Integrating China in the International Consortium for Personalised Medicine: a position paper on innovation and digitalization in Personalized Medicine.

BACKGROUND: The advent of Personalized Medicine (PM) holds significant promise in revolutionizing healthcare by tailoring treatments to individual patients based on their data. However, its successful implementation requires the seamless integration of innovative technologies and presents formidable challenges in terms of sustainability. To tackle these challenges head-on, the International Consortium for Personalized Medicine (ICPerMed) was established, and the IC2PerMed project, as part of this consortium, seeks to foster collaboration between the European Union (EU) and China in the field of Personalized Medicine. Based on the results collected by the project, the objective of this study is to discern the key priorities for the implementation of Personalised Medicine concerning Information and Communication Technologies (ICT) and Big Data and digital solutions, with a particular emphasis on data management and protection. METHODS: A Delphi survey was conducted to gather expert's consensus on the main priorities for actions on Information and Communication Technologies (ICT) and Big Data and digital solutions in the field of Personalized Medicine. RESULTS: The survey identified seven priorities in the area of Big Data and digital solutions, including data interoperability, standards, security measures, and international partnerships. Additionally, twelve priorities were identified for the innovation-to-market process, emphasizing cost-effectiveness, need assessment, and value definition in resource allocation. CONCLUSIONS: The effective implementation of new technologies in Personalized Medicine research and practice is essential for the advancement of healthcare systems in both the European and Chinese contexts. The identified priorities play a pivotal role in promoting the sustainability of health systems and driving innovation in the implementation of Personalized Medicine. Addressing challenges related to data interoperability, standards, security, international collaboration, cost-effectiveness, and value assessment is of utmost importance in order to propel the progress of Personalized Medicine in healthcare systems.

Integrating China in the International Consortium for Personalized Medicine: A Position Paper on Personalized Medicine in Sustainable Healthcare.

INTRODUCTION: Over the last decade, the emergence and spread of personalized medicine (PM) have defined a substantial revolution in healthcare. In principle, healthcare system sustainability is challenged by the investments required for research and development, as well as the adoption of PM techniques in routine clinical care. The "Integrating China in the International Consortium for Personalized Medicine" (IC2PerMed) EU-funded project aims to integrate China into the "International Consortium for Personalized Medicine" (ICPerMed). IC2PerMed aims to align the EU and China's research agendas in this field to enable a swift development of approaches in the EU and China with strong leverage upon EU-Chinese collaborations. METHODS: Within this project, we first mapped relevant policies on PM in both the EU and China, and then we involved European and Chinese experts in PM in workshops and Delphi surveys in order to identify relevant priorities for the implementation of PM in sustainable healthcare. RESULTS: As a result of this process, we identified nine overarching priorities, each addressing specific aspects of the sustainability of healthcare systems and PM implementation, with the main goal of supporting policymakers in integrating PM approaches in the EU and China. DISCUSSION/CONCLUSION: The implementation of PM in health systems is appealing in terms of improved accuracy in diagnostics, treatment, and prevention of disease, as well as reduction of the side effects resulting from inefficient use of drugs. Research, development, and implementation of needed techniques require time and resources that can slow the adoption of PM in healthcare systems. The nine priorities we identified address some of the most critical points, trying to lay the foundations for a comprehensive approach.

Public attitudes, knowledge and educational needs toward genetic testing and omics sciences: a pilot survey conducted in Italy.

Advancements in genomics have significant implications for public health, making citizens' education vital for informed decision-making. Based on two literature reviews' findings and a survey conducted with experts from the Italian Network of Genomics in Public Health, we conducted a pilot survey on Italian citizens' attitudes, knowledge and educational needs toward genetic testing and omics sciences. Our results demonstrate a widespread interest in genetic testing and uncertainties regarding associated risks, with 99% of participants acknowledging insufficient knowledge of genetic testing. There is an urgent need for educational tools to improve citizens' literacy and engagement in this rapidly evolving field.

Strengthening and promoting digital health practice: results from a Global Digital Health Partnership's survey.

