Circuital modelling in muscle tissue impedance measurements.

Electrical impedance spectroscopy (EIS) stands as a widely employed characterization technique for studying muscular tissue in both physio/pathological conditions. This methodology commonly involves modeling tissues through equivalent electrical circuits, facilitating a correlation between electrical parameters and physiological properties. Within existing literature, diverse equivalent electrical circuits have been proposed, varying in complexity and fitting properties. However, to date, none have definitively proven to be the most suiTable for tissue impedance measurements. This study aims to outline a systematic methodology for EIS measurements and to compare the performances of three widely used electrical circuits in characterizing both physiological and pathological muscle tissue conditions. Results highlight that, for optimal fitting with electrical parameters relevant to tissue characterization, the choice of the circuit to be fitted closely hinges on the specific measurement objectives, including measurement parameters and associated physiological features. Naturally, this necessitates a balance between simplicity and fitting accuracy.

Last Trends in Point-of-Care (POC) Diagnostics for the Management of Hematological Indices in Home Care Patients.

Today, complete blood count (CBC) analyses are highly automated and allow for high throughput and accurate and reliable results. However, new analytical tools are in great demand to provide simple, rapid and cost-effective management of hematological indices in home care patients. Chronic disease monitoring at home has become a benefit for patients who are finding cost savings in programs designed to monitor/treat patients in offsite locations. This review reports the latest trends in point-of-care (POC) diagnostics useful for home testing of key hematological counts that may be affected during home therapy treatment.

The Impact of Hospital Accessibility on Interregional Patient Mobility in Italy.

Patient mobility represents a proxy measure to assess the quality and availability of hospital services, especially in decentralized health systems. Different studies have been focused on the interregional mobility in Italy to capture factors influencing this phenomenon. Among them, hospital capacity is generally captured through the number of beds per population. However, this indicator does not consider the distance to hospitals and the accessibility of extra-regional beds, in particular for patients living at the regional borders. The aim of this paper is to analyse the effect of extra-regional spatial accessibility component on patient mobility among the Italian regions. This can help to capture the level of equity in the provision of services across the country providing a snapshot of the distribution of beds over the territory. Moreover, this study contributes to gain a deeper understanding of the allocation of health resources providing input for policy makers on the basis of the principles of service accessibility.

Headache onset after vaccination against SARS-CoV-2: a systematic literature review and meta-analysis.

BACKGROUND: Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are used to reduce the risk of developing Coronavirus Disease 2019 (COVID-19). Despite the significant benefits in terms of reduced risk of hospitalization and death, different adverse events may present after vaccination: among them, headache is one of the most common, but nowadays there is no summary presentation of its incidence and no description of its main features. METHODS: We searched PubMed and EMBASE covering the period between January 1st 2020 and August 6th, 2021, looking for record in English and with an abstract and using three main search terms (with specific variations): COVID-19/SARS-CoV-2; Vaccination; headache/adverse events. We selected manuscript including information on subjects developing headache after injection, and such information had to be derived from a structured form (i.e. no free reporting). Pooled estimates and 95% confidence intervals were calculated. Analyses were carried out by vaccine vs. placebo, by first vs. second dose, and by mRNA-based vs. "traditional" vaccines; finally, we addressed the impact of age and gender on post-vaccine headache onset. RESULTS: Out of 9338 records, 84 papers were included in the review, accounting for 1.57 million participants, 94% of whom received BNT162b2 or ChAdOx1. Headache was generally the third most common AE: it was detected in 22% (95% CI 18-27%) of subjects after the first dose of vaccine and in 29% (95% CI 23-35%) after the second, with an extreme heterogeneity. Those receiving placebo reported headache in 10-12% of cases. No differences were detected across different vaccines or by mRNA-based vs. "traditional" ones. None of the studies reported information on headache features. A lower prevalence of headache after the first injection of BNT162b2 among older participants was shown. CONCLUSIONS: Our results show that vaccines are associated to a two-fold risk of developing headache within 7 days from injection, and the lack of difference between vaccine types enable to hypothesize that headache is secondary to systemic immunological reaction than to a vaccine-type specific reaction. Some descriptions report onset within the first 24 h and that in around one-third of the cases, headache has migraine-like features with pulsating quality, phono and photophobia; in 40-60% of the cases aggravation with activity is observed. The majority of patients used some medication to treat headache, the one perceived as the most effective being acetylsalicylic acid.

Functional connectivity changes in complex migraine aura: beyond the visual network.

