The meta-projects of the new community health centers, community hospitals and local operative centers for the Italian country.

BACKGROUND AND AIM: COVID-19 highlighted significant criticalities of the Italian National Healthcare System (NHS) and recently the Italian Government approved the National Recovery and Resilience Plan (NRRP) to relaunch its economy and at the same time to promote health, sustainability and digital innovation. Specifically, M6C1 (Mission 6 Component 1) wants to introduce Community Health Centers (CHCs), Community Hospitals (CHs) and Local Operative Centers (LOCs) to strength territorial healthcare services. Starting from the Italian Ministerial Decree n. 77 (2022), AGENAS (National Agency for Regional Healthcare System) and POLIMI (Politecnico di Milano) working group developed the meta-design guidelines for CHCs, CHs and LOCs facilities with the aim of supporting decision-makers to define spatial features and building performances in order to be responsive to functional issues. METHODS: The spatial strategies of these facilities have been elicited through three different steps: a) a survey about the current national and international scenario regarding the territorial healthcare; b) a review of all national and regional regulations; c) the development of the meta-design guidelines have been elaborated from the analysis of the a) and b) steps. RESULTS: The regulatory instructions and scientific indications collected through the literature have been translated into spatial and functional layouts. The services have been organized by homogeneous macro-areas and defined in a synoptic framework which shows the performance approach and their features. Each macro-area, sorted by type of functions, has been subdivided into a list of all its specific spatial units. CONCLUSIONS: The study conducted aims at supporting the planning of these facilities in relation to the catchment area and their sizing. It will be necessary to define the location by evaluating the possibility of setting them up within existing hospitals, as well as to guarantee a sustainable approach in the realization of these infrastructures.

Healthcare costs of diabetic foot disease in Italy: estimates for event and state costs.

OBJECTIVE: This study aimed to estimate healthcare costs of diabetic foot disease (DFD) in a large population-based cohort of people with type-2 diabetes (T2D) in the Tuscany region (Italy). DATA SOURCES/STUDY SETTING: Administrative healthcare data of Tuscany region, with 2018 as the base year. STUDY DESIGN: Retrospective study assessing a longitudinal cohort of patients with T2D. DATA COLLECTION/EXTRACTION METHODS: Using administrative healthcare data, DFD were identified using the International Classification of Diseases, Ninth Revision, Clinical Modification codes. METHODS: We examined the annual healthcare costs of these clinical problems in patients with T2D between 2015 and 2018; moreover, we used a generalized linear model to estimate the total healthcare costs. PRINCIPAL FINDINGS: Between 2015 and 2018, patients with T2D experiencing DFD showed significantly higher average direct costs than patients with T2D without DFD (p < 0.0001). Among patients with T2D experiencing DFD, those who experienced complications either in 2015-2017 and in 2018 incurred the highest incremental costs (incremental cost of € 16,702) followed by those with complications in 2018 only (incremental cost of € 9,536) and from 2015 to 2017 (incremental cost of € 800). CONCLUSIONS: DFD significantly increase healthcare utilization and costs among patients with TD2. Healthcare costs of DFD among patients with T2D are associated with the timing and frequency of DFD. These findings should increase awareness among policymakers regarding resource reallocation toward preventive strategies among patients with T2D.

Monitoring Appropriate Monoclonal Antibodies Prescribing via Administrative Data: An Application to Psoriasis.

The Italian Medicines Agency (AIFA) and the Italian Regional Health Systems have implemented measures together with data collection and analysis to improve medicines' appropriate prescription. Administrative databases represent rich Real-World Evidence (RWE) sources that may be leveraged for research purposes. Thus, such heritage may allow for appropriate prescription studies to be carried out on complex pharmaceutical molecules, as the appropriateness of prescriptions is essential both for patients' treatment and to ensure healthcare systems' sustainability. This study analyzed the appropriate monoclonal antibodies (mAbs) prescribed in psoriasis treatment across Tuscany, Italy. Data were extracted from several large administrative databases collected by the Tuscan Regional Healthcare System through record linkages. The analysis showed that over 30% of the 2020 cohort of psoriatic patients could be regarded as potentially inappropriate treated, signaling that mAbs are often prescribed as first-line treatment contrary to guidelines. Variation was observed in the appropriate prescription of mAbs, across different types of mAbs and areas. The study revealed potential inappropriate prescription, and its geographic variation should raise awareness among managers about the appropriate use of resources. Despite limitations, this could represent a pilot for future studies to evaluate the appropriate prescription of mAbs in other clinic conditions and across time.