Background and objective: The capacity to promote and disseminate the best evidence-based practices in terms of digital health innovations and technologies represents an important goal for countries and governments. To support the digital health maturity across countries the Global Digital Health Partnership (GDHP) was established in 2019. The mission of the GDHP is to facilitate global collaboration and knowledge-sharing in the design of digital health services, through the administration of surveys and white papers. Objective: The scope of this study is to critically analyze and discuss results from the Evidence and Evaluation GDHP Work Stream's survey, understand how governments and countries intend to address main obstacles to the digital health implementation, identify their strategies for a communication of effective digital health services, and promote the sharing of international based best practices on digital health. Methods: This survey followed a cross-sectional study approach. A multiple-choice questionnaire was designed to gather data. Choices were extracted from research publications retrieved through a rapid review. Results: Out of 29 countries receiving the survey, 10 returned it. On a scale from 1 to 5, eHealth systems/platforms (mean = 3.56) were indicated as the most important tool for centralized infrastructure to collect information on digital health, while primary care (mean = 4.0) represented the most voted item for healthcare services to collect information on digital health. Seven Countries out of 10 identified lack of organization, skepticism of clinicians, and accessibility of the population as a barriers to adopt digital health implementation, resulting to be the most voted items. Finally, the most endorsed priorities in digital health for Countries were the adoption of data-driven approaches (6 Countries), and telehealth (5 Countries). Conclusion: This survey highlighted the main tools and obstacles for countries to promote the implementation of evidence-based digital health innovations. Identifying strategies that would communicate the value of health care information technology to healthcare professionals are particularly imperative. Effective communication programs for clinicians and the general population in addition to improved digital health literacy (both for clinicians and citizens) will be the key for the real implementation of future digital health technologies.

Integrating China in the international consortium for personalised medicine. a position paper on healthcare professionals' education and citizens' empowerment in personalised medicine.

BACKGROUND: Personalised medicine (PM) has been fostered by technological and medical advances, but all stakeholders, including healthcare professionals, citizens and policy makers, should achieve adequate health literacy to promote PM implementation. The "Integrating China in the International Consortium for Personalised Medicine" (IC2PerMed) project, funded by the International Consortium for Personalised Medicine, focuses on this issue by highlighting the need to educate healthcare professionals and empower citizens. Within the aforementioned project, building on a mapping of European and Chinese policies in PM, experts in the field of PM participated in an online workshop and a following two-round Delphi survey, in order to identify the priority areas of intervention for healthcare professionals' education and curricula, engagement and empowerment of citizens and patients. RESULTS: Nine experts completed the survey and reached a consensus on seventeen priorities: seven were related to health professionals' education and curricula, whereas ten on citizen and patients' awareness and empowerment. CONCLUSION: These priorities emphasized the importance of education and health literacy, multidisciplinary and international collaboration, public trust, and consideration of ethical, legal, and social issues. The present experience highlights the relevance of the involvement of stakeholders in informing decision-makers, developing appropriate national plans, strategies, and policies, and ensuring the adequate implementation of PM in health systems.

Research and innovation in personalized medicine: a descriptive synthesis of actors in the EU and China.

Aim: Research and innovation (R&I) actors are fundamental in shortening the translational gap of personalized medicine in health systems. In the context of the 'Integrating China in the International Consortium for Personalized Medicine' project, we aimed to map the current landscape of R&I actors in the field of personalized medicine in the EU and China. Methods: A two-phase desk research study was conducted. Results: We identified 78 R&I actors. Research and technology organizations were the most frequent in both the EU and China. The identified R&I actors were active in a wide range of fields. The EU and China have many different R&I actors addressing personalized medicine-related issues, with few characteristics in common. Conclusion: More efforts are needed to ensure these R&I actors are encouraged to work together to bridge each other's gaps.

Novel Variant in the USP9X Gene Is Associated with Congenital Heart Disease in a Male Patient: A Case Report and Literature Review.

Introduction: The X-chromosomal USP9X gene encodes a deubiquitylating enzyme involved in protein turnover and TGF-ß signaling during fetal and neuronal development. USP9X variants in females are primarily associated with complete loss-of-function (LOF) alleles, leading to neurodevelopmental delay and intellectual disability, as well as a wide range of congenital anomalies. In contrast, USP9X missense variants in males often result in partial rather than complete LOF, specifically affecting neuronal migration and development. USP9X variants in males are associated with intellectual disability, behavioral disorders, global developmental delay, speech delay, and structural CNS defects. Facial dysmorphisms are found in almost all patients. Case Presentation: We report the case of an Italian boy presenting dysmorphism, intellectual disability, structural brain anomalies, and congenital heart disease. Using next-generation sequencing analysis, we identified a hemizygous de novo variant in the USP9X gene (c.5470A>G, p.Met1824Val) that was never reported in the literature. Conclusion: We provide an overview of the available literature on USP9X variants in males, in order to further expand the genotypic and phenotypic landscape of male-restricted X-linked mental retardation syndrome. Our findings confirm the involvement of USP9X variants in neuronal development and corroborate the possible association between the novel USP9X variant and congenital heart malformation.

