This review proposes and explores the significance of "experience-based medical education" (EXPBME) in the context of an artificial intelligence (AI)-driven society. The rapid advancements in AI, particularly driven by deep learning, have revolutionized medical practices by replicating human cognitive functions, such as image analysis and data interpretation, significantly enhancing efficiency and precision across medical settings. The integration of AI into healthcare presents substantial potential, ranging from precise diagnostics to streamlined data management. However, non-technical skills, such as situational awareness on recognizing AI's fallibility or inherent risks, are critical for future healthcare professionals. EXPBME in a clinical or simulation environment plays a vital role, allowing medical practitioners to navigate AI failures through sufficient reflections. As AI continues to evolve, aligning educational frameworks to nurture these fundamental non-technical skills is paramount to adequately prepare healthcare professionals. Learner-centered EXPBME, combined with the AI literacy acquirement, stands as a key pillar in shaping the future of medical education. In recent years, the remarkable advancements in the field of artificial intelligence (AI) have led to the emergence of third-generation AI, predominantly powered by deep learning. This cutting-edge form of AI is revolutionizing numerous aspects of the medical domain, showcasing immense potential for transformative applications. One of the key strengths of this AI paradigm is its ability to replicate and utilize intellectual processes akin to that of humans, thereby greatly augmenting the efficiency and effectiveness of various medical settings .First-generation AI, often referred to as "symbolic AI" or "good old-fashioned AI," focused on rule-based systems and symbolic reasoning. Researchers programmed explicit rules and logic to represent knowledge and solve problems. These systems were rule-bound and lacked learning capabilities. Examples include expert systems and early natural language processing. Second-generation AI witnessed a shift toward machine learning and statistical methods. Rather than relying solely on handcrafted rules, AI systems were designed to learn patterns and make predictions from data. Techniques, such as neural networks, decision trees, support vector machines, and clustering algorithms, became prevalent. This era saw significant advancements in supervised learning, unsupervised learning, and reinforcement learning .In contrast to first- or second-generation AI, third-generation AI, through its sophisticated algorithms and neural networks, can engage in complex tasks comparable to human cognitive functions. Third-generation AI includes intricate processes, such as pattern recognition, data analysis, discovery of hidden patterns and correlations within vast datasets, and learning from previous experiences. By effectively mimicking these higher-order cognitive functions, AI can significantly contribute to medical research, diagnosis, and treatment planning . An illuMoreover, the integration of third-generation AI into healthcare systems has brought about a substantial transformation in the management and analysis of medical information . AI systWhile AI technology has dramatically evolved, aligning educational frameworks to nurture these fundamental non-technical skills associated with AI's fallibility or inherent risks is paramount to adequately prepare healthcare professionals. To cultivate these non-technical skills, active reflection learners' own experience is warranted. In other words, learner-centered approach on experience is essential. In this review, we propose the significance of learner-centered "experience-based medical education" (EXPBME) and the acquisition of AI literacy as essential components in shaping the future of medical education.Transformative potential of third-generation AI in healthcareThe ongoing advancements in third-generation AI are poised to bring about a paradigm shift in healthcare, augmenting medical practices, empowering healthcare professionals, and ultimately enhancing the quality of care provided to patients . The intLooking forward, as AI technology continues to evolve and mature, it is poised to revolutionize the entire healthcare ecosystem. AI accelerates drug discovery by analyzing vast datasets to predict drug behaviors, identify potential compounds, and optimize drug properties. This expedites the research and development process, saving time and resources. AI tailors medical treatments to individuals by analyzing genetic, clinical, and lifestyle data. This enables customized therapies and medication plans, optimizing outcomes based on a person's unique characteristics and health history. AI enhances telemedicine by providing diagnostic support, remote monitoring, and personalized health recommendations. It improves accessibility to healthcare services, especially in remote or underserved areas, by leveraging technology for virtual consultations and efficient healthcare delivery. This evolution is expected to progressively shift the traditional workflows of physicians, placing a stronger emphasis on patient-centered care and multidisciplinary collaboration . The synThe collaborative integration of AI with the medical field holds immense promise, paving the way for a future where healthcare is more personalized, efficient, and effective .Ethical and educational imperatives in AI integration for enhanced healthcareStriking a harmonious balance between technological advancements and ethical integrity is central to realizing the full potential of AI integration in medical practice for the betterment of healthcare outcomes and patient welfare. The rapid proliferation of AI applications within the realms of medical and healthcare necessitates a heightened awareness among medical educators on a global scale regarding AI and the multifaceted challenges it entails ,11. ThisHowever, in this promising landscape of AI-driven advancements in healthcare, ethical and legal concerns loom large. Issues relating to data privacy, algorithmic bias, accountability, and the potential for overreliance on AI require careful deliberation and the establishment of appropriate regulatory frameworks . MedicalTo ensure that medical students are well prepared for the evolving healthcare landscape, academic institutions are proactively reshaping their curricula to encompass AI and data science literacy . The objA critical aspect of this educational paradigm involves integrating competency development related to AI and its legal and ethical issues into medical education curricula . It is eIn sum, as AI applications continue to gain prominence within the medical and healthcare domains, a proactive and informed approach to medical education becomes paramount. The evolution of educational frameworks to encompass AI and data science literacy, coupled with a strong emphasis on ethical considerations and competency development, will play a pivotal role in preparing future healthcare professionals to navigate and capitalize on the dynamic healthcare landscape effectively .Caution to excessive digital dependency in medical education in the AI eraDigital transfer in the medical environment refers to the application of information and communication technologies (ICTs) driven by AI to support health and healthcare, including electronic medical records, videoconferencing technology, and wearable devices, such as mobile applications or virtual/augmented reality ,21. ThesThe onset of the COVID-19 pandemic served as a catalyst, accelerating the digitization of medical education through the widespread adoption of remote classes and virtual training platforms . This shExtensive research has shed light on the elevated levels of digital dependency observed among medical students . While dA comprehensive approach could involve using interactive educational platforms for the practical application of theoretical knowledge. Combining AI resources with hands-on experiences through blended learning creates a holistic learning environment. The AI-driven digital age offers transformative potential for medical education and practice. It is vital to balance digital advancements with experiential