BACKGROUND AND PURPOSE: Although the majority of migraine with aura (MwA) patients experience simple visual aura, a discrete percentage also report somatosensory, dysphasic or motor symptoms (the so-called complex auras). The wide aura clinical spectrum led to an investigation of whether the heterogeneity of the aura phenomenon could be produced by different neural correlates, suggesting an increased visual cortical excitability in complex MwA. The aim was to explore whether complex MwA patients are characterized by more pronounced connectivity changes of the visual network and whether functional abnormalities may extend beyond the visual network encompassing also the sensorimotor network in complex MwA patients compared to simple visual MwA patients. METHODS: By using a resting-state functional magnetic resonance imaging approach, the resting-state functional connectivity (RS-Fc) of both visual and sensorimotor networks in 20 complex MwA patients was compared with 20 simple visual MwA patients and 20 migraine without aura patients. RESULTS: Complex MwA patients showed a significantly higher RS-Fc of the left lingual gyrus, within the visual network, and of the right anterior insula, within the sensorimotor network, compared to both simple visual MwA and migraine without aura patients (p < 0.001). The abnormal right anterior insula RS-Fc was able to discriminate complex MwA patients from simple aura MwA patients as demonstrated by logistic regression analysis (area under the curve 0.83). CONCLUSION: Our findings suggest that higher extrastriate RS-Fc might promote cortical spreading depression onset representing the neural correlate of simple visual aura that can propagate to sensorimotor regions if an increased insula RS-Fc coexists, leading to complex aura phenotypes.

Disconnectome of the migraine brain: a "connectopathy" model.

BACKGROUND: In the past decades a plethora of studies has been conducted to explore resting-state functional connectivity (RS-FC) of the brain networks in migraine with conflicting results probably due to the variability and susceptibility of signal fluctuations across the course of RS-FC scan. On the other hand, the structural substrates enabling the functional communications among the brain connectome, characterized by higher stability and reproducibility, have not been widely investigated in migraine by means of graph analysis approach. We hypothesize a rearrangement of the brain connectome with an increase of both strength and density of connections between cortical areas specifically involved in pain perception, processing and modulation in migraine patients. Moreover, such connectome rearrangement, inducing an imbalance between the competing parameters of network efficiency and segregation, may underpin a mismatch between energy resources and demand representing the neuronal correlate of the energetically dysfunctional migraine brain. METHODS: We investigated, using diffusion-weighted MRI imaging tractography-based graph analysis, the graph-topological indices of the brain "connectome", a set of grey matter regions (nodes) structurally connected by white matter paths (edges) in 94 patients with migraine without aura compared to 91 healthy controls. RESULTS: We observed in migraine patients compared to healthy controls: i) higher local and global network efficiency (p < 0.001) and ii) higher local and global clustering coefficient (p < 0.001). Moreover, we found changes in the hubs topology in migraine patients with: i) posterior cingulate cortex and inferior parietal lobule (encompassing the so-called neurolimbic-pain network) assuming the hub role and ii) fronto-orbital cortex, involved in emotional aspects, and visual areas, involved in migraine pathophysiology, losing the hub role. Finally, we found higher connection (edges) probability between cortical nodes involved in pain perception and modulation as well as in cognitive and affective attribution of pain experiences, in migraine patients when compared to healthy controls (p < 0.001). No correlations were found between imaging and clinical parameters of disease severity. CONCLUSION: The imbalance between the need of investing resources to promote network efficiency and the need of minimizing the metabolic cost of wiring probably represents the mechanism underlying migraine patients' susceptibility to triggers. Such changes in connectome topography suggest an intriguing pathophysiological model of migraine as brain "connectopathy".

Developing an infrastructure for secure patient summary exchange in the EU context: Lessons learned from the KONFIDO project.

BACKGROUND: The increase of healthcare digitalization comes along with potential information security risks. Thus, the EU H2020 KONFIDO project aimed to provide a toolkit supporting secure cross-border health data exchange. METHODS: KONFIDO focused on the so-called "User Goals", while also identifying barriers and facilitators regarding eHealth acceptance. Key user scenarios were elaborated both in terms of threat analysis and legal challenges. Moreover, KONFIDO developed a toolkit aiming to enhance the security of OpenNCP, the reference implementation framework. RESULTS: The main project outcomes are highlighted and the "Lessons Learned," the technical challenges and the EU context are detailed. CONCLUSIONS: The main "Lessons Learned" are summarized and a set of recommendations is provided, presenting the position of the KONFIDO consortium toward a robust EU-wide health data exchange infrastructure. To this end, the lack of infrastructure and technical capacity is highlighted, legal and policy challenges are identified and the need to focus on usability and semantic interoperability is emphasized. Regarding technical issues, an emphasis on transparent and standards-based development processes is recommended, especially for landmark software projects. Finally, promoting mentality change and knowledge dissemination is also identified as key step toward the development of secure cross-border health data exchange services.

