive complex 1 (PRC1) that deposits repressive histone H2AK119 mono-ubiquitination (H2AK119ub1), which is essential for mouse intestinal homeostasis by preserving stem cell functions. However, the specific role of different PRC1 forms, which are defined by the six distinct PCGF1-6 paralogs, remains largely unexplored in vivo. We report that PCGF6 regulates mouse intestinal Tuft cell differentiation independently of H2AK119ub1 deposition. We show that PCGF6 chromatin occupancy expands outside Polycomb repressive domains, associating with unique promoter and distal regulatory elements. This occurs in the absence of RING1A/B and involves MGA-mediated E-BOX recognition and specific H3K9me2 promoter deposition. PCGF6 inactivation induces an epithelial autonomous accumulation of Tuft cells that was not phenocopied by RING1A/B loss. This involves direct PCGF6 association with a Tuft cell differentiation program that identified Polycomb-independent properties of PCGF6 in adult tissues homeostasis.

The ERM experience of the Lombardy Region as a tool for improving the safety of the regional health care system.

The Regional Center for Healthcare Risk Management and Patient Safety of the Lombardy Region, with the technical partnership of Aon, designed an innovative Healthcare Enterprise Risk Management Model (hereafter HERM) to meet the following objectives: 1) Improve the safety of the Regional Healthcare System through the implementation of methods and tools aimed to identify, analyze and mange in an integrated way all the risks to which are exposed the healthcare companies. 2) Preserve the creation of social value in the medium-long term and the sustainable achievement of strategic and operational objectives. 3) Optimize risk management costs. 4) Reduce/mitigate adverse events in all business processes. 5) Enable the ability to anticipate and react to changes. 6) Establish sound long-term and risk-based strategies. This paper describes the structuring of the overall HERM Model Framework, and the related information flows, the tools supporting the Healthcare Enterprise Risk Management Methodology (such as the Risk Model and the Assessment Metrics) and presents the preliminary result of first experience of Healthcare ERM in Italy.

Patient Safety and Surgery: the Experience of the Lombardy Region. A Project on External Evaluation of Best Practices Implementation.

Meta-analysis studies published over the past 20 years document that approximately 10 -14 % of hospitalised patients have an adverse event in Surgery and at least half of these adverse events are considered preventable using the current standards of care. In order to improve the safety of surgical patients and increasing adherence to current standard of care in surgery, including communication within the team and teamwork, in 2007 the WHO launched the campaign "Safe Surgery Saves Lives". The WHO has also built a checklist for safety in the operating room containing 19 item in support of the operating team. The Ministry of Health in 2009 has taken the instruments produced by WHO in the "Guide to Safety in the operating room: Recommendations and Checklist". Studies conducted in industrialized countries report a strong heterogeneity in compliance to the check list for the surgical safety, with a range of between 38% and 96%. The aim of this project was to adopt the methodology of the external "peer review" to improve quality and patient safety applied to the surgical process and assess the degree of implementation of good practice in the operating room, both in public and private structures. Between 2015 and 2018 we have carried out 16 external evaluation visits. These visits included a first plenary session followed by the inspection of the operating theaters identified and a second plenary session. Several factors emerged during the visits; these factors represent both the strengths and criticalities of the organizations. The creation of a team of experts, coordinated by the Lombardy Region with the role of leadership, using the "peer review" methodology, is the leverage to promote among operators the growth of awareness of the usefulness of the tools.

PRC2.1- and PRC2.2-specific accessory proteins drive recruitment of different forms of canonical PRC1.

Polycomb repressive complex 2 (PRC2) mediates H3K27me3 deposition, which is thought to recruit canonical PRC1 (cPRC1) via chromodomain-containing CBX proteins to promote stable repression of developmental genes. PRC2 forms two major subcomplexes, PRC2.1 and PRC2.2, but their specific roles remain unclear. Through genetic knockout (KO) and replacement of PRC2 subcomplex-specific subunits in naïve and primed pluripotent cells, we uncover distinct roles for PRC2.1 and PRC2.2 in mediating the recruitment of different forms of cPRC1. PRC2.1 catalyzes the majority of H3K27me3 at Polycomb target genes and is sufficient to promote recruitment of CBX2/4-cPRC1 but not CBX7-cPRC1. Conversely, while PRC2.2 is poor at catalyzing H3K27me3, we find that its accessory protein JARID2 is essential for recruitment of CBX7-cPRC1 and the consequent 3D chromatin interactions at Polycomb target genes. We therefore define distinct contributions of PRC2.1- and PRC2.2-specific accessory proteins to Polycomb-mediated repression and uncover a new mechanism for cPRC1 recruitment.