learning to nurture healthcare professionals proficient in technology and clinical skills, optimizing healthcare outcomes in today's digital landscape.Essential role of non-technical skills derived from experience in the AI-driven societyBoth medical educators and learners should remain cognizant of the potential risks associated with an overreliance on AI-generated information and emphasize the continued importance of developing non-technical skills through experiential learning. Balancing the integration of AI-driven advancements with the essential cultivation of non-technical skills will be fundamental in preparing healthcare professionals to deliver safe, efficient, and compassionate care in the ever-evolving AI-dominated medical landscape. In the rapidly evolving landscape of the AI era, the significance of both technical and non-technical skills in medical practice cannot be overstated, as they play pivotal roles in ensuring optimal clinical outcomes and fostering advancements in patient care and medical safety ,32. TechHere, we propose the idea of EXPBME, which is based on various reflections based on experiences. EXPBME through clinical or simulation experience stands as an efficacious instructional method in cultivating both technical prowess and these crucial non-technical crisis management skills across diverse medical settings . EXPBME However, as we transition further into the AI era, a new layer of complexity is added to the acquisition of non-technical skills. Medical practitioners must now not only grapple with assimilating this vast trove of AI-generated data but also maintain their focus on developing the nuanced non-technical skills that are equally critical for effective patient care.Significance of learner-centered EXPBME in the AI-driven societyThe constantly changing field of medicine, driven by technology and breakthroughs in research, requires doctors to keep learning and improving their skills continuously . TraditiMedical students must embrace the concept of lifelong learning and commence career design strategies early in their educational journey, preferably during their initial clinical training period following the attainment of their M.D. degree. Learner-centered EXPBME, such as early exposure to diverse clinical settings or mentored research experiences, plays a crucial role in shaping their career trajectories . These eFrom the viewpoint of learner-centered EXPBME, incorporating professional development and career-oriented modules into the medical curriculum can further enhance students' readiness to design their careers effectively . These mSignificance of learner-centered EXPBME for acquiring non-technical skills regarding AI literacyExperience-based learning, particularly through simulation exercises employing a rescue method, emerges as a cornerstone in equipping medical professionals with the indispensable competencies needed to mitigate and manage AI errors in real time. Emphasizing learner-centered EXPBME is crucial for developing non-technical AI skills in the medical field. It is rooted in core principles, preparing learners for AI's evolving role in healthcare education. In the AI era, EXPBME gains central importance in shaping medical education.The ongoing transformation within healthcare, driven by the integration of AI and its allied technologies, necessitates a parallel evolution in medical education. Medical learners must develop advanced research skills that enable them to delve deeply into the intricate world of AI, not merely understanding the algorithms and mechanisms that power it but also critically evaluating and validating the outcomes that AI-powered systems produce . While AI is precise and efficient, it is crucial to acknowledge its fallibility and the potential for errors. Healthcare professionals bear the responsibility for AI-driven diagnoses or suggestions, highlighting the need for human oversight. Understanding the complex deep learning mechanisms of AI can be challenging, underscoring the importance of non-technical skills in detecting AI failures. This underscores the necessity of integrating experiential learning methodologies, designed to simulate AI failures and immerse learners in situations that prompt swift and effective responses.Learners must not only develop AI literacy but also acquire a high level of competency in non-technical skills through practical experiences. These skills empower them to identify errors or mistakes made by AI effectively. This, in turn, enhances patient safety and ultimately leads to the delivery of optimal healthcare outcomes in an AI-powered medical landscape that is in a constant state of evolution.Further roles of learner-centered EXPBME in the AI eraIn the evolving landscape of healthcare technology, the role of learner-centered EXPBME transcends its foundational principles, taking on a multifaceted significance in the AI era. Medical education programs, deeply rooted in learner-centered approaches, can elevate AI literacy development by replicating a spectrum of scenarios where AI systems may provide incorrect diagnoses or treatment recommendations. Through hands-on experiences in managing such diverse situations, medical learners not only cultivate a keen awareness of AI errors but also acquire the ability to devise appropriate corrective actions, thus honing their problem-solving skills in a practical context.These AI literacy programs, an integral part of learner-centered EXPBME, can be thoughtfully designed to simulate a wide array of possible AI failures. By exposing healthcare professionals to various AI failure scenarios, these programs ensure that learners are well prepared to navigate the intricacies and challenges that may emerge in a technologically advanced healthcare environment. As AI technology continues its relentless advancement and becomes increasingly interwoven into the very fabric of healthcare delivery, the timeless learning theories that form the bedrock of medical education retain their crucial relevance.Moreover, underscoring the complementary role of non-technical skills, such as effective communication, critical thinking, and ethical decision-making, becomes paramount in the context of learner-centered medical education within clinical settings. The integration of these non-technical skills is instrumental, not only to ensure that medical professionals are proficient in leveraging AI for optimal patient care but also to equip them with the essential skills necessary to navigate the complexities and uncertainties that accompany the integration of AI in modern healthcare. In other words, learner-centered EXPBME with sufficient reflection on experience can cultivate non-technical skill on controlling AI.By embracing the principles of learner-centered EXPBME and prioritizing the holistic development of a well-rounded skill set, the medical community is poised to effectively harness the transformative potential of AI. Through this approach, the healthcare ecosystem can elevate patient care and safety to unparalleled heights, upholding the highest standards while embracing the technological wave of AI with a robust foundation of educational excellence.Despite rapid technological advancements, the fundamental experiential learning theory has shown resilience to changes. As we navigate the AI era, it becomes imperative to introduce an updated medical education curriculum that delves beyond the application and operation of AI, emphasizing a profound understanding of its principles and associated risks. While AI technology rapidly advances, the core learning theories remain steadfast. Therefore, an essential focus should be placed on recognizing the complementary function of non-technical skills in nurturing learner-centered EXPBME combined with AI literacy, accompanied by a commitment to continuous enhancement. Considering a learner-centered approach in EXPBME, integrating modules focused on professional development and career orientation into the medical curriculum can significantly improve students' preparedness in effectively planning their future careers. Learner-centered EXPBME, built upon these fundamental principles, acts as an essential resource to equip medical learners for the complex and constantly evolving role of AI in the field of medicine.


