Istituto Superiore di Sanità

Background: Non-communicable diseases (NCDs) represent a global health challenge that requires coordination across various healthcare settings. Purpose: This study in Tuscany, Italy, investigates professional integration between primary care physicians (PCPs) and specialists in NCD management. Research Design: A self-developed survey was used to explore professionals’ views on clinical and organizational collaboration, accountability, and service improvement. Study Sample: The study involved primary care physicians (PCPs) and specialists working in the field of NCD management. Data Collection and/or Analysis: The survey gathered data on professionals' perceptions of clinical protocol use, care integration effectiveness, and other aspects of collaboration in NCD management. Results: Findings reveal disparities between PCPs and specialists in clinical protocol use and care integration effectiveness. Conclusions: The study emphasizes the need to reduce bureaucratic obstacles and enhance information sharing. Promoting peer relationships and innovative performance evaluation tools is vital for improving chronic disease management. This survey contributes valuable insights for the development of integrated care models, aiding healthcare decision-makers in enhancing chronic care system performance.

Background An effective strategy to reduce perinatal mortality requires an active surveillance system. This includes monitoring cases, organizing multidisciplinary local audits, conducting Confidential Enquiries, identifying avoidable factors, and facilitating changes in the healthcare system. In 2017, the Italian Obstetric Surveillance System launched the SPItOSS pilot Perinatal Surveillance System. The aim of this paper is to describe the results of the SPItOSS Confidential Enquiries on perinatal deaths focusing on the emergent critical aspects in obstetric and neonatal care, as well as on the healthcare facilities organization. Methods SPItOSS, a population-based surveillance system, collected and analysed incident perinatal deaths from July 2017 to June 2019 in three Regions encompassing 32.3% of Italian births. Cases were defined according to WHO definition as fetuses born dead ≥ 28 weeks of gestation and live newborn died within 7 days from birth. The International Statistical Classification of Diseases and related Health Problem-Perinatal Mortality was adopted for coding causes of death and contributing maternal and placenta-related conditions. Confidential Enquiries, prioritized according to perinatal deaths preventability, were conducted by expert committees at Regional and National level. Results A total of 830 incident perinatal deaths were notified, with 58.3% classified as antepartum, 4.3% as intrapartum, and 37.3% as neonatal deaths. According to the SPItOSS protocol, Confidential Enquiries evaluated only the most preventable deaths, including 19 intrapartum and 70 neonatal deaths. Of these, 43.8% were assessed as unavoidable with appropriate care; 29.2% as unavoidable with improvable care, and 15.7% as avoidable due to inappropriate care. Most intrapartum deaths were attributed to intrauterine hypoxia, while neonatal deaths recognized a multifactorial aetiology. Different aspects of inappropriate care were highlighted, such as failure to recognise maternal or fetal problems before labour, delayed or inappropriate neonatal resuscitation, and poor or suboptimal neonatal monitoring. Conclusions The SPItOSS Confidential Enquires provided insights for improving maternity and perinatal services. By targeting key areas of obstetric and neonatal care, the surveillance can generate recommendations and actions to prevent avoidable perinatal deaths.

Background In Parkinson's Disease (PD), upper limb tremor during walking (TW) is observed and clinical observations suggest it may represent a variant of rest tremor. However, its neurophysiological characteristics remain unexplored. Objectives This study compared the neurophysiological features of TW with other PD tremors and tested whether TW arises from reduced ipsilateral arm swing. Methods Inertial measurement units were used to measure frequency and amplitude of tremors and arm swing during walking in 25 PD patients. Results TW shared a similar frequency with rest and re‐emergent tremor (RET) but showed significantly greater amplitude. A positive correlation was observed between the amplitude and frequency of TW with those of rest and RET on the same side. TW distribution was unrelated to reduced arm swing during walking, suggesting TW is not due to decreased ipsilateral arm movement. Conclusions These findings suggest that walking may act as a provocation maneuver, triggering rest tremor.

