Digital biomarkers: 3PM approach revolutionizing chronic disease management - EPMA 2024 position.

Non-communicable chronic diseases (NCDs) have become a major global health concern. They constitute the leading cause of disabilities, increased morbidity, mortality, and socio-economic disasters worldwide. Medical condition-specific digital biomarker (DB) panels have emerged as valuable tools to manage NCDs. DBs refer to the measurable and quantifiable physiological, behavioral, and environmental parameters collected for an individual through innovative digital health technologies, including wearables, smart devices, and medical sensors. By leveraging digital technologies, healthcare providers can gather real-time data and insights, enabling them to deliver more proactive and tailored interventions to individuals at risk and patients diagnosed with NCDs. Continuous monitoring of relevant health parameters through wearable devices or smartphone applications allows patients and clinicians to track the progression of NCDs in real time. With the introduction of digital biomarker monitoring (DBM), a new quality of primary and secondary healthcare is being offered with promising opportunities for health risk assessment and protection against health-to-disease transitions in vulnerable sub-populations. DBM enables healthcare providers to take the most cost-effective targeted preventive measures, to detect disease developments early, and to introduce personalized interventions. Consequently, they benefit the quality of life (QoL) of affected individuals, healthcare economy, and society at large. DBM is instrumental for the paradigm shift from reactive medical services to 3PM approach promoted by the European Association for Predictive, Preventive, and Personalized Medicine (EPMA) involving 3PM experts from 55 countries worldwide. This position manuscript consolidates multi-professional expertise in the area, demonstrating clinically relevant examples and providing the roadmap for implementing 3PM concepts facilitated through DBs.

Mediterranean diet in the targeted prevention and personalized treatment of chronic diseases: evidence, potential mechanisms, and prospects.

The prevalence of chronic diseases is currently a major public health issue worldwide and is exploding with the population growth and aging. Dietary patterns are well known to play a important role in our overall health and well-being, and therefore, poor diet and malnutrition are among the most critical risk factors for chronic disease. Thus, dietary recommendation and nutritional supplementation have significant clinical implications for the targeted treatment of some of these diseases. Multiple dietary patterns have been proposed to prevent chronic disease incidence, like Dietary Approaches to Stop Hypertension (DASH) and Diabetes Risk Reduction Diet (DRRD). Among them, the MedDiet, which is one of the most well-known and studied dietary patterns in the world, has been related to a wide extent of health benefits. Substantial evidence has supported an important reverse association between higher compliance to MedDiet and the risk of chronic disease. Innovative strategies within the healthcare framework of predictive, preventive, and personalized medicine (PPPM/3PM) view personalized dietary customization as a predictive medical approach, cost-effective preventive measures, and the optimal dietary treatment tailored to the characteristics of patients with chronic diseases in primary and secondary care. Through a comprehensive collection and review of available evidence, this review summarizes health benefits of MedDiet in the context of PPPM/3PM for chronic diseases, including cardiovascular disease, hypertension, type 2 diabetes, obesity, metabolic syndrome, osteoporosis, and cancer, thereby a working hypothesis that MedDiet can personalize the prevention and treatment of chronic diseases was derived.

Energy metabolism as the hub of advanced non-small cell lung cancer management: a comprehensive view in the framework of predictive, preventive, and personalized medicine.