Effectiveness and Safety of CGRP-mAbs in Menstrual-Related Migraine: A Real-World Experience.

INTRODUCTION: Migraine shows a significantly higher prevalence in women, especially during reproductive age when menstrual-related hormonal fluctuations represent the most common migraine trigger. Indeed, over 50% of patients report a higher occurrence of migraine attacks during the perimenstrual window. Menstrual migraine attacks are consistently referred to as more disabling, less responsive to symptomatic treatments, longer in duration, and more prone to relapse than non-menstrual migraine attacks. Evidence strongly suggests that estrogen fluctuations are involved in migraine attacks worsening during the perimenstrual window through several mechanisms directly or indirectly involving the CGRP pathway. We aimed to evaluate whether mAbs blocking CGRP-ligand or receptor (CGRP-mAbs) could represent an effective and safe preventive treatment for menstrual migraine attacks in patients with menstrual-related migraine (MRM) with previous treatment failures. METHODS: Forty patients with MRM with at least three previous treatment failures received monthly CGRP-mAbs. At the baseline and after six CGRP-mAbs administrations, patients underwent to extensive interviews to assess frequency, duration, intensity, and responsiveness to painkiller intake of migraine attacks occurring during the perimenstrual window. RESULTS: After six administrations of CGRP-mAbs we observed a reduction of median menstrual migraine frequency (from 5 to 2 days per month), pain intensity (from 8/10 to 6/10), and attacks duration (from 24 to 8 h) (p < 0.001). Nevertheless, a significant increase in the percentage of responding to migraine painkillers was observed from 42.5% at baseline to 95% at T1 (p < 0.001). CONCLUSIONS: CGRP-mAbs could represent a safe and effective preventive therapeutic strategy able to reduce the disabling burden of menstrual migraine attack frequency, duration, intensity, and significantly improve the response to painkillers. These findings could be related to and further indirectly prove the greater influence of CGRP-mediated mechanisms in the pathophysiology of menstrual migraine attacks.

Spatial Inequity in Access to Intensive Care Unit Beds at Regional Level in Italy.

The high demand of hospitalization in the intensive care units (ICUs) during the first wave of the COVID-19 outbreak brought out the critical issues of the limited capacity of the regional systems to deal with high patient inflows in a short period of time. In this view, a rapid and efficient reallocation of resources is one of the main challenges to be addressed by regional systems to prevent overload and saturation. Aim of this study is to assess the spatial accessibility of ICU beds in the 20 Italian regions to capture the equity distribution of critical care services across the country. This analysis may contribute to gain a deeper understanding of the allocation of health resources. It can provide input for policy makers in view of a possible reorganization of the national system in terms of both its preparedness for emergency period and routine capability.

Refractory migraine profile in CGRP-monoclonal antibodies scenario.

OBJECTIVE: Refractory migraine (Ref-M) represents a conundrum that headache experts have to face with. We aim to investigate whether a peculiar profile may characterize patients with Ref-M according to 2020 European Headache Federation criteria. Furthermore, to substantiate a dysfunctional dopaminergic pathway involvement in these patients, we explored the effectiveness of olanzapine. MATERIALS & METHODS: Eighty-four patients (fitting previous Ref-M criteria of the 2014) were treated with erenumab for six months. Differences between clinical and demographic features of responder (Ref-M according to 2014 criteria) and not-responder (Ref-M according to 2020 criteria) patients to CGRP-mAbs were investigated and their predictive values assessed. In fifteen patients with Ref-M not responders to CGRP-mAbs, olanzapine was administered (5 mg/die) for 3 months and frequency and pain intensity of migraine attacks were estimated. RESULTS: Patients with Ref-M not responsive to CGRP-mAbs (29/84) when compared with Ref-M responsive to CGRP-mAbs showed higher baseline frequency of migraine attacks, medication overuse and pain catastrophizing scale (PCS) scores. Logistic regression analyses showed that frequency of attacks, medication overuse and PCS score represent independent negative predictors of CGRP-mAbs response. A ≥50% reduction of headache days/month was observed after olanzapine treatment in 67% of patients with Ref-M not responsive to CGRP-mAbs. CONCLUSIONS: We outline that higher frequency of migraine attacks, medication overuse and pain catastrophizing characterize patients with Ref-M not responsive to CGRP-mAbs. In this frame, olanzapine effectiveness on frequency and pain intensity of migraine attacks supports the hypothesis that migraine refractoriness may be subtended by a prominent involvement of the dopaminergic pathway.