People with mental disorder experience an increased risk of physical diseases due to the high rate of physical comorbidities, which leads to an overall reduced life expectancy compared to the general population. There is a great potential for physical activity and sport to overcome, at least partially, health inequality experienced by individuals with mental disorders. Indeed, an active lifestyle has been shown to bring important benefits to the general population as well as to individuals at risk or experiencing mental disorder. There is now sufficient scientific evidence to include this type of activity in psychoeducational interventions as it also has the potential for fostering social relationships, increasing resilience and combating stigma. While more basic research and specific clinical trials are needed to assess the potential (positive) interaction of physical activity with pharmacological and psychotherapeutic treatments, the current evidence and the guidelines issued by important scientific societies, such as the European Psychiatric Association (EPA), call for acting now to incorporate physical activity programmes as a new standard of care for mental disorders.

Among the intrathecal inflammatory niches where compartmentalized inflammation persists and plays a pivotal role in progressive multiple sclerosis (MS), choroid plexus (CP) has recently received renewed attention. To better characterize the neuropathological/molecular correlates of CP in progressive MS and its potential link with other brain inflammatory compartments, such as perivascular spaces and leptomeninges, the levels, composition and phenotype of CP immune infiltration in lateral ventricles of the hippocampus were examined in 40 post‐mortem pathologically confirmed MS and 10 healthy donors, using immunochemistry/immunofluorescence and in‐situ sequencing. Significant inflammation was detected in the CP of 21 out of the 40 MS cases (52%). The degree of CP inflammation was found correlated with: number of CP macrophages (R: 0.878, p = 1.012 x 10‐13) and high frequency of innate immune cells expressing the markers MHC‐class II, CD163, CD209, CD11c, TREM2 and TSPO; perivascular inflammation (R: 0.509, p = 7.921 x 10‐4), and less with meningeal inflammation (R: 0.365, p = 0.021); number of active lesions (R: 0.51, p: 3.524 x 10‐5). However, it did not significantly correlate with any clinical/demographic characteristics of the examined population. In‐situ sequencing analysis of gene expression in the CP of 3 representative MS cases and 3 controls revealed regulation of inflammatory pathways mainly related to ‘type 2 immune response’, ‘defense to infections’, ‘antigen processing/presentation’. Analysis of 78 inflammatory molecules in paired post‐mortem CSF, the levels of fibrinogen (R: 0.640, p = 8.752 x 10‐6), PDGF‐bb (R: 0.470, p = 0.002), CXCL13 (R: 0.428, p = 0.006) and IL15 (R: 0.327, p = 0.040) were correlated with extent of CP inflammation. Elevated fibrinogen and complement deposition were found in CP and in underlying subependymal periventricular areas, according to “surface‐in” gradient associated with concomitant prominent microglia activation. CP inflammation, predominantly characterized by innate immunity, represents another key determinant of intrathecal, compartmentalised inflammation persisting in progressive MS, which may be possibly activated by fibrinogen and influence periventricular pathology, even without substantial association with clinical features.

RASopathies are caused by variants in more than 20 genes functionally converging toward the upregulation of intracellular signaling through the RAS/mitogen-associated protein kinase (MAPK) cascade. These disorders are largely transmitted as autosomal dominant traits, though recessive forms are emerging. More than 10 genes have been causally linked to Noonan syndrome, the most common and clinically variable RASopathy; genetic heterogeneity characterizes also cardio-facio-cutaneous syndrome and Noonan syndrome with loose anagen hair, also known as Mazzanti syndrome. On the other hand, allelic heterogeneity also occurs, as in the case of PTPN11, KRAS, and BRAF. A large proportion of cases result from de novo mutations; however, families transmitting the disorder are common in Noonan syndrome. In RASopathies, increased RAS/MAPK signaling can result from the upregulated activity of various GTPases of the RAS family, increased function of signal transducers positively controlling RAS activity or favoring RAS interactions with RAF kinases, functional upregulation of the three tiers belonging to the MAPK cascade, or inefficient signaling switch-off operating at different levels. While the MAPK cascade is virtually upregulated in almost all RASopathies, upregulation of the PI3K-AKT-mTOR pathway also represents an alternative driver or contributing mechanism. Genetic evidence also suggests the involvement of signaling dysregulation via other networks (e.g., small RHO GTPases signaling) to disease pathogenesis. Here, we summarize key concepts on the molecular genetics of these disorders, discussing the involved genes and the molecular circuits implicated in RAS/MAPK signaling dysregulation, including those that had previously remained uncharacterized due to their minor impact on oncogenesis.