Energy metabolism is a hub of governing all processes at cellular and organismal levels such as, on one hand, reparable vs. irreparable cell damage, cell fate (proliferation, survival, apoptosis, malignant transformation etc.), and, on the other hand, carcinogenesis, tumor development, progression and metastazing versus anti-cancer protection and cure. The orchestrator is the mitochondria who produce, store and invest energy, conduct intracellular and systemically relevant signals decisive for internal and environmental stress adaptation, and coordinate corresponding processes at cellular and organismal levels. Consequently, the quality of mitochondrial health and homeostasis is a reliable target for health risk assessment at the stage of reversible damage to the health followed by cost-effective personalized protection against health-to-disease transition as well as for targeted protection against the disease progression (secondary care of cancer patients against growing primary tumors and metastatic disease). The energy reprogramming of non-small cell lung cancer (NSCLC) attracts particular attention as clinically relevant and instrumental for the paradigm change from reactive medical services to predictive, preventive and personalized medicine (3PM). This article provides a detailed overview towards mechanisms and biological pathways involving metabolic reprogramming (MR) with respect to inhibiting the synthesis of biomolecules and blocking common NSCLC metabolic pathways as anti-NSCLC therapeutic strategies. For instance, mitophagy recycles macromolecules to yield mitochondrial substrates for energy homeostasis and nucleotide synthesis. Histone modification and DNA methylation can predict the onset of diseases, and plasma C7 analysis is an efficient medical service potentially resulting in an optimized healthcare economy in corresponding areas. The MEMP scoring provides the guidance for immunotherapy, prognostic assessment, and anti-cancer drug development. Metabolite sensing mechanisms of nutrients and their derivatives are potential MR-related therapy in NSCLC. Moreover, miR-495-3p reprogramming of sphingolipid rheostat by targeting Sphk1, 22/FOXM1 axis regulation, and A2 receptor antagonist are highly promising therapy strategies. TFEB as a biomarker in predicting immune checkpoint blockade and redox-related lncRNA prognostic signature (redox-LPS) are considered reliable predictive approaches. Finally, exemplified in this article metabolic phenotyping is instrumental for innovative population screening, health risk assessment, predictive multi-level diagnostics, targeted prevention, and treatment algorithms tailored to personalized patient profiles-all are essential pillars in the paradigm change from reactive medical services to 3PM approach in overall management of lung cancers. This article highlights the 3PM relevant innovation focused on energy metabolism as the hub to advance NSCLC management benefiting vulnerable subpopulations, affected patients, and healthcare at large. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-024-00357-5.

Mini-encyclopedia of mitochondria-relevant nutraceuticals protecting health in primary and secondary care-clinically relevant 3PM innovation.

Despite their subordination in humans, to a great extent, mitochondria maintain their independent status but tightly cooperate with the "host" on protecting the joint life quality and minimizing health risks. Under oxidative stress conditions, healthy mitochondria promptly increase mitophagy level to remove damaged "fellows" rejuvenating the mitochondrial population and sending fragments of mtDNA as SOS signals to all systems in the human body. As long as metabolic pathways are under systemic control and well-concerted together, adaptive mechanisms become triggered increasing systemic protection, activating antioxidant defense and repair machinery. Contextually, all attributes of mitochondrial patho-/physiology are instrumental for predictive medical approach and cost-effective treatments tailored to individualized patient profiles in primary (to protect vulnerable individuals again the health-to-disease transition) and secondary (to protect affected individuals again disease progression) care. Nutraceuticals are naturally occurring bioactive compounds demonstrating health-promoting, illness-preventing, and other health-related benefits. Keeping in mind health-promoting properties of nutraceuticals along with their great therapeutic potential and safety profile, there is a permanently growing demand on the application of mitochondria-relevant nutraceuticals. Application of nutraceuticals is beneficial only if meeting needs at individual level. Therefore, health risk assessment and creation of individualized patient profiles are of pivotal importance followed by adapted nutraceutical sets meeting individual needs. Based on the scientific evidence available for mitochondria-relevant nutraceuticals, this article presents examples of frequent medical conditions, which require protective measures targeted on mitochondria as a holistic approach following advanced concepts of predictive, preventive, and personalized medicine (PPPM/3PM) in primary and secondary care.

An ecosystemic perspective of the factors affecting the learning experiences of learners with dyslexia in mainstream schools in England.

A systematic literature review (SLR) of seven papers written between 2015 and 2021 explored the educational experiences of learners with dyslexia in mainstream schools in England from an ecosystemic perspective and how to improve the situation. The analysis employed keywords for database searches and followed the PRISMA flow protocol. It synthesised evidence using thematic analysis and identified seven themes: dyslexia challenges; differential treatment; negative stereotypes; early intervention; teachers' training; power dynamics; and collaboration. The results suggest that several factors can influence the learning experiences of learners with dyslexia in English mainstream schools. Similarly, such factors can, in turn, be dependent on education policies. On that premise, this systematic literature review recommends that to promote positive learning experiences for learners with dyslexia, classroom strategies targeting interventions should be supported with broader environmental strategies shaping individuals' learning experience and offer support from different perspectives. A whole-school approach to providing intervention, teachers' training, parents and school partnerships, and professional collaboration can improve learners' educational experiences. A further recommendation is for learning interventions to target all learners, to prevent differential treatment of learners with dyslexia and to avoid them standing out from their peers and creating a negative experience.