The dysregulation of psychophysiological responses to mental stressors is a common issue addressed in individuals with psychiatric conditions, while brain circuit abnormalities are often associated with psychiatric conditions and their manifestations. However, to our knowledge, there is no systematic overview that would comprehensively synthesize the literature on psychophysiological responses during laboratory-induced psychosocial stressor and neural correlates in people with mental disorders. Thus, we aimed to systematically review the existing research on psychophysiological response during laboratory-induced stress and its relationship with neural correlates as measured by magnetic resonance imaging techniques in mental disorders.The systematic search was performed on PubMed/Medline, EBSCOhost/PsycArticles, Web of Science, and The Cochrane Library databases during November 2021 following the PRISMA guidelines. Risk of bias was evaluated by employing the checklists for cross-sectional and case-control studies from Joanna Briggs Institute (JBI) Reviewers Manual.Out of 353 de-duplicated publications identified, six studies were included in this review. These studies were identified as representing two research themes: (1) brain anatomy and psychophysiological response to mental stress in individuals with mental disorders, and (2) brain activity and psychophysiological response to mental stress in individuals with mental disorders.Overall, the evidence from studies exploring the interplay between stress psychophysiology and neural correlates in mental disorders is limited and heterogeneous. Further studies are warranted to better understand the mechanisms of how psychophysiological stress markers interplay with neural correlates in manifestation and progression of psychiatric illnesses. Dysregulated psychophysiological responses to psychological stressors is a common feature of people with psychiatric conditions –3, signaConsidering the biological mechanisms involved in the development and progression of mental disorders, morpho-functional changes of brain circuits are often linked with psychiatric conditions and their manifestations –19, compDespite the evident relevance of psychophysiological stress biomarkers and neural correlates in psychiatric conditions, studies examining the interplay between these two groups of biomarkers in clinical populations have been relatively scarce. There have been several narrative reviews on laboratory-induced stress responses and neural correlates in general , 26. Howclinicaltrials.gov and the GSK Clinical Study Register. The following search query was employed: (“psychophysiolog*” OR “cardiovascular” OR “cortisol”) AND “stress” AND  AND (“response*” OR “reaction*” OR “reactivity”) AND (“magnetic resonance imaging” OR “brain imaging” OR “fmri” OR “DTI”) AND .The strategy used in this review was in line with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines . PubMed/The selection criteria were based on PICOS  approach . PublicaRelevant studies were retrieved on November 2021 employing the platform of Rayyan Systems Inc. Selected studies were independently reviewed by two assessors (JGS and MGR). Inclusion and exclusion criteria were determined beforehand. After initial screening of title and abstracts, the assessors reviewed full-text publications, which were retrieved and independently verified for eligibility. Disagreements were acknowledged and resolved through discussions and unified consensus, or with revision of a third senior assessor (MB). Data that was retrieved from publications were analyzed taking a narrative synthesis approach.Two independent reviewers (JGS and MGR) performed critical appraisal by using Joanna Briggs Institute (JBI) Reviewers Manual , 30, a sA flow diagram illustrating the studies selection process is presented in Overall, bias in study methodology was low. However, most of the studies lacked information on confounding variables and/or statistical analysis, while controlling for possible covariates . Whilst two studies addressed the possible confounding factors , 35, then = 4) used fMRI , and 25 were matched healthy controls (HC). The primary interest was to evaluate the callosal abnormalities and its manifestation in those with APD. Additionally, the authors also measured how callosal abnormalities were associated with emotional deficits, including reduced autonomic stress responses. To measure autonomic reactivity  to stress, a public speaking task was performed, during which the participants had to prepare (2 min.) and talk (2 min.) about their worst faults (n = 83) community sample, in which APD-related characteristics were assessed via the Psychopathy Checklist . The results remained significant even when controlled for PTSD diagnosis, smoking history, alcohol use and study site.Further, the cross-sectional study  evaluateWe found four studies , 35–37 tn = 36), rMDE (n = 33), and HC (n = 36) with the primary aim to examine state-independent (trait) and state-dependent neural responses to psychological stress in the study participants. Psychiatric diagnosis was confirmed with administration of SCID-I. The MIST was adapted to elicit psychological stress during fMRI. When compared with HC, both rMDE and MDE groups showed higher stress-related cortisol response and similar brain activations, including lower activation of ventromedial prefrontal cortex and greater activation of precuneus, cingulate, and paracentral lobule. Regarding the interplay between neural correlates and psychophysiological stress responses, it was found that stress-induced changes in ventromedial prefrontal cortex activation was inversely associated with higher cortisol response during mental stress in all three groups. According to the authors, the results highlighted the importance of the medial prefrontal cortex in regulation of hypothalamic-pituitary-adrenal axis stress reactivity. These results may possibly explain that the differences found between HC and MDE/rMDE are more attributable to trait effect of depression rather than state or clinical status of onset/remission of depression.Two cross-sectional studies focused on affective disorders, studying individuals with current or remitted MDE   or bipolIn the second study, conducted in the Netherlands , 80 men One cross-sectional study , conductFinally, a cross-sectional study conducted in Germany  investigIn this current scoping review, we identified six studies examining psychophysiological response to laboratory-induced stress and neural correlates, measured with MRI. Two themes were identified, including (1) brain anatomy and psychophysiological response to mental stress in individuals with mental disorders, and (2) brain activity and psychophysiological response to mental stress in individuals with mental disorders. With regards to brain anatomy, there is some limited knowledge on callosal abnormalities and autonomic stress reactivity in individuals with APD and regional brain volumes and cortisol stress response in those with PTSD. In terms of brain activity, there is some evidence from observational studies, investigating ventromedial prefrontal cortex activation, ventral striatal responses, and cortisol response in affective disorders as well as cerebral correlates and cortisol stress response in postpartum women with OCD.n = 15), but on the