Additive Interaction Between Onabotulinumtoxin-A and Erenumab in Patients With Refractory Migraine.

In the last decade, notable progresses have been observed in chronic migraine preventive treatments. According to the European Headache Federation and national provisions, onabotulinumtoxin-A (BTX-A) and monoclonal antibodies acting on the pathway of calcitonin gene-related peptide (CGRP-mAbs) should not be administered in combination due to supposed superimposable mechanism of action and high costs. On the other hand, preclinical observations demonstrated that these therapeutic classes, although operating directly or indirectly on the CGRP pathway, act on different fibers. Specifically, the CGRP-mAbs prevent the activation of the Aδ-fibers, whereas BTX-A acts on C-fibers. Therefore, it can be argued that a combined therapy may provide an additive or synergistic effect on the trigeminal nociceptive pathway. In the present study, we report a case series of 10 patients with chronic migraine who experienced significant benefits with the combination of both erenumab and BTX-A compared to each therapeutic strategy alone. A reduction in frequency and intensity of headache attacks (although not statistically significant probably due to the low sample size) was observed in migraine patients treated with a combined therapy with BTX-A and erenumab compared to both BTX-A and erenumab alone. Moreover, the combined therapy with BTX-A and erenumab resulted in a statistically significant reduction in the symptomatic drug intake and in migraine-related disability probably related to a reduced necessity or also to a better responsiveness to rescue treatments. Present data suggest a remodulation of current provisions depriving patients of an effective therapeutic strategy in peculiar migraine endophenotypes.

The efficiency in the ordinary hospital bed management: A comparative analysis in four European countries before the COVID-19 outbreak.

During COVID-19 emergency the majority of health structures in Europe saturated or nearly saturated their availabilities already in the first weeks of the epidemic period especially in some regions of Italy and Spain. The aim of this study is to analyse the efficiency in the management of hospital beds before the COVID-19 outbreak at regional level in France, Germany, Italy and Spain. This analysis can indicate a reference point for future analysis on resource management in emergency periods and help hospital managers, emergency planners as well as policy makers to put in place a rapid and effective response to an emergency situation. The results of this study clearly underline that France and Germany could rely on the robust structural components of the hospital system, compared to Italy and Spain. Presumably, this might have had an impact on the efficacy in the management of the COVID-19 diffusion. In particular, the high availability of beds in the majority of the France regions paired with the low occupancy rate and high turnover interval led these regions to have a high number of available beds. Consider also that this country generally manages complex cases. A similar structural component is present in the German regions where the number of available beds is significantly higher than in the other countries. The impact of the COVID-19 was completely different in Italy and Spain that had to deal with a relevant large number of patients relying on a reduced number of both hospital beds and professionals. A further critical factor compared to France and Germany concerns the dissimilar distribution of cases across regions. Even if in these countries the hospital beds were efficiently managed, the concentration of hospitalized patients and the scarcity of beds have put pressure on the hospital systems.

Use of a 3D reconstruction model in a patient with severe atresia auris for optimal placement of Bonebridge transcutaneous bone conduction implant.

PURPOSE: Patients affected by severe atresia auris (AA) can be a challenge during hearing restoration surgery due to the abnormal position of vascular and nervous structures in the bone. A 3D reconstruction model of malformed temporal bones can be helpful for planning surgery and optimizing intra-, peri-, and post-operative results. METHOD: A 5-year-old girl with severe AA on the right side was implanted with a Bonebridge transcutaneous bone conduction implant (tBCI). 3D printing was used to reproduce the malformed temporal bone, find a good position for the tBCI and plan out the surgical details in advance. Hearing tests were performed before and after surgery and information about intra-, peri-, and post-operative outcomes were collected. RESULTS: The patient did not show any negative outcomes and, thanks to the Bonebridge, completely recovered hearing on the right side. CONCLUSIONS: 3D printing is a useful tool for planning surgery in AA patients and for preventing possible risks related to the unknown malformed anatomy.