[Associations between puberty timing and cardiovascular metabolic risk factors among primary and secondary students].

OBJECTIVE: To explore the relationship between puberty timing and cardiovascular metabolic risk factors among primary and secondary students with different genders in Beijing. METHODS: Using the method of stratified cluster sampling by urban and rural areas and school sections, 3 067 students from 16 primary and secondary schools in Fangshan District of Beijing were selected in October 2012, with questionnaire survey, physical examination and serum laboratory testing. In this study, we controlled for confounding factors such as school segments, current residence of the family, birth weight, feeding method, only child, highest educational level of parents, and monthly family income, and then the associations between cardiovascular metabolic risk factors and puberty timing among the primary and secondary students was analyzed by multivariate Logistic analysis. To ensure the reliability of the data, this study adopted strict quality control. RESULTS: A total of 3 067 primary and middle school students aged 7 to 16 years were included in this study, including 1 575 boys and 1 492 girls. The prevalence of premature puberty was 14.73% among the boys and 12.89% among the girls, respectively. The prevalence of delayed puberty was 9.49% among the boys and 10.99% among the girls, respectively. The detection rates of central obesity, hypertension, hyperglycemia, and dyslipidemia among the primary and secondary students were 35.87%, 19.95%, 2.54% and 26.31%, respectively. The detection rates of 1 risk factor clustering, 2 risk factors clustering and more than 3 risk factors clustering were 29.21%, 16.17% and 9.36%, respectively. The difference in the detection rate of cardiovascular and metabolic risk factors in different youth stages was insignificant (P>0.05), the detection rate of risk factor aggregation of 0 was lower than that of the timely group and delayed group, and the detection rate of risk factors aggregation of 2 was higher than that of the timely group (P < 0.05).After adjusting the effects of learning stage, region, birth weight, feeding patterns, one-child, family income and the parents' educational levels, multivariate Logistic regression analysis showed that, compared with the on-time puberty group, the risk of 1 risk factor clustering, 2 risk factors clustering and more than 3 risk factors clustering increased by 1.94 times (95% CI=1.29-2.91), 2.97 times (95% CI=1.89-4.67) and 2.02 times (95% CI= 1.13-3.63) among the girls; It had not been found that the relationship between puberty timing and cardiovascular risk factor clustering among the boys (P>0.05). CONCLUSION: Premature puberty is an independent risk factor for the clustering of cardiometabolic risk factors in girls, and primary prevention strategies should be implemented to reduce the burden of cardiovascular metabolic diseases in the population.

Integrating Histology and Phytohormone/Metabolite Profiling to Understanding Rooting in Yellow Camellia Cuttings.

Vegetative propagation through cutting is a widely used clonal approach for maintaining desired genotypes. However, some woody species have difficulty forming adventitious roots (ARs) with this approach, including yellow camellia (YC) C. nitidissima. Yellow camellias, prized for their ornamental value and potential health benefits in tea, remain difficult to propagate clonally due to this rooting recalcitrance. As part of the efforts to understand YC cuttings' recalcitrance, we conducted a detailed investigation into AR formation in yellow camellia cuttings via histology and endogenous phytohormone dynamics during this process. We also compared YC endogenous phytohormone and metabolite phytohormone profiles with those of easy-to-root poplar and willow cuttings. Our results indicate that the induction of ARs in YC cuttings is achievable through auxin treatment, and YC ARs are initiated from cambial derivatives and develop a vascular system connected with that of the stem. During AR induction, endogenous hormones showed a dynamic profile, with IAA continuing to increase starting 9 days after auxin induction. JA, JA-Ile, and OPDA showed a similar trend as IAA but decreased by the 45th day. Cytokinin first decreased to its lowest level by the 18th day and then increased. SA largely exhibited an increasing trend with a drop on the 36th day, while ABA first increased to its peak level by the 18th day and then decreased. Compared to poplar, YC cuttings had a low level of IAA, IAA-Asp, and OPDA, and a high level of cytokinin and SA. Metabolite profiling highlighted significant down-accumulation of compounds associated with AR formation in yellow camellias, such as citric and ascorbic acid, fructose, sucrose, flavonoids, and phenolic acid derivatives. Our study reveals the unfavorable endogenous hormone and metabolite profiles underlying the rooting recalcitrance of YC cuttings, providing valuable knowledge for addressing this challenge in clonal propagation.