Background: Atrial fibrillation (AF) is associated with an increased fall risk, partly due to AF-related comorbid-ities. We investigated the impact of different comorbidity patterns on fall risk in older adults with AF. Methods: Using the Swedish National Patient Register, we identified 203,042 adults (45 % females) with AF and at least one comorbidity, aged 65 years or older, on 01/01/2017. The primary study outcome was any fall requiring medical attention. Secondary outcomes were falls with fractures, falls with hip fractures, and falls with head trauma. Comorbidity patterns were identified through latent class analysis, and their association with 3-year fall risk was tested through Cox regressions. Results: The sample mean age was 79.6 (SD: 7.9) years, and the mean number of chronic diseases was 6.6 (SD 3.2). We identified one unspecific (34.2 %) and six specific comorbidity patterns characterized by neuropsy-chiatric (6.6 %), eye (17.4 %), musculoskeletal (7.2 %), metabolic (15.8 %), cardiovascular (7.4 %), and complex (11.3 %) chronic conditions coexisting with AF. Older adults with AF and complex (HR=1.63, 95 %CI: 1.56-1.70), neuropsychiatric (HR=1.48, 95 %CI: 1.41-1.56), cardiovascular (HR=1.21, 95 %CI: 1.15-1.27), eye (HR=1.16, 95 %CI: 1.12-1.20), and musculoskeletal (HR=1.07, 95 %CI: 1.01-1.13) comorbidity had an increased fall risk compared to those with unspecific comorbidity. The highest risk of falls with fractures or head trauma was found in older adults displaying a complex or neuropsychiatric disease pattern, respectively. Higher estimates emerged in males and those aged <80 years. Conclusions: Evaluating comorbidity patterns in older AF patients could help stratify the risk of falls in this population and support targeted preventive interventions.

This systematic review investigates the association between environmental pollutants and the risk of diarrhea, a critical public health issue, particularly in low- and middle-income countries. The review synthesizes findings from various studies that highlight the impact of contaminants such as pesticides, heavy metals, polycyclic aromatic hydrocarbons (PAHs), microplastics, and parabens on gastrointestinal health. Following PRISMA guidelines, a comprehensive literature search across databases including PubMed, Scopus, and Google Scholar yielded 496 articles, of which 11 met the inclusion criteria for detailed analysis. The results indicate a significant correlation between exposure to specific pollutants—particularly pesticides like dichlorodiphenyltrichloroethane (DDT), PAHs, arsenic, cadmium, and microplastics—and increased incidences of diarrhea. Notably, studies revealed that prenatal exposure to DDT is linked to higher diarrhea rates among boys in urban settings, while pesticide exposure in childhood correlates with inflammatory bowel disease in adulthood. Mechanistically, these pollutants may disrupt gastrointestinal function through cholinergic effects and endocrine disruption, leading to altered gut motility and microbiome imbalances. Moreover, the review emphasizes the immunosuppressive effects of heavy metals such as mercury and cadmium, which compromise the immune response and increase susceptibility to gastrointestinal infections. Despite the identified associations, there is a notable gap in research regarding geographic distribution and pollutant impacts on health outcomes. The review underscores the necessity for public health interventions aimed at reducing exposure to these environmental pollutants to mitigate their adverse health effects. In conclusion, this systematic review highlights the urgent need for further epidemiological studies in underrepresented areas to enhance our understanding of how environmental pollutants influence public health globally. Recommendations include rigorous monitoring of pollutant levels, public health initiatives to reduce exposure, and policies that restrict emissions of harmful substances. Addressing environmental pollution is crucial for mitigating diarrheal diseases and protecting vulnerable populations from its detrimental effects.