Protecting higher education institutions from COVID-19: insights from an Italian experience.

Higher education institutions (HEIs) worldwide have been deeply affected by the Coronavirus Disease 2019 (COVID-19) pandemic and subsequent lockdown measures. HEIs are environments at high risk of COVID-19 diffusion, due to the high number of people sharing the same environment, and complex to protect, because of the multiple functions present (e.g. teaching rooms, research facilities, dormitories). Protection of HEIs is therefore a serious, but apparently neglect, public health issue. Italy was the first country to be heavily hit in Europe by COVID-19. Italian HEIs had to quickly respond to the emergency with multifaceted interventions to protect all the people on campus while guaranteeing the continuity of research and teaching activities. The purpose of this viewpoint is to propose and discuss a list of priority actions for the protection of HEIs, based on international guidelines and the experience of a small size Italian Public University and Research campus.

Learning from Excellence to Improve Healthcare Services: The Experience of the Maternal and Child Care Pathway.

The ability to deal with adversity and the resilience of people and groups are shown to depend positively on the tendency to nurture positivity. Therefore, the aim of this study is to evaluate whether Learning from Excellence (LfE) can be an effective method to manage systematic health systems, when transparent disclosure and benchmarking of data are adopted in performance evaluation. This study consists of a quantitative and a qualitative phase. In the former, maternal care is investigated at the regional level, starting from performance data and indicators of the maternity pathway referred to 98 healthcare providers in 10 Italian regions, that share the same evaluation system. The second phase investigates qualitatively the organizational determinants and the experience of professionals involved in the pathway, through the organization of on-site workshops. We identified the seven best practices among the 42 units of analysis. Communication, trust and shared goals among health professionals involved in the pathway emerged as core themes from the qualitative analysis. This study confirms that LfE under the conditions of benchmarking assessment and transparent disclosure of data can be implemented systematically in management practice, in order to boost health personnel's resilience and, in general, the organizational climate in the working environment.

Environmental Pollution by Benzene and PM10 and Clinical Manifestations of Systemic Sclerosis: A Correlation Study.

Atmospheric air pollution has been associated with a range of adverse health effects. The environment plays a causative role in the development of Systemic Sclerosis (SSc). The aim of the present study is to explore the association between particulate (PM10) and benzene (B) exposure in Italian patients with systemic sclerosis and their clinical characteristics of the disease. A correlation study was conducted by enrolling 88 patients who suffer from SSc at the Fondazione Policlinico "A. Gemelli" in Rome (Italy) in the period from January 2013 to January 2014. The average mean concentrations of B (in 11 monitoring sites) and PM10 (in 14 sites) were calculated using data from the Regional Environmental Protection Agency's monitoring stations located throughout the Lazio region (Italy) and then correlated with the clinical characteristics of the SSc patients. Of the study sample, 92.5% were female. The mean age was 55 ± 12.9 years old and the mean disease duration from the onset of Raynaud's phenomenon was 13.0 ± 9.4 years. The Spearman's correlation showed that concentrations of B correlate directly with the skin score (R = 0.3; p ≤ 0.05) and inversely with Diffusing Lung Carbon Monoxide (DLCO) results (R = -0.36; p = 0.04). This study suggests a possible role of B in the development of diffuse skin disease and in a worse progression of the lung manifestations of SSc.

Workplace health promotion for older workers: a systematic literature review.