Cost-effectiveness and budget impact analysis of screening and preventive interventions for cardiovascular disease in Myanmar: an economic modelling study.

Background: Cardiovascular diseases (CVD) remains a leading cause of mortality in Myanmar. Despite the burden, CVD preventive services receive low government and donor budgets, which has led to poor CVD outcomes. Methods: We conducted a cost-effective analysis and a budget impact analysis on CVD prevention strategies recommended by the WHO. A Markov model was used to analyse the cost and quality-adjusted life year (QALY) from healthcare provider and societal perspectives. We calculated transition probabilities from WHO CVD risk data and obtained treatment effects and costs from secondary sources. Subgroup analysis was performed on different sex and age groups. We framed the budget impact analysis from a healthcare provider perspective to assess the affordability of providing CVD preventive care. Findings: The most cost-effective strategy from the healthcare provider perspective varied. The combination of screening, primary prevention, and secondary prevention (Sc-PP-SP) (incremental cost-effectiveness ratio [ICER]: US$1574/QALY) is most cost-effective at the three times gross domestic product (GDP) per capita threshold, while at one time the GDP per capita threshold, secondary prevention is the most cost-effective strategy (ICER: US$160/QALY). Sc-PP-SP is the most cost-effective strategy from the societal perspective (ICER: US$647/QALY). Among age groups, intervention at age 45 years appeared to be the most cost-effective option for both men and women. The budget impact revealed the Sc-PP-SP would avert 55,000 acute CVD events and 28,000 CVD-related deaths with a cost of US$157 million for the first year of CVD preventive care. Interpretation: A combination of screening, primary prevention, and secondary prevention is cost-effective to reduce CVD-related deaths in Myanmar. This study provides evidence for the government and development partners to increase investment in and support for CVD prevention. These findings not only provide a basis for efficient resource allocation but also underscore the importance of adopting a total cardiovascular risk approach to CVD prevention, in alignment with global health goals. Funding: Pilot grant from Duke Global Health Institute, USA.

Differences in Discounting Behavior and Brain Responses for Food and Money Reward.

Most neuroeconomic research seeks to understand how value influences decision-making. The influence of reward type is less well understood. We used functional magnetic resonance imaging (fMRI) to investigate delay discounting of primary (i.e., food) and secondary rewards (i.e., money) in 28 healthy, normal-weighted participants (mean age = 26.77; 18 females). To decipher differences in discounting behavior between reward types, we compared how well-different option-based statistical models (exponential, hyperbolic discounting) and attribute-wise heuristic choice models (intertemporal choice heuristic, dual reasoning and implicit framework theory, trade-off model) captured the reward-specific discounting behavior. Contrary to our hypothesis of different strategies for different rewards, we observed comparable discounting behavior for money and food (i.e., exponential discounting). Higher k values for food discounting suggest that individuals decide more impulsive if confronted with food. The fMRI revealed that money discounting was associated with enhanced activity in the right dorsolateral prefrontal cortex, involved in executive control; the right dorsal striatum, associated with reward processing; and the left hippocampus, involved in memory encoding/retrieval. Food discounting, instead, was associated with higher activity in the left temporoparietal junction suggesting social reinforcement of food decisions. Although our findings do not confirm our hypothesis of different discounting strategies for different reward types, they are in line with the notion that reward types have a significant influence on impulsivity with primary rewards leading to more impulsive choices.

The impact of boarding school on student development in primary and secondary schools: a meta-analysis.

As a long-established model of schooling, the boarding system is commonly practiced in countries around the world. Numerous scholars have conducted a great deal of research on the relationship between the boarding school and student development, but the results of the research are quite divergent. In order to clarify the real effects of boarding school on students' development, this study used meta-analysis to quantify 49 (91 effect sizes) experimental or quasi-experimental studies on related topics at home and abroad. The results find that: (1) Overall, boarding school has no significant predictive effect on student development, with a combined effect size of 0.002 (p > 0.05); (2) Specifically, boarding school has a significant positive predictive effect on students' cognitive development (g = 0.248, p < 0.001), a significant negative predictive effect on students' affective and attitudinal development (g = -0.159, p < 0.05), and no significant predictive effect on students' behavioral development (g = -0.115, p > 0.05) and physical development (g = -0.038, p > 0.05); (3) The relationship between the two is moderated by the school stage and the type of boarding school, but not by the instruments; (4) Compared with primary school students, senior high school students and urban boarding students, the negative predictive effect of boarding system on junior middle school students and rural boarding students is more significant. In addition, there are some limitations in the study, such as the limited number of moderator variables included, the results of the study are easily affected by the quality of the included literature, and the dimensionality of the core variable "student development" is not comprehensive enough. In the future, further validation should be conducted through in-depth longitudinal or experimental studies.