wider community-based sample from which this target group was drawn (n = 83). Thus, attributing those results to clinical APD should be done cautiously. It is also important to note that the sample of both studies included men only.The first two studies , 34 inveAdditional four studies found associations between brain activity  and psychophysiological responses  to stress in women with remitted MDE , men witRegarding further studies, based on the results of this scoping review, it is evident that there is a need for more interdisciplinary research of stress psychophysiology and brain imaging in people with mental disorders. Most mental disorders are currently still under-represented within the research of neuroimaging and stress psychophysiology, even though brain changes and psychobiology of stress in mental disorders are known to be altered relative to healthy populations , 13–16. The limitations of this scoping review are worth mentioning. We found a small number of studies, precluding us from making systematic comparisons across the research or from providing a broader map on the existing literature within this topic. This overview was also limited to only English-language articles, thus excluding potentially relevant studies. Further, due to high heterogeneity of the studies, the comparison between studies were challenging. Specifically, it was difficult to disentangle what findings were determined by disorder specific reasons and which one depicted the unique and transdiagnostic interplay between neural and cardiovascular/endocrine correlates. In fact, high levels of heterogeneity could be observed not only regarding the mental disorders, but also types of stress test , biomarkers , sMRI brain structures  or fMRI modalities . However, in terms of the strengths, this review used transparent, systematic, and rigorous methods throughout the entire process, employing a broad search of the literature with four different databases, and ensuring a good quality of the selected studies with additional quality assessment.Our scoping review provided a critical systematic overview of the existing empirical research on psychophysiology of laboratory induced-stress and neurobiological measures during magnetic resonance imaging in psychiatric in-patient and out-patient populations. The selected studies provided further knowledge of the importance to study neural correlates and its interplay with stress psychophysiology in individuals with mental disorder. However, many limitations exist related to the methodology and heterogeneity of the studies. Further research may concentrate on larger study samples, employing more diversity in terms of mental disorders and sex. Also, longitudinal studies are still warranted, allowing to draw the causal relationship between stress psychophysiology and brain circuit abnormalities.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.JG-S: conceptualization and writing—original draft. MGR: conceptualization and writing—review and editing. PB and MB: conceptualization and supervision. BH and NM: writing—review and editing and supervision. All authors contributed to the article and approved the submitted version.


Tauopathies are disorders associated with tau protein dysfunction and insoluble tau accumulation in the brain at autopsy. Multiple lines of evidence from human disease, as well as nonclinical translational models, suggest that tau has a central pathologic role in these disorders, historically thought to be primarily related to tau gain of toxic function. However, a number of tau-targeting therapies with various mechanisms of action have shown little promise in clinical trials in different tauopathies. We review what is known about tau biology, genetics, and therapeutic mechanisms that have been tested in clinical trials to date. We discuss possible reasons for failures of these therapies, such as use of imperfect nonclinical models that do not predict human effects for drug development; heterogeneity of human tau pathologies which may lead to variable responses to therapy; and ineffective therapeutic mechanisms, such as targeting of the wrong tau species or protein epitope. Innovative approaches to human clinical trials can help address some of the difficulties that have plagued our field’s development of tau-targeting therapies thus far. Despite limited clinical success to date, as we continue to refine our understanding of tau’s pathogenic mechanism(s) in different neurodegenerative diseases, we remain optimistic that tau-targeting therapies will eventually play a central role in the treatment of tauopathies. Tauopathies are neurodegenerative diseases defined by the accumulation of misfolded, insoluble tau protein aggregates in neuronal and/or glial inclusions detectable in the brain at autopsy . These dMAPT, toxic gain of function has been historically suggested as the cause of tauopathies , to stabilize cytoskeleton and regulate axonal transport. It also affects a diverse array of other cellular processes, including synaptic function, gene expression, and energy metabolism . It is uopathies . Abnormaopathies , 14.Here, we review normal and abnormal tau biology, tau genetics, nonclinical models and their relationship to human disease, and hypotheses regarding proposed roles of tau in neurodegeneration. Despite strong evidence for a central pathologic role of tau in neurodegenerative tauopathies, recent human clinical trials of experimental tau-targeting therapies have failed to demonstrate clinical benefit, including drugs purported to interfere with pathologic aggregation, processing, and accumulation of tau , 16.Despite a variety of potential explanations for the negative clinical trials, the lack of efficacy of tau therapies tested to date has raised important questions regarding what is truly understood about tau and its suitability as a drug target in human neurodegenerative disease. Though tau therapeutics have improved pathology in nonclinical models of tauopathy, do the recent negative human clinical trial results reflect flawed nonclinical models that inadequately model human disease? Are the models potentially predictive of therapeutic effects in human disease, but not the disease(s) in which the therapies were tested? Or is the lack of human efficacy explained by problems related to drug development, such as the wrong therapeutic target, inadequate dose, or lack of target engagement? Given these challenges, is it time to rebalance the approach to development of tau therapeutics using nonclinical models and early-stage human clinical trials?MAPT gene by alternative splicing of exons 2, 3, and 10 ; 4R tauopathies, such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), argyrophilic grain disease (AGD), and globular glial tauopathy (GGT); and combined 3R/4R tauopathies, such as Alzheimer’s disease (AD), chronic traumatic encephalopathy (CTE), and primary age-related tauopathy (PART).Tauopathies can also be classified based on whether tau is the only aggregated protein found in the brain at autopsy or whether other proteins or pathogenic events are believed to initiate tau pathology. See MAPT mutations, which lead to hereditary forms of frontotemporal lobar degeneration. Different MAPT mutations are associated with specific clinical phenotypes and biomarker profiles  have demonstrated conversion of tau