Healthcare Management, avoidable mortality, telemedicine to improve health of the diabetic population.

BACKGROUND: Worldwide the International Diabetes Federation (IDF) estimated that in 2021 9.2% of adults (536.6 million, between 20 and 79 years of age) are diabetic and 32.6% under 60 years (6.7 million) die because of diabetes. This disease is set to become the leading cause of disability and mortality by 2030. In Italy, the prevalence of Diabetes is about 5%; in the pre-pandemic period, from 2010 to 2019, diabetes was responsible for 3% of deaths recorded, while during the pandemic in 2020, these deaths increased to about 4%. The present work aimed to measure the outcomes obtained from the ICPs (integrated care pathways) implemented by a Health Local Authority according to the model of the Lazio region and its impact on avoidable mortality, i.e., those deaths potentially avoidable with primary prevention interventions, early diagnosis and targeted therapies, adequate hygienic conditions and proper health care. MATERIALS AND METHODS: Data from 1675 patients enrolled in the diagnostic treatment pathway were analyzed, 471 with type 1 diabetes and the remainder with type 2 (mean age 17.5 and 69, respectively). 987 patients with type 2 diabetes also had comorbidities: in 43% obesity, 56% dyslipidemia, 61% hypertension, 29% COPD. In 54% they had at least 2 comorbidities. All patients enrolled in the ICPs were equipped with a glucometer and an app capable of recording results on capillary blood, 269 with type 1 diabetes were equipped with continuous and 198 insulin pump measurement devices. All enrolled patients recorded at least one daily blood glucose reading, one weekly weight reading, and recorded steps taken daily. They also underwent glycated hemoglobin monitoring, periodic visits and scheduled instrumental checks. A total of 5500 parameters were measured for patients with type 2 diabetes and 2345 for patients with type 1 diabetes. RESULTS: Analysis of medical records revealed that 93% of patients with type 1 diabetes were found to be adherent to the treatment pathway, adherence of patients with type 2 diabetes was recorded in 87% of enrolled cases. The analysis of accesses to the Emergency Department for decompensated diabetes saw only 21% of patients enrolled in the ICPs, but recording poor compliance. The mortality in enrolled patients was 1.9% compared with 4.3 percent in patients not enrolled in ICPs, and patients amputated for diabetic foot resulted in 82% of patients not enrolled in ICPs. Finally, it is noted that patients also enrolled in the telerehabilitation pathway or home care rehabilitation (28%), with the same conditions of severity of neuropathic and vasculopathic picture presented a reduction of 18% in leg or lower limb amputation compared to patients not enrolled or not adhering to ICPs, a reduction of 27% in metatarsal amputation and 34% in toes amputation. CONCLUSIONS: Telemonitoring of diabetic patients allows for greater patient empowerment with increased adherence, as well as a reduction in Emergency Department and inpatient admissions, thus resulting in ICPs being a tool for both standardization of quality of care and standardization of the average cost of the chronic patient with diabetic disease. Likewise, telerehabilitation can reduce the incidence of amputations from diabetic foot disease if associated with adherence to the proposed pathway with ICPs.

Healthcare Quality Management and Integrated Care Pathways (ICPs).