Predictive, preventive and personalised approach as a conceptual and technological innovation in primary and secondary care of inflammatory bowel disease benefiting affected individuals and populations.

Inflammatory bowel disease (IBD) is a global health burden which carries lifelong morbidity affecting all age groups in populations with the disease-specific peak of the age groups ranging between 15 and 35 years, which are of great economic importance for the society. An accelerating incidence of IBD is reported for newly industrialised countries, whereas stabilising incidence but increasing prevalence is typical for countries with a Westernised lifestyle, such as the European area and the USA. Although the aetiology of IBD is largely unknown, the interplay between the genetic, environmental, immunological, and microbial components is decisive for the disease manifestation, course, severity and individual outcomes. Contextually, the creation of an individualised patient profile is crucial for the cost-effective disease management in primary and secondary care of IBD. The proposed pathomechanisms include intestinal pathoflora and dysbiosis, chronic inflammation and mitochondrial impairments, amongst others, which collectively may reveal individual molecular signatures defining IBD subtypes and leading to clinical phenotypes, patient stratification and cost-effective protection against health-to-disease transition and treatments tailored to individualised patient profiles-all the pillars of an advanced 3PM approach. The paradigm change from reactive medical services to predictive diagnostics, cost-effective targeted prevention and treatments tailored to individualised patient profiles in overall IBD management holds a promise to meet patient needs in primary and secondary care, to increase the life-quality of affected individuals and to improve health economy in the area of IBD management. This article analyses current achievements and provides the roadmap for future developments in the area in the context of 3P medicine benefiting society at large.

The paradigm change from reactive medical services to 3PM in ischemic stroke: a holistic approach utilising tear fluid multi-omics, mitochondria as a vital biosensor and AI-based multi-professional data interpretation.

Worldwide stroke is the second leading cause of death and the third leading cause of death and disability combined. The estimated global economic burden by stroke is over US$891 billion per year. Within three decades (1990-2019), the incidence increased by 70%, deaths by 43%, prevalence by 102%, and DALYs by 143%. Of over 100 million people affected by stroke, about 76% are ischemic stroke (IS) patients recorded worldwide. Contextually, ischemic stroke moves into particular focus of multi-professional groups including researchers, healthcare industry, economists, and policy-makers. Risk factors of ischemic stroke demonstrate sufficient space for cost-effective prevention interventions in primary (suboptimal health) and secondary (clinically manifested collateral disorders contributing to stroke risks) care. These risks are interrelated. For example, sedentary lifestyle and toxic environment both cause mitochondrial stress, systemic low-grade inflammation and accelerated ageing; inflammageing is a low-grade inflammation associated with accelerated ageing and poor stroke outcomes. Stress overload, decreased mitochondrial bioenergetics and hypomagnesaemia are associated with systemic vasospasm and ischemic lesions in heart and brain of all age groups including teenagers. Imbalanced dietary patterns poor in folate but rich in red and processed meat, refined grains, and sugary beverages are associated with hyperhomocysteinaemia, systemic inflammation, small vessel disease, and increased IS risks. Ongoing 3PM research towards vulnerable groups in the population promoted by the European Association for Predictive, Preventive and Personalised Medicine (EPMA) demonstrates promising results for the holistic patient-friendly non-invasive approach utilising tear fluid-based health risk assessment, mitochondria as a vital biosensor and AI-based multi-professional data interpretation as reported here by the EPMA expert group. Collected data demonstrate that IS-relevant risks and corresponding molecular pathways are interrelated. For examples, there is an evident overlap between molecular patterns involved in IS and diabetic retinopathy as an early indicator of IS risk in diabetic patients. Just to exemplify some of them such as the 5-aminolevulinic acid/pathway, which are also characteristic for an altered mitophagy patterns, insomnia, stress regulation and modulation of microbiota-gut-brain crosstalk. Further, ceramides are considered mediators of oxidative stress and inflammation in cardiometabolic disease, negatively affecting mitochondrial respiratory chain function and fission/fusion activity, altered sleep-wake behaviour, vascular stiffness and remodelling. Xanthine/pathway regulation is involved in mitochondrial homeostasis and stress-driven anxiety-like behaviour as well as molecular mechanisms of arterial stiffness. In order to assess individual health risks, an application of machine learning (AI tool) is essential for an accurate data interpretation performed by the multiparametric analysis. Aspects presented in the paper include the needs of young populations and elderly, personalised risk assessment in primary and secondary care, cost-efficacy, application of innovative technologies and screening programmes, advanced education measures for professionals and general population-all are essential pillars for the paradigm change from reactive medical services to 3PM in the overall IS management promoted by the EPMA.