Analysis of the Different Approaches Adopted in the Italian Regions to Care for Patients Affected by COVID-19.

As the Italian health system is regionally based, COVID-19 emergency actions are based on a general lockdown imposed by national authority and then management at local level by 21 regional authorities. Therefore, the pandemic response plan developed by each region led to different approaches. The aim of this paper is to analyze whether differences in patient management may have influenced the local course of the epidemic. The analysis on the 21 Italian regions considers the strategies adopted in terms of hospitalization, treatment in the ICU and at home. Moreover, an in-depth analysis was carried out on: Lombardia, which adopted a hospitalization approach; Veneto, which tended to confine patients at home; and Emilia Romagna, which adopted a mixed hospitalization-home based approach. The majority of regions implemented a home-based approach, while the hospital approach was followed in three regions (Lombardia, Piemonte, and Lazio), mainly limited to the first period of the outbreak. All regions in the later phases tended to reduce hospitalization, preferring to confine patients at home. This comparison, highlighting the different phases of the pandemic, outlined that the adoption of home-based practices contributed to limiting infection rates among patients and health professionals as well as decreasing the number of deaths.

The efficiency in the ordinary hospital bed management in Italy: An in-depth analysis of intensive care unit in the areas affected by COVID-19 before the outbreak.

Since the end of February 2020 a severe diffusion of COVID-19 has affected Italy and in particular its northern regions, resulting in a high demand of hospitalizations in particular in the intensive care units (ICUs). Hospitals are suffering the high degree of patients to be treated for respiratory diseases and the majority of the health structures, especially in the north of Italy, are or are at risk of saturation. Therefore, the question whether and to what extent the reduction of hospital beds occurred in the past years has biased the management of the emergency has come to the front in the public debate. In our opinion, to start a robust analysis it is necessary to consider the Italian health system capacity prior to the emergency. Therefore, the aim of this study is to analyse the availability of hospital beds across the country as well as to determine their management in terms of complexity and performance of cases treated at regional level. The results of this study underlines that, despite the reduction of beds for the majority of the hospital wards, ICUs availabilities did not change between 2010 and 2017. Moreover, this study confirms that the majority of the Italian regions have a routinely efficient management of their facilities allowing hospitals to treat patients without the risk of having an overabundance of patients and a scarcity of beds. In fact, this analysis shows that, in normal situations, the management of hospital and ICU beds has no critical levels.

Multidimensional assessment of the effects of erenumab in chronic migraine patients with previous unsuccessful preventive treatments: a comprehensive real-world experience.

BACKGROUND: erenumab was safe and effective in clinical trials for the prevention of migraine. However, real-life data are still lacking. Here we report the clinical experience from an Italian real-world setting using erenumab in patients with chronic migraine experiencing previous unsuccessful preventive treatments. METHODS: Seventy patients with chronic migraine and failure to ≥4 migraine preventive medication classes initially received monthly erenumab 70 mg s.c. Patients without a clinically meaningful improvement, considered as a > 30% reduction in headache days per month, after ≥3 months of therapy switched to monthly erenumab 140 mg. At the first administration and after 3 and 6 months, patients underwent extensive interviews to assess clinical parameters of disease severity and migraine-related disability and impact, and validated questionnaires to explore depression/anxiety, sleep, and quality of life (QoL). Finally, the Pain Catastrophizing Scale, Allodynia Symptom Checklist-12 and MIGraine attacks-Subjective COGnitive impairments scale (MIG-SCOG) were administered. RESULTS: 70% of patients were "responders" after the third administration of erenumab 70 mg, whereas 30% switched to erenumab 140 mg; 29% (6 pts) responded after the sixth administration. The headache-day frequency was reduced from 21.1 ± 0.7 to 11.4 ± 0.9 days after the third administration (p < 0.001) and to 8.9 ± 0.7 days after the sixth administration (p < 0.001). 53% and 70% of patients, respectively, showed a reduction of ≥50% of headache days/month after the third and the sixth administrations. Also improved were headache pain severity, migraine-related disability, and impact on daily living, QoL, pain catastrophizing and allodynia (all p < 0.001), quality of sleep, symptoms of depression or anxiety (p < 0.05) but not MIG-SCOG. There were no new adverse event signals. CONCLUSION: These real-world data support monthly erenumab 70 or 140 mg s.c. as a safe and effective preventive treatment to reduce headache frequency and severity in chronic migraine patients experiencing previous unsuccessful preventive treatments.