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is one of the largest causes of morbidity and chronic mortality and a public health problem of high importance. In Italy, COPD afflicts 5.6% of adult (3.5 million people) and is responsible for 55% of all deaths related to respiratory diseases. Smokers have a higher risk, in fact up to 40% develop the disease. From the Covid-19 pandemic, the most affected population is the elderly (mean age 80 years old), with previous chronic diseases, in 18% with chronic respiratory. The aim of the present work was to validate and measure the outcomes produced by the recruitment and care of COPD patients enrolled by an Healthcare Local Authority in the corresponding Integrated Care Pathways (ICPs) in order to measure how a multidisciplinary, systemic and e-health monitored care impacts upon mortality and morbidity. MATERIALS AND METHODS: Enrolled patients were stratified through the GOLD guidelines classification, a unified method to discriminate the various degrees of severity of COPD, using specific spirometric cut-points and providing homogeneous classes of patients. Monitoring examinations include simple spirometry, global spirometry, diffusing capacity measurement, pulse oximetry, EGA, 6-minute walk test. Chest Rx, chest CT, ECG may also be required. The severity of COPD identifies the timing of monitoring, which involves a fixed annual re-assessment for mild offset clinical forms, biannually in case of exacerbation, a quarterly cadence in moderate forms that becomes bimonthly in severe forms. RESULTS: In 2344 enrolled patients (46% women and 54% men, mean age 78 yo) 18% had GOLD severity 1, 35% GOLD 2, 27% GOLD 3 and 20% GOLD 4. In addition, 73% of patients had at least one other chronic comorbidity, mainly diabetes or hypertension, and in 48% both. The data analysis showed that the population followed in e-health presented a 49% reduction in improper hospital admissions and a 68% reduction in clinical exacerbations compared to the population enrolled in the ICPs but not followed also in e-health. Smoking habits present at the time of patient enrollment in the ICPs remained in 49% of the total population enrolled and in 37% of the population enrolled in e-health. The patients enrolled in GOLD 1 and 2 obtained the same benefits both if treated in e- health and if treated in the clinic. However, GOLD 3 and 4 patients instead presented better compliance if treated in e-health and continuous monitoring allowed punctual and early interventions such as to reduce complications and hospitalization. CONCLUSION: The e-health approach made possible to ensure proximity medicine and personalization of care. Indeed, the implemented diagnostic treatment protocols, if properly followed and monitored, are able to control complications and impact the mortality and disability of chronic disease. The advent of e-health and ICT tools are demonstrating a great support capacity for care taking that also allows greater adherence to patient care pathways, even more than the protocols up to now identified, characterized by a monitoring programmed over time, enhancing a patients and their families quality of life improvement.

Management of an Integrated Care Pathways (ICPs): an Italian Study.

BACKGROUND: The World Health Organization defines chronic disease as long duration and generally slow progression disease, with a continuous treatment over decades. The management of such diseases is complex, as the aim of treatment is not cure, but maintenance of a good quality of life and prevention of possible complications. Cardiovascular diseases are the leading cause of death worldwide (18 million deaths per year) and hypertension remains the largest preventable cause of cardiovascular disease globally. In Italy, the prevalence of hypertension was of 31.1%. The goal of antihypertensive therapy should be to reduce blood pressure back to physiological levels or to a range of values identified as targets. The National Chronicity Plan identifies an Integrated Care Pathways (ICPs) for several acute or chronic conditions, at different stages of disease and care levels, in order to optimize the healthcare processes. The aim of the present work was to perform a cost-utility analysis of management models of Hypertension ICPs to assist frail patients with hypertension following the National Health Service (NHS) guidelines in order to reduce morbidity and mortality rates. In addition, the paper emphasizes the importance of e-Health technologies for the implementation of chronic care management models based on the Chronic Care Model (CCM). MATERIALS AND METHODS: The management of the health needs of frail patients in a Healthcare Local Authority finds an effective tool in the Chronic Care Model, involving the analysis of the epidemiological context. Hypertension Integrated Care Pathways (ICPs) includes a series of first-level laboratory and instrumental tests necessary at the beginning of the intake, for accurate pathology assessment, and annually for adequate surveillance of the hypertensive patient. For the cost-utility analysis were investigated the flows of pharmaceutical expenditure for cardiovascular drugs and the measurement of the outcomes of the patients assisted by the Hypertension ICPs. RESULTS: The average cost of a patient included in the ICPs for hypertension is 1636.21 euros/year, reduced to 1345 euros/year using telemedicine follow-up. The data collected by Rome Healthcare Local Authority on 2143 enrolled patients allow us to measure both the effectiveness of prevention and the monitoring of adherence to therapy and thus the maintenance of hematochemical and instrumental tests in a range of compensation such that it is possible to impact on the outcomes, resulting in the 21% reduction in the expected mortality and the 45 % reduction in avoidable mortality due to cerebrovascular accidents, with related impact on potential disability. It was also estimated that patients included in ICPs and followed by telemedicine compared to outpatient care, obtained a 25% reduction in morbidity, with greater adherence to therapy and better empowerment results. The patients enrolled in the ICPs who accessed the Emergency Department (ED) or hospitalization presented adherence to therapy in 85% of cases and a change in lifestyle habits in 68%, compared to the population not enrolled in the ICPs, which presented a 56% adherence to therapy and a change in lifestyle habits of 38%. CONCLUSIONS: The performed data analysis allows to standardize an average cost and to evaluate the impact of primary and secondary prevention on the costs of hospitalizations associated with a lack of effective treatment management, and e-Health tools lead to a positive impact on adherence to therapy.