monomers to oligomers, and then to insoluble fibrils (The trans-synaptic spread (“prion”) hypothesis of tau spread has garnered recent interest. This hypothesis is supported by the predictable progression intracerebrally of tau protein in various diseases, including AD, correlating with clinical symptoms . In AD,  fibrils . In thes fibrils , 36. Pat fibrils .It is more difficult to connect tau burden with clinical presentation in “incidental” tauopathies, which are often subclinical in nature, noted as co-pathologies or contributing pathologies in brain autopsies, with phosphorylated tau (p-tau) aggregates, and also termed age-related tauopathies . They inMAPT gene reduce tau’s ability to bind microtubules and promote microtubule assembly, causing an FTD with Parkinsonism phenotype  mutation carrier with a protective apolipoprotein E (apoE) mutation who had reduced tau accumulation and preserved cognition also implicates apoE in this process (Other possible routes of pathogenicity include the interaction of tau with other proteins involved in neurodegenerative disease. Amyloid-β (Aβ) and tau in AD have a pathogenic interaction in human disease . In an A process .Tau, α-synuclein, and TAR DNA-binding protein 43 (TDP-43) appear to have synergistic neurotoxic effects, based on their colocalization in humans at autopsy and in vivo model data , 60. BasMAPT are the cause of autosomal dominant forms of frontotemporal lobar degeneration (FTLD) that present most commonly with behavioral variant FTD, but sometimes with movement disorders. Other mutations, including R406W and V337M, produce mixed 3R/4R tau pathology similar to AD, presenting with an amnestic AD-like syndrome and tau that binds AD tau PET tracers. Overall, nearly 60 mutations in MAPT have been identified as pathogenic  ε4 allele may increase risk of earlier-onset FTD   , P301S) –83. Thes, P301S) . HoweverWith this knowledge, close attention should be paid to recent tau-directed antibody failures. For example, nonclinical testing of semorinemab was in a mouse model expressing P301L tau, a mutation found in FTLD , with subsequent clinical testing in AD patients . ConversOther key differences exist between mice and humans that may explain poor translation of mouse tau biology to therapeutics. Murine tau lacks 11 N-terminal amino acids that are present in the human version. These differences in the N-terminus affect tau secretion, protein interaction, and tau phosphorylation , modulate posttranslational modification (PTM), disrupt tau aggregation, passively clear tau, and vaccinate against tau — see Notably, the pathogenic tau species has not been definitively identified in living humans. Soluble tau, in the form of oligomers (including dimers), is being explored as a possible source of key neurotoxic species. Alternatively, insoluble tau in the form of both NFTs and other aggregates might represent the toxic species . In suppIn general, given the heterogeneity of tau isoforms, tau PTMs, and aggregate structures in tauopathies, some diseases may respond better than others to specific tau-targeting agents. There is cryo–electron microscopic evidence for differences in the structures of tau filaments in different diseases, including Pick’s disease, AD, chronic traumatic encephalopathy (CTE), CBD, globular glial tauopathy (GGT), AGD, and PSP. Particularly, a three-layered fold is noted in PSP and GGT, while a four-layer fold is noted in CBD and AGD , 99. TauAgents targeting tau PTMs, particularly hyperphosphorylation, have included protein kinase inhibitors that aim to reduce tau aggregation. All of the agents discussed below demonstrated signal in nonclinical models. Concerns with these agents have included potential lack of target specificity and potential for off-target effects. Over 90 phosphorylation sites for tau exist, and specific interventions balancing efficacy with tolerability may be difficult to achieve. Glycogen synthase kinase 3β (GSK-3β) hyperactivity contributes to hyperphosphorylation, which has been considered the major target for pathologic aggregation . LithiumO-GlcNAcylation (OGA) targeting may decrease hyperphosphorylation, and a small-molecule inhibitor (MK-8719) showed nonclinical mouse model signal in decreasing tau aggregation, but did not advance to phase II clinical trials in humans . Other OTau acetylation can prevent physiologic clearance; salsalate, a small-molecule acetylation inhibitor, did not show a treatment effect in a futility study of 10 patients with PSP, nor was there evidence of efficacy in a small randomized, placebo-controlled trial in mild to moderate AD  , 109.Tau aggregation disruption aims to prevent the paired helical filament conformation observed in NFTs, and a derivative of methylene blue (LMTM), which prevents this in mouse models, was evaluated in a phase III trial of behavioral variant FTD without evidence of efficacy . MultiplMicrotubule stabilization designed to ameliorate putative loss of physiologic function has been attempted. Davunetide is derived from activity-dependent neurotrophic protein (ADNP), a neuroprotective agent that decreased hyperphosphorylated tau in nonclinical models through an unclear mechanism. It did not demonstrate any clear benefits in randomized trials in 144 patients with mild cognitive impairment nor in 313 patients with PSP , 112. AbMAPT mRNA to reduce tau expression. This strategy is based on data in mouse models showing that reducing human tau expression improves hippocampal volume loss and cognitive deficits (Antisense oligonucleotides (ASOs) are directed against deficits . In thisdeficits . A phaseImprovement of tau clearance has been assayed using proteolysis-targeting chimera (PROTAC) molecules to selectively enhance ubiquitination and proteolysis of tau proteins, as demonstrated in nonclinical models, including patient-derived neural cell models , 116. ThBoth active (vaccine) and passive (mAb-mediated) immune therapies are being investigated in tauopathies.AADvac1 was the first tau-directed vaccine tested in trials, employing a truncated version of the tau protein that was thought to be the pathogenic fragment in the MTBR triggering aggregation. Immunogenicity was demonstrated in a phase I trial, but unfortunately in a phase II trial versus placebo in mild AD dementia, slowing of cognitive and functional decline was not demonstrated, although it slowed the increase in blood neurofilament light chain . AnotherMonoclonal antibodies targeting the N-terminal tau domain have been tested in multiple phase II trials, largely without clinical benefit despite evidence for target engagement via reduction of N-terminal CSF tau. These trials have included gosuranemab (in PSP and early AD), tilavonemab (in PSP and AD), and zagotenemab . NotablyAnother possible reason for the lack of observed clinical benefit in trials is that mAbs have targeted extracellular tau. This mechanism was thought to be valuable on the basis that extracellular tau may undergo spread to other neurons . However, it is unknown whether recent tau mAbs have reached a high enough concentration in the brain parenchyma to affect these species, since there are no human biomarkers to measure soluble tau levels in the brain parenchyma. By analogy to anti-amyloid antibodies, it may be necessary to activate immune-mediated clearance for efficacy, but most anti-tau