BACKGROUND: Aging of the workforce is a growing problem. As workers age, their physical, physiological and psychosocial capabilities change. Keeping older workers healthy and productive is a key goal of European labor policy and health promotion is a key to achieve this result. Previous studies about workplace health promotion (WHP) programs are usually focused on the entire workforce or to a specific topic. Within the framework of the EU-CHAFEA ProHealth65+ project, this paper aims to systematically review the literature on WHP interventions specifically targeted to older workers (OWs). METHODS: This systematic review was conducted by making a comprehensive search of MEDLINE, ISI Web of Science, SCOPUS, The Cochrane Library, CINAHL and PsychINFO databases. Search terms included ageing (and synonyms), worker (and synonyms), intervention (and synonyms), and health (and synonyms). The search was limited to papers in English or Italian published between January, 1(st) 2000 and May, 31(st) 2015. Relevant references in the selected articles were also analyzed. RESULTS: Of the 299 articles initially identified as relating to the topic, 18 articles met the inclusion criteria. The type, methods and outcome of interventions in the WHP programs retrieved were heterogenous, as was the definition of the age at which a worker is considered to be 'older'. Most of the available studies had been conducted on small samples for a limited period of time. CONCLUSION: Our review shows that, although this issue is of great importance, studies addressing WHP actions for OWs are few and generally of poor quality. Current evidence fails to show that WHP programs improve the work ability, productivity or job retention of older workers. In addition, there is limited evidence that WHP programs are effective in improving lifestyles and concur to maintain the health and well-being of older workers. There is a need for future WHP programs to be well-designed so that the effectiveness and cost-benefit of workplace interventions can be properly investigated.

Design and synthesis of 2-oxindole based multi-targeted inhibitors of PDK1/Akt signaling pathway for the treatment of glioblastoma multiforme.

Aggressive behavior and diffuse infiltrative growth are the main features of Glioblastoma multiforme (GBM), together with the high degree of resistance and recurrence. Evidence indicate that GBM-derived stem cells (GSCs), endowed with unlimited proliferative potential, play a critical role in tumor development and maintenance. Among the many signaling pathways involved in maintaining GSC stemness, tumorigenic potential, and anti-apoptotic properties, the PDK1/Akt pathway is a challenging target to develop new potential agents able to affect GBM resistance to chemotherapy. In an effort to find new PDK1/Akt inhibitors, we rationally designed and synthesized a small family of 2-oxindole derivatives. Among them, compound 3 inhibited PDK1 kinase and downstream effectors such as CHK1, GS3Kα and GS3Kß, which contribute to GCS survival. Compound 3 appeared to be a good tool for studying the role of the PDK1/Akt pathway in GCS self-renewal and tumorigenicity, and might represent the starting point for the development of more potent and focused multi-target therapies for GBM.

In vitro studies of antifibrotic and cytoprotective effects elicited by proto-berberine alkaloids in human dermal fibroblasts.

BACKGROUND: The pathogenic mechanisms of skin fibrosis are still not completely understood, unlike the profibrotic role played by inflammatory cytokines and transforming growth factor-ß1 (TGF-ß1). Few antifibrotic drugs are available. Nevertheless, folk medicine suggests numerous treatments of fibrotic conditions. Based on information from folk medicine and literature, the hypothesis was made that proto-berberine alkaloids could act as antifibrotic and cytoprotective agents. METHODS: The effects of berberine, dihydroberberine, canadine, stylopine, and coptisine were investigated on an in vitro model of fibrosis purposely set up. The study is based on the use of human dermal fibroblasts (HDF). The ability of the proto-berberine alkaloids investigated to modulate mitochondrial dehydrogenase activity, cell proliferation, collagen production, and inflammatory cytokine (IL-1ß and IL-6) production was tested on HDF cells grown under standard growth conditions, in the presence of 100 µM H(2)O(2), simulating oxidative stress conditions, and in the presence of 34 ng/ml TGF-ß1, simulating fibrotic conditions. Antiradical activity was assayed as well, as it could contribute to cytoprotection. RESULTS: Each alkaloid tested showed peculiar effects on HDF. In particular, all of the alkaloids tested, with the exception of coptisine, inhibited TGF-ß1-induced collagen production. CONCLUSIONS: Due to its irritant effects and the lack of desired properties, coptisine has low exploitation potentialities. The other proto-berberine alkaloids investigated resulted all endowed with activities for which they can be exploited as antifibrotic and cytoprotective agents. Stylopine globally proved to be the most promising compound, being endowed with revitalizing, anti-inflammatory, antifibrotic and wound-healing promoting activities, and showing no toxic effects.

Enzyme kinetics studies on 29-kDa human liver cathepsin L.