Background Tumor-Associated Macrophages (TAMs) play a critical role in the pathogenesis and progression of ovarian cancer, a lethal gynecologic malignancy. [¹²⁴I]iodo-DPA-713 is a PET radiotracer that is selectively trapped within reactive macrophages. We have employed this radioligand here as well as a fluorescent analog to image TAMs associated with primary tumors, secondary pulmonary metastases and gastrointestinal tract-associated macrophages, associated with ascites accumulation in a syngeneic mouse model of metastatic ovarian cancer. Intact female C57BL/6 mice were engrafted with ID8-Defb29-VEGF tumor pieces. One month after engraftment, the mice were selected for positive bioluminescence to show primary and secondary tumor burden and were then scanned by PET/MRI with [¹²⁴I]iodo-DPA-713, observing a 24 h uptake time. PET data were overlayed with T2-weighted MRI data to facilitate PET uptake tissue identity. Additionally, mice were imaged ex vivo using Near IR Fluorescence (NIRF), capturing the uptake and sequestration of DPA-713-IRDye800CW, a fluorescent analog of the radioligand used here. Additionally, cell culture uptake of DPA-713-IRDye680LT in ID8-DEFb29-VEGF, IOSE hTERT and RAW264.7 cells was conducted to measure tracer uptake in ovarian cancer cells, ovarian epithelial cells and macrophage. Results PET/MRI data show an intense ring of radiotracer uptake surrounding primary tumors. PET uptake is also associated with lung metastases, but not healthy lung. Mice displaying ascites also display PET uptake along the gastrointestinal tract while sham-operated mice show minimal gastrointestinal uptake. All mice show specific kidney uptake. Mice imaged by NIRF confirmed TAMs uptake mostly at the rim of primary tumors while 1 mm secondary tumors in the lungs displayed robust, homogeneous uptake of the radio- and fluorescent analog. Ex vivo biodistribution of [¹²⁴I]iodo-DPA-713 showed that contralateral ovaries in middle-stage disease had the highest probe uptake with tissues sampled in mid- and late-stage disease showing increasing uptake. Conclusion [¹²⁴I]iodo-DPA-713 and DPA-713-IRDye800CW sensitively identify and locate TAMs in a syngeneic mouse model of metastatic ovarian cancer.

Background: Adherence to optimal practices in the preparation and issuance of pediatric blood components can significantly influence patient care outcomes. This study aims to examine the blood banking procedures across prominent Italian children's hospitals, with the goal of identifying both consistent and potentially divergent standards within this field. Materials and methods: A survey was conducted among the blood banks affiliated with the Italian Association of Pediatric Hospitals. Modeled after the AABB Neonatal and Pediatric Blood Bank Practices Survey, the questionnaire comprised 25 questions covering hospital characteristics, definitions of the neonatal period, pre-transfusion tests, blood component availability, and irradiation protocols. Results: Fourteen out of the sixteen invited blood banks participated in the survey. The findings revealed a wide range of practices among the surveyed hospitals. Major differences were noted in the neonatal period definition, pre-transfusion compatibility procedures, and platelet transfusion protocols. All hospitals provided leukodepleted packed red blood cells (pRBCs), with differences in availability of autologous blood and reconstituted whole blood. Irradiated blood components were universally accessible, with differences in post-irradiation acceptable storage time. Additionally, differences in dosages for packed red blood cells (pRBCs) and platelet concentrates (PCs) were observed across hospitals. Conclusions: Standardized guidelines for pediatric transfusion practices within Italian blood banks are of paramount importance. The observed variability underscores the necessity for sharing best practices among centers supplying blood components to pediatric patients.