Narrative Review of the COVID-19 Pandemic's First Two Years in Italy.

Italy was the first country in the western world to be affected by the COVID-19 pandemic, arguably among the worst-affected ones, counting 12 million cases and 150 thousand deaths two years since the first case. Facing new challenges, Italy has enacted different strategies and policies to limit the spread of the SARS-CoV-2 virus and treat those affected by COVID-19. This narrative review provided an overview of factors, measures, and actions that shaped Italy's first two years of the COVID-19 pandemic by investigating epidemiological data and using a mixed-method approach. This narrative review aimed to summarize the most relevant aspects and measures and analyze available data to provide policymakers and healthcare providers with the instruments to learn from this pandemic and improve their preparedness for future pandemic events. The first two years of the pandemic differ in that, during the first year, significant necessary changes to the way health systems were organized were implemented, increasing healthcare spending and adopting social and physical distancing measures that were stricter than the ones adopted in the second year. However, as the pandemic progressed, increased knowledge of the virus and related variants, as well as the introduction of highly effective vaccines, which were not equally available to the whole population, resulted in a stratification of COVID-19 infections and deaths based on factors such as age, vaccination status, and individual susceptibility to the virus.

Big data and ICT solutions in the European Union and in China: A comparative analysis of policies in personalized medicine.

Introduction: Several countries are either planning or implementing national strategies for the development and integration of Personalized Medicine (PM) into their healthcare systems. Personalized Medicine is an undisputed priority of the European Commission (EC), which has funded the project "Integrating China into the International Consortium for Personalized Medicine" (IC2PerMed), in order to ensure a common basis for Sino-European collaborations. By mapping the current PM landscape in the European Union (EU) and in China, IC2PerMed aims to provide key solutions toward a synergistic and coordinated approach in the field of PM. Methods: An extensive desk research was conducted, aimed at identifying documents on PM-related policies, programs, and action plans in the EU and in China, published up to November 2020. The search was conducted by exploring scientific and gray literature, and official institutional repositories. A descriptive summary condensed the information retrieved for both. Results: Since 2013, the year of publication of the first PM policy by the EC "Use of omics technologies in PM development," several documents have been published. PM is a key element of the policy agenda also in China, which in 2016 integrated PM into the 13th National Five-Year Plan, followed by the publication of several policies on technology infrastructure and big data. Both in the EU and China, especially in recent years, these policies addressed in detail the issues of big data, data interoperability and exchange, while defining the standards of information and communication infrastructures. Conclusions: In order to allow optimal collaboration, it is essential to understand similarities and differences between the respective policy strategies, with particular attention to data management and adopted infrastructures. The results of this project may enable the development of joint Sino-European research and innovation initiatives, promoting developments in the field of PM.

Approaches to priority identification in digital health in ten countries of the Global Digital Health Partnership.

Background: To promote shared digital health best practices in a global context, as agreed within the Global Digital Health Partnership (GDHP), one of the most important topics to evaluate is the ability to detect what participating countries believe to be priorities suitable to improve their healthcare systems. No previously published scientific papers investigated these aspects as a cross-country comparison. Objective: The aim of this paper is to present results concerning the priorities identification section of the Evidence and Evaluation survey addressed to GDHP members in 2021, comparing countries' initiatives and perspectives for the future of digital health based on internationally agreed developments. Methods: This survey followed a cross-sectional study approach. An online survey was addressed to the stakeholders of 29 major countries. Results: Ten out of 29 countries answered the survey. The mean global score of 3.54 out of 5, calculated on the whole data set, demonstrates how the global attention to a digital evolution in health is shared by most of the evaluated countries. Conclusion: The resulting insights on the differences between digital health priority identification among different GDHP countries serves as a starting point to coordinate further progress on digital health worldwide and foster evidence-based collaboration.

Scoping review of the current landscape of AI-based applications in clinical trials.

Background: Clinical trials are essential for bringing new drugs, technologies and procedures to the market and clinical practice. Considering the design and the four-phase development, only 10% of them complete the entire process, partly due to the increasing costs and complexity of clinical trials. This low completion rate has a huge negative impact in terms of population health, quality of care and health economics and sustainability. Automating some of the process' tasks with artificial intelligence (AI) tools could optimize some of the most burdensome ones, like patient selection, matching and enrollment; better patient selection could also reduce harmful treatment side effects. Although the pharmaceutical industry is embracing artificial AI tools, there is little evidence in the literature of their application in clinical trials. Methods: To address this issue, we performed a scoping review. Following the PRISMA-ScR guidelines, we performed a search on PubMed for articles on the implementation of AI in the development of clinical trials. Results: The search yielded 772 articles, of which 15 were included. The articles were published between 2019 and 2022 and the results were presented descriptively. About half of the studies addressed the topic of patient recruitment; 12 articles reported specific examples of AI applications; five studies presented a quantitative estimate of the effectiveness of these tools. Conclusion: All studies present encouraging results on the implementation of AI-based applications to the development of clinical trials. AI-based applications have a lot of potential, but more studies are needed to validate these tools and facilitate their adoption.