Enzyme kinetics studies reported in the literature showed that human liver Cathepsin L is active only at lysosomal acidic pH values, while biochemical studies in living cells showed that the enzyme works even at neutral pH values (in a condition compatible with the extracellular compartment). Such an apparent ambiguity highlighted the need of analysing in depth the kinetics of ~29-kDa Cathepsin L, which is the form commonly used in experiments. The stability and catalytic activity of this enzyme were investigated at different pH values, reducing and non-reducing environments, presence of copper, iron and zinc ions, and presence of the natural modulator/inhibitor cystatin B. Our experiments showed that ~29-kDa human liver Cathepsin L is stable and catalytically functional even at neutral pH values and under non-reducing conditions, which simulate the extracellular compartment. Under these conditions, Cathepsin L was also proved to interact with cystatin B, being also modulated by physiological concentrations of Cu(++) , Fe(++) and Zn(++) . This paper suppose an advance in the comprehension of the catalytic properties of human liver Cathepsin L, its implications in different physiological processes and its potential use within a drug screening programme in which agents acting extracellularly are being considered.

Berberine exposure triggers developmental effects on planarian regeneration.

The mechanisms of action underlying the pharmacological properties of the natural alkaloid berberine still need investigation. Planarian regeneration is instrumental in deciphering developmental responses following drug exposure. Here we report the effects of berberine on regeneration in the planarian Dugesia japonica. Our findings demonstrate that this compound perturbs the regenerative pattern. By real-time PCR screening for the effects of berberine exposure on gene expression, we identified alterations in the transcriptional profile of genes representative of different tissues, as well as of genes involved in extracellular matrix (ECM) remodeling. Although berberine does not influence cell proliferation/apoptosis, our experiments prove that this compound causes abnormal regeneration of the planarian visual system. Potential berberine-induced cytotoxic effects were noticed in the intestine. Although we were unable to detect abnormalities in other structures, our findings, sustained by RNAi-based investigations, support the possibility that berberine effects are critically linked to anomalous ECM remodeling in treated planarians.

N-[9-(ortho-fluorobenzyl)-2-phenyl-8-azapurin-6-yl]-amides as potent and selective ligands for A1 adenosine receptors.

A series of N-[9-(ortho-fluorobenzyl)-2-phenyl-8-azapurin-6-yl]-amides were synthesized and tested for their affinity toward A1, A2A , and A3 adenosine receptor subtypes. Biological results demonstrated that the introduction of a fluorine atom at the ortho position of the 9-benzyl group generally enhanced affinity toward A1 subtype and did not significantly affect A2A and A3 affinity. Very interesting is the compound bearing a meta-fluorophenyl substituent on the carbonyl carbon of the amide group, which shows significantly high A1/A2A-A3 selectivity. Compounds of this new series, together with the previously published analogs without the fluorine atom on the 9-benzyl group, constituted the starting dataset for the development of QSAR models. The models obtained were able to rationally describe the affinity trends resulting from biological testing and to enable investigation of the role of different substituents on the 8-azapurine scaffold, as well as the influence of the newly introduced fluorine atom on the benzyl moiety. The said QSAR models can also assist in the design of new compounds selectively active on A1 adenosine receptors. Furthermore, a molecular docking study was carried out to assess hypothetical binding mode of N-[9-(ortho-fluorobenzyl)-2-phenyl-8-azapurin-6-yl]-amides to A1 adenosine receptors.

The in vivo effect of chelidonine on the stem cell system of planarians.

The presence of adult pluripotent stem cells and the amazing regenerative capabilities make planarian flatworms an extraordinary experimental model to assess in vivo the effects of substances of both natural and synthetic origin on stem cell dynamics. This study focuses on the effects of chelidonine, an alkaloid obtained from Chelidonium majus. The expression levels of molecular markers specific for stem or differentiated cells were compared in chelidonine-treated and control planarians. The use of these markers demonstrates that chelidonine produces in vivo a significant anti-proliferative effect on planarian stem cells in a dose-dependent fashion. In response to chelidonine treatment mitotic abnormalities were also observed and the number of cells able to proceed to anaphase/telophase appeared significantly reduced with respect to the controls. Our results support the possibility that chelidonine acts on cell cycle progression by inhibition of tubulin polymerization. These studies provide a basis for preclinical evaluation in vivo of the effects of chelidonine on physiologically proliferating stem cells.

Structure-activity relationships on purine and 2,3-dihydropurine derivatives as antitubercular agents: a data mining approach.