Light oxygenated volatile organic compound concentrations in an Eastern Mediterranean urban atmosphere rivalling those in megacities.

Highly resolved measurements of primary and secondary oxygenated volatile organic compounds (OVOCs) by proton-transfer-reaction mass spectrometry (PTR-MS) and the AMOVOC sampler (Airborne Measurements Of VOC) were performed in Beirut, Lebanon, during the ECOCEM (Emissions and Chemistry of Organic Carbon in the East Mediterranean) experiments. The OVOC concentrations (0.15-7.0 ppb) rival those reported for international megacities like Paris, Tokyo, or São Paulo (0.3-6.5 ppb). This study highlights the seasonal variability of OVOCs, the potential role of background pollution on OVOC concentrations, traffic emissions of OVOCs, and the secondary production of OVOCs during both summer and winter. The primary and secondary OVOC fractions were estimated using two methods based on the night-time emission ratio and photochemical age. Our calculations coupled with a correlation analysis revealed the following: firstly, background concentrations contributed significantly, especially for longer-lived OVOCs, such as methanol and acetone (30%-80%). Secondly, secondary production in summer increased up to 60%, except for methanol and isoprene oxidation products, i.e., for methacrolein and methyl vinyl ketone. Thirdly, the secondary production in the Eastern Mediterranean persisted in winter, and finally, strong primary traffic emissions dominated the primary biogenic emissions. Finally, the emission ratios were used to evaluate the global anthropogenic emission inventories downscaled to Lebanon. Although limited to two individual non-lumped species (formaldehyde and acetone), the emission ratios compared well, within a factor of 2. However, the emissions of aldehydes and ketones from the CAMS, Edgar, and MACCITY inventories showed discrepancies of up to three orders of magnitude. This demonstrates a need for improved OVOC representation in emission inventories, considering the atmospheric relevance and abundance of OVOCs and their use in volatile chemical products.

Advanced Data Processing of Pancreatic Cancer Data Integrating Ontologies and Machine Learning Techniques to Create Holistic Health Records.

The modern healthcare landscape is overwhelmed by data derived from heterogeneous IoT data sources and Electronic Health Record (EHR) systems. Based on the advancements in data science and Machine Learning (ML), an improved ability to integrate and process the so-called primary and secondary data fosters the provision of real-time and personalized decisions. In that direction, an innovative mechanism for processing and integrating health-related data is introduced in this article. It describes the details of the mechanism and its internal subcomponents and workflows, together with the results from its utilization, validation, and evaluation in a real-world scenario. It also highlights the potential derived from the integration of primary and secondary data into Holistic Health Records (HHRs) and from the utilization of advanced ML-based and Semantic Web techniques to improve the quality, reliability, and interoperability of the examined data. The viability of this approach is evaluated through heterogeneous healthcare datasets pertaining to personalized risk identification and monitoring related to pancreatic cancer. The key outcomes and innovations of this mechanism are the introduction of the HHRs, which facilitate the capturing of all health determinants in a harmonized way, and a holistic data ingestion mechanism for advanced data processing and analysis.

Gastric cancer screening in Western countries: A call to action.