COVID-19 Vaccination Campaign among the Health Workers of Fondazione Policlinico Universitario Agostino Gemelli IRCCS: A Cost-Benefit Analysis.

Vaccinations generate health, economic and social benefits in both vaccinated and unvaccinated populations. The aim of this study was to conduct a cost-benefit analysis to estimate the costs and benefits associated with the COVID-19 vaccination campaign for health workers in Fondazione Policlinico Universitario Agostino Gemelli IRCCS (FPG). The analysis included 5152 healthcare workers who voluntarily received the Pfizer-BioNTech COVID-19 vaccine, divided into physicians, nurses and other health workers. Data about vaccine cost, administration and materials were derived from administrative databases of the FPG from 28 December 2020 to 31 March 2021. The costs associated with the COVID-19 vaccination campaign amounted to EUR 2,221,768, while the benefits equaled EUR 10,345,847. The benefit-to-cost ratio resulted in EUR 4.66, while the societal return on investment showed a ratio of EUR 3.66. The COVID-19 vaccination campaign for health workers in FPG has high social returns and it strengthens the need to inform and update decision-making about the economic and social benefits associated with a vaccination campaign. Health economic evaluations on vaccines should always be considered by decision-makers when considering the inclusion of a new vaccine into the national program.

Change in age distribution of COVID-19 deaths with the introduction of COVID-19 vaccination.

OBJECTIVES: Most countries initially deployed COVID-19 vaccines preferentially in elderly populations. We aimed to evaluate whether population-level vaccine effectiveness is heralded by an increase in the relative proportion of deaths among non-elderly populations that were less covered by vaccination programs. ELIGIBLE DATA: We collected data from 40 countries on age-stratified COVID-19 deaths during the vaccination period (1/14/2021-5/31/2021) and two control periods (entire pre-vaccination period and excluding the first wave). MAIN OUTCOME MEASURES: We meta-analyzed the proportion of deaths in different age groups in vaccination versus control periods in (1) countries with low vaccination rates; (2) countries with age-independent vaccination policies; and (3) countries with standard age-dependent vaccination policies. RESULTS: Countries that prioritized vaccination among older people saw an increasing share of deaths among 0-69 year old people in the vaccination versus the two control periods (summary proportion ratio 1.32 [95 CI% 1.24-1.41] and 1.35 [95 CI% 1.26-1.44)]. No such change was seen on average in countries with age-independent vaccination policies (1.05 [95 CI% 0.78-1.41 and 0.97 [95 CI% 0.95-1.00], respectively) and limited vaccination (0.93 [95 CI% 0.85-1.01] and 0.95 [95 CI% 0.87-1.03], respectively). Proportion ratios were associated with the difference of vaccination rates in elderly versus non-elderly people. No significant changes occurred in the share of deaths in age 0-49 among all 0-69 deaths in the vaccination versus pre-vaccination periods. CONCLUSIONS: The substantial shift in the age distribution of COVID-19 deaths in countries that rapidly implemented vaccination predominantly among elderly provides evidence for the population level-effectiveness of COVID-19 vaccination and a favorable evolution of the pandemic towards endemicity with fewer elderly deaths.

Expanding the phenotype associated to KMT2A variants: overlapping clinical signs between Wiedemann-Steiner and Rubinstein-Taybi syndromes.

Lysine-specific methyltransferase 2A (KMT2A) is responsible for methylation of histone H3 (K4H3me) and contributes to chromatin remodeling, acting as "writer" of the epigenetic machinery. Mutations in KMT2A were first reported in Wiedemann-Steiner syndrome (WDSTS). More recently, KMT2A variants have been described in probands with a specific clinical diagnosis comprised in the so-called chromatinopathies. Such conditions, including WDSTS, are a group of overlapping disorders caused by mutations in genes coding for the epigenetic machinery. Among them, Rubinstein-Taybi syndrome (RSTS) is mainly caused by heterozygous pathogenic variants in CREBBP or EP300. In this work, we used next generation sequencing (either by custom-made panel or by whole exome) to identify alternative causative genes in individuals with a RSTS-like phenotype negative to CREBBP and EP300 mutational screening. In six patients we identified different novel unreported variants in KMT2A gene. The identified variants are de novo in at least four out of six tested individuals and all of them display some typical RSTS phenotypic features but also WDSTS specific signs. This study reinforces the concept that germline variants affecting the epigenetic machinery lead to a shared molecular effect (alteration of the chromatin state) determining superimposable clinical conditions.