Erenumab Efficacy on Comorbid Cluster Headache in Patients With Migraine: A Real-World Case Series.

BACKGROUND: Monoclonal antibodies (mABs) against calcitonin gene-related peptide (CGRP) or its receptor have emerged as effective and well-tolerated preventive medications for migraine. The key role played by CGRP has been recently demonstrated also in the pathophysiology of cluster headache (CH), paving the way for studies aimed to investigate the effectiveness of mABs targeting CGRP also in CH. However, no trials have been conducted so far to test the efficacy and tolerability of erenumab as CH preventive treatment. CASE SERIES: We describe the cases of 5 patients with both migraines and CH with previous failures of preventive treatments. All patients were treated with monthly erenumab (70 or 140 mg) showing good results not only on migraine but also on CH attacks frequency and intensity. Improvements of both intensity and frequency of CH attacks occurred only after at least 3 months of treatment, with monthly erenumab 140 mg, suggesting that longer treatment and higher doses are needed in CH in comparison to migraine. DISCUSSION AND CONCLUSION: Our findings support the efficacy and tolerability of monthly erenumab 140 mg as a preventive treatment in patients suffering from both migraines without aura and CH. We speculate that erenumab could represent a low-risk alternative for CH patients (with or without comorbid migraine) who did not tolerate common CH preventatives therapies or for whom the therapies were not successful. Certainly, randomized trials are needed to confirm these observations and we hope that our data, showing a delayed therapeutic effect only with the highest dose of erenumab (140 mg/month), can be taken into account in designing future trials.

A subjective cognitive impairments scale for migraine attacks: validation of the Italian version of the MIG-SCOG.

BACKGROUND: The MIG-SCOG is a questionnaire to assess self-reported subjective cognitive symptoms during migraine attacks, consisting of 9 items evaluating executive functions and language. The aim of the study was to evaluate the psychometric properties of the Italian version of the MIG-SCOG (I-MIG-SCOG) in patients with migraine without aura. METHODS: The I-MIG-SCOG underwent 20 Italian healthy subjects to assess its comprehensibility. Reliability and divergent validity of the I-MIG-SCOG were evaluated in a sample of 153 migraines without aura patients. They also underwent Montreal Cognitive Assessment, Beck Depression Inventory and Apathy Evaluation Scale. RESULTS: The final I-MIG-SCOG was easily comprehensible. There were no missing data, no floor and ceiling effects; mean I-MIG-SCOG score was 7.54 ± 3.98; Cronbach's alpha was 0.814. The I-MIG-SCOG score correlated poorly with Montreal Cognitive Assessment, Beck Depression Inventory and Apathy Evaluation Scale. CONCLUSION: The I-MIG-SCOG should represent a reliable and valid patient-centred and disease-related instrument to identify cognitive symptoms experienced during migraine attacks and to monitor the divergent effects of symptomatic treatments on cognitive functions also in Italian migraine patients.

The European cross-border health data exchange roadmap: Case study in the Italian setting.

Health data exchange is a major challenge due to the sensitive information and the privacy issues entailed. Considering the European context, in which health data must be exchanged between different European Union (EU) Member States, each having a different national regulatory framework as well as different national healthcare structures, the challenge appears even greater. Europe has tried to address this challenge via the epSOS ("Smart Open Services for European Patients") project in 2008, a European large-scale pilot on cross-border sharing of specific health data and services. The adoption of the framework is an ongoing activity, with most Member States planning its implementation by 2020. Yet, this framework is quite generic and leaves a wide space to each EU Member State regarding the definition of roles, processes, workflows and especially the specific integration with the National Infrastructures for eHealth. The aim of this paper is to present the current landscape of the evolving eHealth infrastructure for cross-border health data exchange in Europe, as a result of past and ongoing initiatives, and illustrate challenges, open issues and limitations through a specific case study describing how Italy is approaching its adoption and accommodates the identified barriers. To this end, the paper discusses ethical, regulatory and organizational issues, also focusing on technical aspects, such as interoperability and cybersecurity. Regarding cybersecurity aspects per se, we present the approach of the KONFIDO EU-funded project, which aims to reinforce trust and security in European cross-border health data exchange by leveraging novel approaches and cutting-edge technologies, such as homomorphic encryption, photonic Physical Unclonable Functions (p-PUF), a Security Information and Event Management (SIEM) system, and blockchain-based auditing. In particular, we explain how KONFIDO will test its outcomes through a dedicated pilot based on a realistic scenario, in which Italy is involved in health data exchange with other European countries.