Gastric cancer is a major cause of cancer-related death worldwide, despite the reduction in its incidence. The disease is still burdened with a poor prognosis, particularly in Western countries. The main risk factor is the infection by Helicobacter pylori, classified as a class I carcinogen by the IARC, and It is well-known that primary prevention of gastric cancer can be achieved with the eradication of the infection. Moreover, non-invasive measurement of pepsinogens (PGI and PGI/PGII ratio) allows the identification of patients that should undergo upper gastrointestinal (GI) endoscopy. Gastric non-cardia adenocarcinoma is indeed preceded by a well-defined precancerous process that involves consecutive stages, described for the first time by Correa et al. more than 40 years ago, and patients with advance stages of gastric atrophy/intestinal metaplasia and with dysplastic changes should be followed-up periodically with upper GI endoscopies. Despite these effective screening and surveillance methods, national-level screening campaigns have been adopted only in few countries in eastern Asia (Japan and South Korea). In this review, we describe primary and secondary preventive measures for gastric cancer, discussing the need to introduce screening also in Western countries. Moreover, we propose a simple algorithm for screening that could be easily applied in clinical practice.

Study rationale and design of the PEOPLHE trial.

PURPOSE: Lung cancer screening (LCS) by low-dose computed tomography (LDCT) demonstrated a 20-40% reduction in lung cancer mortality. National stakeholders and international scientific societies are increasingly endorsing LCS programs, but translating their benefits into practice is rather challenging. The "Model for Optimized Implementation of Early Lung Cancer Detection: Prospective Evaluation Of Preventive Lung HEalth" (PEOPLHE) is an Italian multicentric LCS program aiming at testing LCS feasibility and implementation within the national healthcare system. PEOPLHE is intended to assess (i) strategies to optimize LCS workflow, (ii) radiological quality assurance, and (iii) the need for dedicated resources, including smoking cessation facilities. METHODS: PEOPLHE aims to recruit 1.500 high-risk individuals across three tertiary general hospitals in three different Italian regions that provide comprehensive services to large populations to explore geographic, demographic, and socioeconomic diversities. Screening by LDCT will target current or former (quitting < 10 years) smokers (> 15 cigarettes/day for > 25 years, or > 10 cigarettes/day for > 30 years) aged 50-75 years. Lung nodules will be volumetric measured and classified by a modified PEOPLHE Lung-RADS 1.1 system. Current smokers will be offered smoking cessation support. CONCLUSION: The PEOPLHE program will provide information on strategies for screening enrollment and smoking cessation interventions; administrative, organizational, and radiological needs for performing a state-of-the-art LCS; collateral and incidental findings (both pulmonary and extrapulmonary), contributing to the LCS implementation within national healthcare systems.

Targeting T regulatory (Treg) cells in immunotherapy-resistant cancers.

Primary or secondary (i.e., acquired) resistance is a common occurrence in cancer patients and is often associated with high numbers of T regulatory (Treg) cells (CD4+CD25+FOXP3+). The approval of ipilimumab and the development of similar pharmacological agents targeting cell surface proteins on Treg cells demonstrates that such intervention may overcome resistance in cancer patients. Hence, the clinical development and subsequent approval of Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) targeting agents can serve as a prototype for similar agents. Such new agents aspire to be highly specific and have a reduced toxicity profile while increasing effector T cell function or effector T/T regulatory (Teff/Treg) ratio. While clinical development with large molecules has shown the greatest advancement, small molecule inhibitors that target immunomodulation are increasingly entering early clinical investigation. These new small molecule inhibitors often target specific intracellular signaling pathways [e.g., phosphoinositide-3-kinase delta (PI3K-δ)] that play an important role in regulating the function of Treg cells. This review will summarize the lessons currently applied to develop novel clinical agents that target Treg cells.

The relationship between physical activity and the health of primary and secondary school teachers: the chain mediating effects of body image and self-efficacy.

BACKGROUND: Active health is a new concept, model, and system to maintain the state of whole-person health. In the context of the increasingly serious health problems of primary and secondary school teachers, it is of great significance to explore the relationship between physical activity and primary and secondary school teachers' health based on the active health perspective. METHODS: The survey involving 741 primary and secondary school teachers across representative provinces in China utilized the International Physical Activity Scale, Body Imagery State Scale, and General Self-Efficacy Scale. Data analysis employed SPSS 25.0 and Amos 24.0 software. RESULTS: While no significant gender disparities were observed in body image and self-efficacy, age groups exhibited a bipartite and "V" shaped distribution. Female teachers demonstrated higher physical activity levels (2456.46) and superior physical fitness compared to males (2297.86). A positive correlation emerged between physical activity, body image, self-efficacy, and health status. Importantly, body image and self-efficacy partially mediated the relationship between physical activity and health status, accounting for 82.31% of the total effect. CONCLUSIONS: Primary and secondary school teachers have real problems such as teachers' physical activity is generally insufficient, teachers' body image status is generally poor, and teachers' self-efficacy is low; physical activity is an important factor in promoting primary and secondary school teachers' health status, and low, medium, and high levels of activity all have a promoting effect on the health of primary and secondary school teachers, and the more active primary and secondary school teachers are in terms of physical activity, the better their body image, self-efficacy, and health status are, and the more active primary and secondary school teachers are in terms of physical activity, the more positive the physical activity, self-efficacy, and health status are. The more physically active primary and secondary school teachers are, the better their physical intention, self-efficacy and health status are. SUGGESTIONS: improve the quality and effectiveness, promote the concept of active health among teachers; empower teachers, strengthen the institutional protection of teachers' health; reduce the burden and increase the quantity,and optimise the supply of health services for teachers.