Increasing HPV Vaccination Uptake among Adolescents: A Systematic Review.

Human Papillomavirus (HPV) vaccination is a well-known fundamental strategy in the prevention of cervical cancer, as it is always caused by HPV infection. In fact, primary prevention of the infection corresponds to primary prevention of HPV-related cancers and other diseases. Since an effective prevention at the population level is the final goal, it is mandatory for healthcare systems to achieve a high HPV vaccination coverage among the adolescents to reduce the circulation of the virus and the burden of HPV-related diseases. This research identified, through a systematic literature review, 38 papers on strategies adopted to increase HPV vaccination coverage among adolescents. The evaluated strategies targeted adolescents/parents and/or healthcare providers and could be grouped in three main types: (1) reminder-based, (2) education, information, and communication activities, and (3) multicomponent strategies. Several types of strategy, such as those relied only on reminders and integrating different interventions, showed a positive impact on vaccination coverage. Nonetheless, the heterogeneity of the interventions suggests the importance to adapt such strategies to the specific national/local contexts to maximize vaccination coverage.

Mutational spectrum and clinical signatures in 114 families with hereditary multiple osteochondromas: insights into molecular properties of selected exostosin variants.

Hereditary multiple osteochondromas (HMO) is a rare autosomal dominant skeletal disorder, caused by heterozygous variants in either EXT1 or EXT2, which encode proteins involved in the biogenesis of heparan sulphate. Pathogenesis and genotype-phenotype correlations remain poorly understood. We studied 114 HMO families (158 affected individuals) with causative EXT1 or EXT2 variants identified by Sanger sequencing, or multiplex ligation-dependent probe amplification and qPCR. Eighty-seven disease-causative variants (55 novel and 32 known) were identified including frameshift (42%), nonsense (32%), missense (11%), splicing (10%) variants and genomic rearrangements (5%). Informative clinical features were available for 42 EXT1 and 27 EXT2 subjects. Osteochondromas were more frequent in EXT1 as compared to EXT2 patients. Anatomical distribution of lesions showed significant differences based on causative gene. Microscopy analysis for selected EXT1 and EXT2 variants verified that EXT1 and EXT2 mutants failed to co-localize each other and loss Golgi localization by surrounding the nucleus and/or assuming a diffuse intracellular distribution. In a cell viability study, cells expressing EXT1 and EXT2 mutants proliferated more slowly than cells expressing wild-type proteins. This confirms the physiological relevance of EXT1 and EXT2 Golgi co-localization and the key role of these proteins in the cell cycle. Taken together, our data expand genotype-phenotype correlations, offer further insights in the pathogenesis of HMO and open the path to future therapies.

Clinical and molecular characterization of a second family with the 12q14 microdeletion syndrome and review of the literature.

The 12q14 microdeletion syndrome is a rare condition characterized by low birth weight, failure to thrive, short stature, learning disabilities, and osteopoikilosis. To date, 20 cases of 12q14 deletion have been reported in the literature, displaying both phenotypic than genetic variability. We report on three familial cases, a mother and two brothers, with severe short stature. The mother and elder brother presented with osteopoikilosis while the younger brother had severe short stature and developmental delay. SNP array analysis revealed a 1.9 Mb heterozygous 12q14.2q14.3 deletion in all three patients encompassing 14 genes and 3 miRNAs. In addition, the younger brother carried a paternal 11q13.4 duplication including the SHANK2 gene. This latter patient was investigated for developmental delay and did not show osteopoikilosis, confirming the role of age in the clinical presentation of this condition. To the best of our knowledge, this is the second family described with the syndrome. Comparing the clinical and molecular data of our patients with those previously reported we performed a detailed genotype-phenotype correlation confirming the association between growth retardation and osteopoikilosis when the rearrangement includes both LEMD3 and HMGA2 genes. In addition, we suggest the XPOT, TBK1, WIF1 genes as candidates for the clinical features observed in our patients and discuss for the first time the possible involvement of some microRNAs, when deleted, in the etiology of the phenotypes in 12q14 microdeletion syndrome patients. We expect the interpretation of our findings to be useful both from a molecular point of view and for genetic counseling.