mAbs tested have been IgG4 with reduced effector domain, which is the least effective isotype to promote microglia phagocytosis . FurtherIt is also important to consider patient effects, including aging, on changes in effectiveness of immune therapies such as vaccination and antibody therapies, related to alterations in the B and T cell compartments termed immunosenescence . DecreasIn recent years, multiple in vivo biomarkers for tau pathology have been evaluated; these are key to detection of tau pathology, clinical trial enrollment, and assessment of the efficacy of tau therapeutics. These are overall better validated in AD than in other tauopathies. Currently, no biomarkers are approved for diagnosing non-AD tauopathies or for following the clinical course of any tauopathies.18F]flortaucipir, was approved for clinical use for the detection of AD by the US Food and Drug Administration (FDA) in May 2020  or pathogenic mechanism (phosphorylation), difficulty in designing the optimal immunologic approach, lack of biomarkers to diagnose early-stage tauopathies and to measure treatment response, the possibility that recent trials have started too late in the course of disease, and insufficient numbers of clinical trials in different human tauopathies that could respond differently to the same tau therapy.It is clear that a novel approach to identifying and testing therapies in humans is needed. We know that nonclinical models are imperfect and that some phenomena studied in these models may not be therapeutically relevant to humans. Further, secondary effects of tau pathology, such as aggregation of other pathogenic proteins and neuroinflammation, may not be addressed by therapies that solely target tau. Timing is also critical: it is possible that even mild cognitive impairment is too late with regard to the development of pathology leading to neurodegeneration in humans. Or perhaps, as suggested by semorinemab’s failure to slow progression of early and mild AD, it is too early?MAPT mutation carriers) to leverage surrogate biomarker endpoints (neurofilament light chain and MRI) to select the optimal inclusion criteria and endpoints to maximize power to detect treatment effects (There is an urgent need to bring therapies to the clinic setting for all patients with neurodegenerative disease, including tauopathies. We believe it is time to refocus on “interventional” human research, as a departure from the current focus on therapeutic design, which entails years of expensive work on nonclinical models. Once therapeutic safety is established in early-phase trials, new approaches will be necessary to efficiently and effectively evaluate multiple therapeutic mechanisms in parallel. Training and departmental support for academic clinical trialists to carry out this work should be prioritized. Therapeutic classes and agents targeting different mechanisms can be tested in basket trials to enhance drug development efficiency by evaluating the effects of one therapy in multiple tauopathies . Umbrell effects .There are gaps in our understanding of the pathobiology of tauopathies, but regardless, an overwhelming amount of circumstantial evidence implicates tau protein as a driver of human disease, particularly in the primary tauopathies. As the science of tau therapy and clinical trials advances, there are likely to be important and unexpected insights into the pathogenic mechanisms of tauopathies that will identify novel agents that should be efficiently tested in clinical trials. Overall, we are optimistic about the future of tau-targeted therapies and our ability as a field to bring them to patients, as we continue to refine our understanding of tau biology and drug development.


Rising medical costs are a significant concern for employers offering health benefits to employees, and there is interest in identifying insurance plan designs that optimize the effect of pharmacy benefits on overall costs. For instance, employers must decide between plans that carve in pharmacy benefits  versus plans that carve out pharmacy benefits (where pharmacy benefits are separately administered through a pharmacy benefit manager). Little is known about the effect of carving in pharmacy benefits on medical utilization and costs.To compare the effect of carving in versus carving out pharmacy benefits on medical utilization, medical costs, and health management program participation in commercial health plans.We performed a propensity score-matched analysis comparing carve-in and carve-out members of a regional health plan in 2018. Our primary outcomes were medical utilization  and costs . We categorized these into the following domains: inpatient, emergency department, outpatient/ambulatory surgery, urgent care, primary care, specialist services, and diagnostics (laboratory testing/imaging). We additionally assessed participation in health plan-based health management programs.We analyzed 9,633 carve-in members matched with 9,633 carve-out members. Compared with carving out pharmacy benefits, carving in was associated with 3.7% lower medical costs, with an $8.73 reduction in PMPM ($225.87 vs. $234.60), and no significant difference in medical utilization; significantly lower inpatient and urgent care claims  and costs ; lower injectable medical therapy costs ($4.32 PMPM reduction); and higher durable medical equipment costs ($2.14 PMPM increase). Carve-in members also experienced 4.9% higher health management program participation.As employers attempt to understand the value of carving in versus carving out pharmacy benefits to health plans, our findings suggest that carving in pharmacy benefits is associated with reduced medical costs and hospitalizations. Our findings can assist in informing employer decision-making processes and, as a result, reducing costs of care. What is already known about this subjectRising medical costs are a significant concern for employers offering health benefits for employees, and there is interest in identifying insurance plan designs that optimize the effect of the pharmacy benefit on overall costs of care.Benefit design options for employers include carve-in plans, where the health plan vendor provides medical and pharmacy benefits, and carve-out plans, where the health plan vendor provides medical benefits but pharmacy benefits are carved out to a pharmacy benefit manager.What this study addsIn this propensity score-matched analysis comparing medical utilization and medical costs among carve-in pharmacy versus carve-out members of a large commercial health plan, carving in pharmacy benefits was associated with significantly lower total medical costs with no change in total medical claims, significantly lower inpatient and urgent care claims and costs, lower injectable medical therapy costs, and higher durable medical equipment costs.Carving in pharmacy benefits was associated with higher participation in insurer-based health management programs.As employers attempt to understand the value of carving in versus carving out pharmacy benefits to health plans, our findings can be instrumental in informing employers’ decision-making processes and, as a result, reducing costs of care.1 Rising costs are a significant concern for employers offering health benefits for employees, and there is substantial interest in identifying insurance plan designs that