Rubinstein–Taybi syndrome (RSTS) is a rare autosomal dominant neurodevelopmental disorder linked to haploinsufficiency of CREBBP (RSTS1) and EP300 (RSTS2) genes. Characteristic features often include distinctive facial traits, broad thumbs and toes, short stature, and various degrees of intellectual disability. The clinical presentation of RSTS is notably variable, making it challenging to establish a clear genotype–phenotype correlation, except for specific variants which cause the allelic Menke–Hennekam syndrome. Trio exome analysis, data collection via networking and GeneMatcher platforms, transcript processing analysis, and DNA methylation profiling were performed. We identified two unrelated patients with de novo variants in EP300 (NM_001429.4: c.3671+5G>C; c.3671+5_3671+8delGTAA) predicted to cause in‐frame exon 20 skipping, confirmed in one patient. In silico 3D protein modeling suggested that exon 20 deletion (comprising 27 amino acids) likely alters the structural conformation between the RING_CBP‐p300 and HAT‐KAT11 domains. Clinically, both patients displayed severe RSTS2‐like clinical features, including autism spectrum disorder, speech delay, hearing loss, microcephaly, developmental delay, and intellectual disability, alongside ocular, respiratory, and cardiovascular abnormalities. Additionally, one patient developed early‐onset colorectal cancer. DNA methylation profiling in Subject #1 confirmed RSTS but did not align with the specific episignatures for RSTS1 or RSTS2. We propose that skipping of exon 20 in EP300 is associated with a distinct form of Rubinstein–Taybi syndrome featuring clinical characteristics not fully aligning with RSTS1 or RSTS2. Our findings increase the understanding of RSTS genetic and molecular basis and stress the need for further research to establish definitive genotype–phenotype correlations.

Children born via cesarean delivery have a higher risk of metabolic, immunological, and neurodevelopmental disorders compared to those born via vaginal delivery, although mechanisms remain unclear. We conducted a meta-analysis of epigenome-wide association studies to examine the associations between delivery mode and blood DNA methylation at birth and its persistence in early childhood. Participants were from 19 pregnancy cohorts (9833 term newborns) and 6 pediatric cohorts (2429 children aged 6 to 10 years). We identified six CpGs in cord blood associated with cesarean delivery (effect size range: 0.4 to 0.7%, P < 1.0 × 10 ⁻⁷ ): MAP2K2 (cg19423175), LIM2 (cg01500140), CNP (cg13917614), BLM (cg18247172), RASA3 (cg22348356), and RUNX3 (cg20674490), independent of cell proportions and other confounders. In childhood, none of these CpGs were associated with cesarean delivery, and no additional CpGs were identified. Delivery mode was associated with cell proportions at birth but not in childhood. Further research is needed to elucidate cesarean delivery’s molecular influence on offspring health.

Background We aimed to estimate XBB.1.5 vaccine effectiveness (VE) against COVID-19-related hospitalizations and deaths during BA.2.86/JN.1 predominance, among EU/EEA individuals with ≥65-years. Research design and methods We linked electronic health records to create historical cohorts in Belgium, Denmark, Italy, Navarre (Spain), Norway, Portugal and Sweden. We included individuals aged ≥65-years eligible for the autumnal 2023 COVID-19 vaccine. Follow-up started when ≥80% of country-specific sequenced viruses were BA.2.86/JN.1 (4/dec/23 to 08/jan/24) and ended 25 February 2024. At study site level, we estimated the vaccine confounder-adjusted hazard ratio (aHR) of COVID-19 hospitalizations and deaths between individuals with ≥14 days after vaccination versus unvaccinated in autumn 2023, overall, by time since vaccination and age groups. VE was estimated as (1-pooled aHR)x100 with a random-effects model. Results XBB.1.5 VE against COVID-19 hospitalizations was 50% (95%CI: 45 to 55) and 41% (95%CI: 35 to 46) in 65–79-year-olds and in ≥80-year-olds, respectively. VE against COVID19-related-death was 58% (95%CI: 42 to 69) and 48% (95%CI: 38 to 57), respectively, in both age groups. VE estimates against each outcome declined in all age groups over time. Conclusion Monovalent XBB.1.5 vaccine had a moderate protective effect against severe and fatal COVID-19 likely caused by BA.2.86/JN.1 during the 2023/2024 winter, among persons aged ≥65.

Exclusive breastfeeding (eBF) in infancy appears to offer a developmental advantage for children’s brains compared to formula-fed counterparts. Existing research has predominantly focused on global brain measures (i.e., total white/grey matter volumes) or on limited sets of specific brain regions, in selected age groups, leaving uncertainties about the impact of eBF on the overall structural connectomes. In this cross-sectional study encompassing participants from childhood to adulthood, partial least squares correlations (PLSC) were employed to assess white and grey matter volumes. Furthermore, a network analytic approach was used to estimate the structural connectome based on cortical thickness data. The results revealed that eBF duration correlated with increased white matter volumes in children and with the volume of the medial orbital gyrus in adults. Structural connectome analyses demonstrated heightened anatomical connectivity in eBF children, evidenced by enhanced network density and local/global efficiency, along with increased node degree and local efficiency in frontal and temporal lobes. Similarly, eBF in adults was associated to an improved node connectivity in the frontal lobe. These findings imply a lasting impact of eBF on brain morphometry and structural connectivity. Childhood benefits include heightened white matter development, while in adulthood, eBF may contribute to reduced neural loss associated with aging and enhanced connectivity, particularly in frontal regions.