Intestinal differentiation involves cleavage of histone H3 N-terminal tails by multiple proteases.

The proteolytic cleavage of histone tails, also termed histone clipping, has been described as a mechanism for permanent removal of post-translational modifications (PTMs) from histone proteins. Such activity has been ascribed to ensure regulatory function in key cellular processes such as differentiation, senescence and transcriptional control, for which different histone-specific proteases have been described. However, all these studies were exclusively performed using cell lines cultured in vitro and no clear evidence that histone clipping is regulated in vivo has been reported. Here we show that histone H3 N-terminal tails undergo extensive cleavage in the differentiated cells of the villi in mouse intestinal epithelium. Combining biochemical methods, 3D organoid cultures and in vivo approaches, we demonstrate that intestinal H3 clipping is the result of multiple proteolytic activities. We identified Trypsins and Cathepsin L as specific H3 tail proteases active in small intestinal differentiated cells and showed that their proteolytic activity is differentially affected by the PTM pattern of histone H3 tails. Together, our findings provide in vivo evidence of H3 tail proteolysis in mammalian tissues, directly linking H3 clipping to cell differentiation.

[Telemedicine: a Proxemics tool of Primary Care?] / La telemedicina: uno strumento di prossemica dell'assistenza territoriale?

The impact of demographic and sociopolitical phenomena such as population aging, economic and social changes derivinf from globalization and the pervasiveness of information technologies, require innovative and efficient responses to new health needs, characterized by the increase o in the numer of healthcare procedures and its complexity. The COVID 19 has had a negative impact on the that context. This paper demonstrates that the telemdicine enables to optimize resources, as well as to ensure the distancing and delivery times of services. The telemedicine in the time of COVID is the new proxemics tool of Primary care.

[Telemedicine and improvement in care quality. The experience of Rome 3 Healthcare Local Autority in home care of patients with amyotrophic lateral sclerosis (ALS)]. / Il miglioramento della qualità assistenziale territoriale dei pazienti affetti da SLA con l'introduzione del telemonitoraggio e del teleconsulto. L'esperienza della ASL ROMA 3.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that results in progressive muscle weakness, disability, and ultimately death. Remote evaluation of ALS patients in home care, by using telemedicine, has been shown to be safe and effective. This study showed improvements in the perceived quality of care in 24 SLA patient, improved patient satisfaction and a 15% reduction in care costs.

[Protocol proposal for the management of tuberculosis cases for healthcare Local Authority]. / Proposta di protocollo per la gestione dei casi di Tubercolosi per le Aziende Sanitarie Locali.

TB is still a major public health problem and a threat to global health security. In Italy, TB control is consistent with the WHO global strategy, in which the role of prevention and, within it, contacts tracing and their management are emphasized. In this work, a protocol for the correct and homogeneous management of TB cases, at local level, is described in all its phases, from reporting to contacts management. The containment of the diffusion of the infection and the prevention of new outbreaks depend on the immediate identification of the index case and the proper performance of the epidemiological investigation. For this reason, the translation of scientific evidence into Recommendations and Guidelines is essential, and of these into operational protocols for the local level, with a clear indication of actions and responsibilities.

[Femicide: a Avoidable Mortality? The "Tivoli" Model]. / Il femminicidio: una mortalità evitabile? Il modello Tivoli.

The Instabul Convention is a normative tool for the prevention of women's violence in Europe. Rome 5 Local Healthcare Authority has implemented a synergistic intervention model in joint ventures with all stakeholders and institutions involved: the Tivoli Model. This model provides a synergistic social, health, legal and training approach to prevent violence against women in a logic of preventing an avoidable mortality.

[New Italian law on malpractice: the impact with risk, insurance and accountability management]. / La gestione del rischio clinico e l'impatto organizzativo richiesto dai cambiamenti apportati dalla cosiddetta legge Gelli (legge n. 24 del 8 marzo 2017).

The new Italian Law on malpractice redefined the risk profile of public and private healthcare Organization. This new law is a legislative response to the Italian medical malpractice insurance crisis. The law, in fact, requires an approach on risk thinking based and accountability. Finally, it also requires a review of the insurance management.