Nowadays, many people still fall victim to tuberculosis, the disease that has a worldwide spreading. Moreover, the problem of resistance to isoniazid and rifampin, the two most effective antitubercular drugs, is assuming an ever-growing importance. The need for new drugs active against Mycobacterium tuberculosis represents nowadays a quite relevant problem in medicinal chemistry. Several purine and 2,3-dihydropurine derivatives have recently emerged, showing considerable antitubercular properties. In this work, a quantitative structure-activity relationship (QSAR) model was developed, which is able to predict whether new purine and 2,3-dihydropurine derivatives belong to an 'Active' or 'Inactive' class against the above micro-organism. The obtained prediction model is based on a classification tree; it was built with a small number of descriptors, which allowed us to outline structural features important to predict antitubercular activity of such classes of compounds.

Enhancer and competitive allosteric modulation model for G-protein-coupled receptors.

A new mathematical model, referred to as Enhancer and Competitive Allosteric Modulator (ECAM) model, developed with the aim of quantitatively describing the interaction of an allosteric modulator with both enhancer and competitive properties towards G-protein-coupled receptors is described here. Model simulations for equilibrium (displacement-like and saturation-like), and kinetic (association and dissociation) binding experiments were performed. The results showed the ability of the model to interpret a number of possible ligand-receptor binding behaviors. In particular, the binding properties of PD81723, an enhancer and competitive allosteric modulator for the adenosine A(1) receptor, were experimentally evaluated by radioligand binding assays and interpreted by the ECAM model. The results also offer a theoretical background enabling the design and optimization of compounds endowed with allosteric enhancer, competitive, agonist, antagonist, and inverse agonist properties.

Chemical reactivity predictions: use of data mining techniques for analyzing regioselective azidolysis of epoxides.

Azidolysis of epoxides followed by reduction of the intermediate azido alcohols constitutes a valuable synthetic tool for the construction of beta-amino alcohols, an important chemical functionality occurring in many biologically active compounds of natural origin. However, depending on conditions under which the azidolysis is carried out, two regioisomeric products can be formed, as a consequence of the nucleophilic attack on both the oxirane carbon atoms. In this work, predictive models for quantitative structure-reactivity relationships were developed by means of multiple linear regression, k-nearest neighbor, locally weighted regression, and Gaussian Process regression algorithms. The specific nature of the problem at hand required the creation of appropriate new descriptors, able to properly reflect the most relevant features of molecular moieties directly involved in the opening process. The models so obtained are able to predict the regioselectivity of the azidolysis of epoxides promoted by sodium azide, in the presence of lithium perchlorate, on the basis of steric hindrance, and charge distribution of the substituents directly attached to the oxirane ring.

Synthesis, biological assays and QSAR studies of N-(9-benzyl-2-phenyl-8-azapurin-6-yl)-amides as ligands for A1 adenosine receptors.

2-Phenyl-9-benzyl-8-azapurines, bearing at the 6 position an amido group interposed between the 8-azapurine moiety and an alkyl or a substituted phenyl group, have been synthesised and assayed as ligands for adenosine receptors. All the compounds show high affinity for the A(1) adenosine receptor, and many of them also show a good selectivity for A(1) with respect to A(2A) and A(3) adenosine receptors. Based on the quite rich library containing such compounds and relevant biological data, QSAR models, able to rationalise the results and to give a quantitative estimate of the observed trends were also developed. The obtained models can assist in the design of new compounds selectively active on A(1) adenosine receptor.

N6-1,3-diphenylurea derivatives of 2-phenyl-9-benzyladenines and 8-azaadenines: synthesis and biological evaluation as allosteric modulators of A2A adenosine receptors.

Some 1-[4-(9-benzyl-2-phenyl-9H-purin-6-ylamino)-phenyl]-3-phenyl-urea derivatives and some 1-[4-(9-benzyl-2-phenyl-9H-8-azapurin-6-ylamino)-phenyl]-3-phenyl-urea derivatives were synthesised and evaluated for their interaction with adenosine receptors. It was found that some of these compounds can act as positive enhancers of agonist and antagonist radioligands for the A(2A) adenosine receptors. This evidence was also strengthened by functional data. Other compounds can act as negative modulators. Furthermore these compounds show inhibitory properties for A(1) and A(3) adenosine receptors.