Nitrogen-Doped Graphene Materials with High Electrical Conductivity Produced by Electrochemical Exfoliation of Graphite Foil.

Nitrogen-doped graphene-based materials are of utmost importance in sensing and energy conversion devices due to their unique physicochemical properties. However, the presence of defects such as pyrrolic nitrogen and oxygenated functional groups reduces their electrical conductivity. Herein, a two-step approach based on the electrochemical exfoliation of graphite foils in aqueous mixed electrolytes followed by thermal reduction at 900 °C is used to prepare high-quality few layers of N-doped graphene-based materials. The exfoliations were conducted in 0.1 M (NH4)2SO4 or H2SO4 and HNO3 (5 mM or 0.1 M) electrolytes mixtures and the HNO3 vol% varied. Chemical analysis demonstrated that the as-prepared graphene oxides contain nitro and amine groups. Thermal reduction is needed for substitutional N-doping. Nitrogen and oxygen surface concentrations vary between 0.23-0.96% and 3-8%, respectively. Exfoliation in (NH4)2SO4 and/or 5 mM HNO3 favors the formation of pyridinic-N (10-40% of the total N), whereas 1 M HNO3 favors the formation of graphitic-N (≈60%). The electrical conductivity ranges between 166-2705 Scm-1. Raman spectroscopy revealed a low density of defects (ID/IG ratio between 0.1 and 0.7) and that most samples are composed of mono-to-bilayer graphene-based materials (IG/I2D integrated intensities ratio). Structural and compositional stability of selected samples after storage in air for three months is demonstrated. These results confirm the high quality of the synthesized undoped and N-doped graphene-type materials.

Primary and Secondary Cardiovascular and Kidney Prevention With Canagliflozin: Insights From the CANVAS Program and CREDENCE Trial.

BACKGROUND: This study evaluated the effects of canagliflozin in patients with type 2 diabetes with and without prevalent cardiovascular disease (secondary and primary prevention). METHODS AND RESULTS: This was a pooled participant-level analysis of the CANVAS (Canagliflozin Cardiovascular Assessment Study) Program and CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial. The CANVAS Program included participants with type 2 diabetes at elevated cardiovascular risk, whereas the CREDENCE trial included participants with type 2 diabetes and albuminuric chronic kidney disease. Hazard ratios (HRs) with interaction terms were obtained from Cox regression models to estimate relative risk reduction with canagliflozin versus placebo across the primary and secondary prevention groups. We analyzed 5616 (38.9%) and 8804 (61.1%) individuals in the primary and secondary prevention subgroups, respectively. Primary versus secondary prevention participants were on average younger (62.2 versus 63.8 years of age) and more often women (42% versus 31%). Canagliflozin reduced the risk of major adverse cardiovascular events (HR, 0.84 [95% CI, 0.76-0.94]) consistently across primary and secondary prevention subgroups (Pinteraction=0.86). Similarly, no treatment effect heterogeneity was observed with canagliflozin for hospitalization for heart failure, cardiovascular death, end-stage kidney disease, or all-cause mortality (all Pinteraction>0.5). CONCLUSIONS: Canagliflozin reduced cardiovascular and kidney outcomes with no statistical evidence of heterogeneity for the treatment effect across the primary and secondary prevention subgroups in the CANVAS Program and CREDENCE trial. Although studies on the optimal implementation of canagliflozin within these populations are warranted, these results reinforce canagliflozin's role in cardiorenal prevention and treatment in individuals with type 2 diabetes. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01032629, NCT01989754, NCT02065791.