optimize the effect of the pharmacy benefit on overall costs of care. When employers consider health plan options, benefit design options include carve-in plans, where the health plan vendor offers medical and pharmacy benefits in an integrated package, and carve-out plans, where the health plan vendor provides medical benefits, but pharmacy benefits are carved out via a direct arrangement between an employer and pharmacy benefit manager (PBM).2Medical costs are anticipated to rise by 5%-6% in 2020, with drug spending being a key driver.3 With carve-out designs, however, PBMs will work directly with employers and generally handle all aspects of pharmacy benefit administration.In carve-in plans, the health plan vendor may administer its pharmacy benefits in-house or may contract with a PBM for some or all aspects of pharmacy benefit management. When health plans contract with PBMs in carve-in designs, they decide which pharmacy administration functions  to designate to PBMs and which to retain in house.17 Critics, however, suggest that carve-in plans have less auditing transparency, are more rigid in plan design, have inadequate focus on drugs, and receive less significant drug price discounts than their carve-out counterparts.3Proponents of carve-in plans report potential advantages of carving in pharmacy benefits, which include the opportunity to streamline and coordinate medical and pharmacy services, integrate medical and pharmacy claims data more easily and subsequently identify value opportunities, and reduce administrative burden by engaging with fewer vendors.17 One recently published peer-reviewed article by Smith et al. (2020) suggests that carving in pharmacy benefits among commercial self-insured beneficiaries resulted in lower medical costs, odds of hospitalization, and odds of emergency department (ED) visits, but there is limited peer-reviewed literature to corroborate these findings.4Despite arguments for and against carving in pharmacy benefits, little is known about the effect of carving in pharmacy benefits on medical utilization and cost outcomes among commercial self-insured beneficiaries. Industry-supported literature suggests that carve-in plans are associated with lower hospitalization rates and medical costs and higher engagement in health management programs, but the magnitude of these associations varies.Using data from UPMC Health Plan’s commercial self-insured beneficiaries, we sought to expand on Smith et al.’s study to compare the effect of carving in versus carving out pharmacy benefits on specific types of medical utilization, medical costs, and participation in health management programs.We used 2018 UPMC Health Plan medical claims to perform a propensity score-matched regression analysis that compared utilization, cost, and health management program participation among members of carve-in versus carve-out plans. UPMC Health Plan is a large health plan in Western Pennsylvania that serves 3.5 million enrollees across all insurance products, including commercial ; exchange; Medicare; Medicaid; special needs plans; Children’s Health Insurance Program; and workers’ compensation products. As part of the commercial insurance product for administrative services only (ASO) employer groups , UPMC Health Plan offers carve-in and carve-out products. For its carve-in clients, UPMC Health Plan contracts with a large PBM to facilitate network pharmacy rate negotiation, benefit configuration, and claims processing, while retaining formulary development and administration, clinical pharmacy policy, coverage determination adjudication, and customer and provider service in-house.Study inclusion was limited to members who were continuously enrolled in ASO commercial health plan products from January 1, 2018, to December 31, 2018. We excluded members who had changes in pharmacy coverage  and those who were enrolled in more than 1 insurance product in the study period.Our primary outcomes were total medical utilization  and cost outcomes . In addition to assessing total medical utilization and costs, we further categorized these outcomes into the following domains: inpatient admissions; ED visits; outpatient/ambulatory surgery; urgent care; primary care services; specialist services; therapy services ; diagnostics (laboratory testing and imaging); durable medical equipment (DME); and injectable medical therapy .18 Of note, 84% of carve-in and 14% of carve-out members were incentivized to participate in health management programs by their employers. We therefore performed a sensitivity analysis of program participation on just those who were incentivized  to that data point. This is considered a “greedy” algorithm because it minimizes the individual distance and removes those data points from potential subsequent matches.20We propensity score-matched each carve-in member to 1 carve-out member. We implemented the SAS gmatch algorithm found on HSR CodeXchange, using nearest neighbor matching without replacement.21 Area Deprivation Index  to account for differences in member demographics and plan medical cost share (defined as percentage of claim expenses paid by the employer over expenses paid by the employer and member) to attempt to account for differences in member plan cost share. Notably, Smith et al.’s study used the same covariate to adjust for plan medical cost share.4We matched members based on covariates as of December 2018, including age, gender, and age-adjusted Charlson Comorbidity Index (CCI) score to adjust for member comorbidities,P < 0.05.We used a gamma model with log link to assess for statistical differences in total medical costs ; zero-inflated gamma models with log link to assess for differences in subcategory costs (due to higher percentages of members with $0 costs in subcategories); and chi-square proportion testing to assess for differences in utilization and engagement in health management programs. We performed sensitivity analyses that excluded shock claims  than carve-out members. The differences in costs were driven by inpatient ($10.08 difference), urgent care ($0.12 difference), and injectable medical therapy costs ($4.32 difference). Conversely, costs for DME were $2.14 PMPM more costly in carve-in compared with carve-out plans. These trends were robust in sensitivity analyses that excluded shock claims, except that certain cost differences were no longer significant . Despite similar differences in costs, our costs were lower than Smith et al. . In addition, they observed a significant reduction in ED visits, whereas we observed no significant difference in ED visits.Our observation that carving in pharmacy benefits was associated with significantly lower medical costs and hospitalizations than carve-out designs is consistent with Smith et al.’s recent study, as well as with industry-supported studies performed by Highmark/Blue Cross Blue Shield, Health Partners, Aetna, and Cigna.We urge caution in comparing differences between the studies, however, as there are likely differences in patient populations, plans, and additional factors which render direct comparisons inappropriate. For example, it is possible that we defined total medical costs differently; we defined them as a combination of costs from our utilization subcategories, whereas it is unclear how total medical costs are defined in the Smith et