Defensive medicine and outcomes for medical malpractice liability.

Defensive medicine is a significant force driving the high costs of healthcare systems and has a substantial influence on physicians' behavior because they primarily concern about malpractice liability and not patient's health protection. This attitude disagrees with deontological duties and could impair physicians' ability of judgment and clinical reasoning. Reducing defensive medicine also could mean improving the quality in healthcare systems and eliminating unnecessary costs.

The private healtcare systems in europe. What can we learn from Russia?

The European healthcare system is characterized by different kinds of funding: public, insurance-based, and mixed. In Italy, the prolonged economic crisis and the need for a cost reduction in the public administrations make necessary a cut in expenditure, which has a significant impact also on the funding of the healthcare system. The comparison of different European healthcare systems may offer useful insights for a better definition of the European and / or national healthcare provision strategies, which would be economically and financially sustainable but also capable to protect the population health. In this regard, it is worth to analyze the Russian healthcare system, which in the last years has undergone significant changes in its structure and in the way healthcare services are supplied. The peculiarity of the Russian healthcare system, which is quite different from the European standards for both professional requirements and theoretical knowledge, makes Russia an absolutely interesting partner for a future joint venture research. This paper describes the Russian national healthcare system highlights the differences in the demographic and socio-economic structures relatively to the Italian model. The paper supports a reflection on the sustainability of the health care systems and on the organizational forms that would guarantee the supply of better healthcare services in terms of quality, appropriateness and safety, compatibly with its economic sustainability.

Rationale and design of a trial evaluating the effects of losartan vs. nebivolol vs. the association of both on the progression of aortic root dilation in Marfan syndrome with FBN1 gene mutations.

BACKGROUND: The major clinical problem of Marfan syndrome (MFS) is the aortic root aneurysm, with risk of dissection when the root diameter approximates 5 cm. In MFS, a key molecule, transforming growth factor-beta (TGF-beta), normally bound to the extracellular matrix, is free and activated. In an experimental setting, TGF-beta blockade prevents the aortic root structural damage and dilatation. The angiotensin receptor 1 blockers (sartanics) exert an anti-TGF-beta effect; trials are now ongoing for evaluating the effect of losartan compared with atenolol in MFS. beta-Adrenergic blockers are the drugs most commonly used in MFS. The third-generation beta-adrenergic blocker nebivolol retains the beta-adrenergic blocker effects on heart rate and further exerts antistiffness effects, typically increased in MFS. METHODS: The open-label phase III study will include 291 patients with MFS and proven FBN1 gene mutations, with aortic root dilation (z-score > or =2.5). The patients will be randomized to nebivolol, losartan and the combination of the two drugs. The primary end point is the comparative evaluation of the effects of losartan, nebivolol and the association of both on the progression of aortic root growth rate. Secondary end points include the pharmacokinetics of the two drugs, comparative evaluation of serum levels of total and active TGF-beta, quantitative assessment of the expression of the mutated gene (FBN1, both 5' and 3'), pharmacogenetic bases of drug responsiveness. The quality of life evaluation in the three groups will be assessed. Statistical evaluation includes an interim analysis at month 24 and conclusive analyses at month 48. CONCLUSION: The present study will add information about pharmacological therapy in MFS, supporting the new application of angiotensin receptor 1 blockers and finding beta-adrenergic blockers that may give more specific effects. Moreover, the study will further deepen understanding of the pathogenetic mechanisms that are active in Marfan syndrome through the pharmacogenomic and transcriptomic mechanisms that may explain MFS phenotype variability.

[Measurement of customer satisfaction and participation of citizens in improving the quality of healthcare services.]. / La misurazione della customer satisfaction come strumento di partecipazione del cittadino al miglioramento della qualità prestazionale in Sanità

Managing quality in health care whilst ensuring equity is a fundamental aspect of the provision of services by healthcare organizations. Measuring perceived quality of care is an important tool for evaluating the quality of healthcare delivery in that it allows the implementation of corrective actions to meet the healthcare needs of patients. The Rome B (ASL RMB) local health authority adopted the UNI EN 10006:2006 norms as a management tool, therefore introducing the evaluation of customer satisfaction as an opportunity to involve users in the creation of quality healthcare services with and for the citizens. This paper presents the activities implemented and the results achieved with regards to shared and integrated continuous improvement of services.