Neuropsychiatric symptoms, such as apathy, disinhibition and irritability, are common in Progressive Supranuclear Palsy (PSP). The Frontal Behaviour Inventory (FBI) is a useful instrument for the evaluation of behavioural disorders in neurodegenerative diseases. The main goal of the present study was to explore the psychometric properties of the FBI in PSP. FBI was administered to the PSP-NET cohort including Italian patients diagnosed according to the Movement Disorder Society criteria. Patients underwent a clinical interview, a motor evaluation, extensive cognitive and behavioural testing. Two hundred and eight subjects were included in this study. The internal consistency was high (Cronbach’s alpha = 0.868) and no improvement of this value was noted upon removal of any item. FBI showed also good acceptability, reliability and validity. The standard error of measurement (SEM) value for FBI total score was 0.169 [SEM = SD √ (1 – Cronbach’s alpha)]. Factor analysis indicated a five-factor structure: Apathy, Behavioural disorders, Impulsivity, Motor and speech frontal behaviour and Executive disorders that explained the 54.92% of the total variance. Linear regression analysis showed that global cognitive impairment significantly affects both Apathy and Motor and speech frontal behaviour factors. In conclusion, FBI is a reliable and valid tool for the assessment of neuropsychiatric symptoms in PSP, despite some constructs, such as euphoria and irritability, are better measured by the NPI. Two third of the cohort was represented by Richardson’s syndrome, thus our data are mainly applicable to such common phenotype. Such data are useful in both clinical and research settings to plan adequate therapeutic interventions and to improve the quality of life of PSP patients and their caregivers.

In the European region, diphtheria is now rarely suspected in patients presenting with upper respiratory tract symptoms. Corynebacterium ulcerans is the underestimated zoonosis that is replacing C. diphtheria infections in industrialized countries, but extensive human and animal prevalence studies are lacking. The range of hosts that can act as reservoirs for C. ulcerans is very broad, companion pets currently being the main source of human infection. We report a case of macrolide-resistant C. ulcerans infection with no apparent zoonotic transmission and outline the efforts required for the public and zooprophylactic management of these cases. We describe the main critical issues to be addressed to comprehensively tackle this zoonosis in the future.

Background Genetic and genomic literacy of health professionals is of utmost importance to realize the full potential of personalized medicine. As part of a European Union project, we piloted an e-learning course on oncogenomics, primarily targeted to physicians, and we assessed both its effectiveness and users’ satisfaction. Methods The course materials were developed in English according to the Problem-Based Learning method. Learning objectives, covering the basic principles of genetics and the OMICS technologies applied to oncology, were defined based on previously identified core competencies. We used a pre-test vs. post-test study design to assess knowledge improvements. Performance results by demographic and professional characteristics of participants were analyzed using univariate or multivariate statistical methods. Results Overall, 346 Italian professionals (61% physicians, 39% biologists) successfully completed the course. Their average post-test score was almost 19% higher than the pre-test (71.6% vs. 52.9%), with no significant differences by sex. Older age (>50 years) and southern area of residence were both correlated with higher gains. The average proportion of correct answers in the final certification test after three attempts was 85% (69% at first attempt), with some differences across professional categories. Methodology, quality of content and usability of the e-learning platform were all highly rated via satisfaction questionnaire (average scores between 4 and 5, scale 1 to 5). Conclusion The pilot phase confirmed the suitability of the e-learning as a cost-effective method to improve oncogenomic literacy of health professionals. Translation into natural languages and accreditation by European or country-specific Continuing Medical Education systems will be the main incentives for wider dissemination.