al. study. Second, Smith et al. covered members of different Blue plans across 3 states. It is therefore likely the plans were heterogeneous in how they embraced their approaches to carving in and carving out pharmacy benefits. For instance, some carve-in plans may integrate medical and pharmacy data and act on identified opportunities better than others. Our study, however, was limited to UPMC Health Plan members, so the approach to differences in benefit design was likely more uniform.23 In contrast, carve-out designs generally do not have efficient ways to coordinate complex medical records with pharmacy claims and require data exchanges between vendors and insurers.Our findings build on the literature by identifying categories that could be responsible for medical cost reduction, including inpatient, urgent care, and injectable medical therapy. These trends could be explained by several factors. First, health plans can leverage the combined medical and pharmacy data of carve-in members to gain a more comprehensive view of their member needs, allowing for more effective identification of those members who might benefit most from health management programs. Although PBMs do provide medication management programs in carve-out plans based on pharmacy claims, medical claims provide more robust information by which targeted interventions for high-risk patients can be designed. For example, at UPMC Health Plan, the benefit of carve-in plans is facilitated by Health Planet, an information technology platform that provides a comprehensive view of members using integrated medical and pharmacy data and houses all case interactions by staff .13Second, health plans could use comprehensive data from carve-in members to identify those who might benefit from care management programs. This is supported by findings from our study and a previous study done by Cigna (2020), both of which indicate that carve-in members have higher engagement and/or participation in health plan-based management programs.Furthermore, carving in pharmacy benefits allows for health plans to more easily identify members who have medication optimization opportunities based on their medical conditions. For instance, access to comprehensive data could assist health plans in identifying and reaching out to patients who have congestive heart failure and high-risk clinical features who would benefit from additional pharmacotherapy. Also, given our observed cost reduction for injectable medical therapies, a comprehensive review of drug use from pharmacy and medical claims could allow for identification of value opportunities for specialty drugs.25 While these differences could be related to differences in plan design and covered populations, these studies suggest that integrated plans may be more motivated to increase drug adherence and appropriate drug use to offset downstream medical costs, whereas stand-alone Part D plans may not have the same prerogative.Since carve-in plans manage medical and pharmacy benefits, they have more authority to optimize pharmacy benefits with the goal of reducing medical utilization. For example, recent studies demonstrate that integrated Medicare Advantage/Part D plans have decreased patient cost sharing and increased spending for chronic disease medications compared with stand-alone Part D plans.Importantly, we observed that the domains with the largest reductions in costs between carve-in and carve-out members included inpatient visits and injectable medical therapy. Although more research is needed to explore the drivers of these differences, if carve-in members truly experienced improved outcomes from more appropriate medication use, better medication adherence, and higher engagement with health management programs, then they could in fact appreciate reduced utilization of these services. Conversely, it is unclear why DME costs increased for carve-in members while utilization did not increase. While we accounted for differences in the presence of comorbidities using CCI scores, it is possible that differences in severity of comorbidities between groups could be an important factor.Our study has limitations to consider. First, the study was confined to ASO commercial health plan members from a single health care organization, so findings may not be generalizable to other health plans and systems.Second, while we tried to account for plan design differences by accounting for employer versus member cost share, we may not have accounted for all individual plan differences. It is therefore possible that specific differences in benefit design that we could not account for could have steered members to differing sites of care.29 For instance, a study by Roebuck et al. (2015) found that a 1% increase in drug spending was associated with a 0.04%-0.167% decrease in nondrug spending in Medicaid,26 while in Medicare, estimates vary—the Congressional Budget Office suggests that a 1% increase in drug spending may lead to 0.2% decrease in utilization,27 and Shang and Goldman (2007) suggest that a $1 increase in prescription drug spending is associated with a $2.06 reduction in medical costs.29 Although these studies are focused on different populations (Medicare and Medicaid) than ours, they suggest that increased medication use may substitute or prevent the need for health care utilization, although it is unclear whether medical savings are completely offset by increased drug costs, especially among commercial enrollees.Third, we did not have adequate access to pharmacy utilization and cost data for our carve-out clients, so we were unable to compare the effect of carving in pharmacy benefits on pharmacy claims and costs. It is therefore unclear whether medical savings translate to total cost savings or whether savings from medical costs may have been substituted by or offset by increased drug costs, thus, leading to similar or increased total costs. The literature on the relationship between medical and pharmacy costs suggests that increased drug costs may offset nondrug savings but to varying degrees.As employers attempt to understand the value of carving in versus carving out pharmacy benefits to health plans, our findings suggest that carve-in members have reduced medical costs and utilization compared with their counterparts. Taken together, our findings can be instrumental in informing employer decision-making processes and, in turn, reducing costs of care for the health care system.


Hypertension can have its origin in early life. During pregnancy, many metabolic alterations occur in the mother that have a crucial role in fetal development. In response to maternal insults, fetal programming may occur after metabolic disturbance, resulting in programmed hypertension later in life. Maternal dietary nutrients act as metabolic substrates for various metabolic processes via nutrient-sensing signals. Different nutrient-sensing pathways that detect levels of sugars, amino acids, lipids and energy are integrated during pregnancy, while disturbed nutrient-sensing signals have a role in the developmental programming of hypertension. Metabolism-modulated metabolites and nutrient-sensing signals are promising targets for new drug discovery due to their pathogenic link to hypertension programming. Hence, in this review, we pay particular attention to the maternal nutritional insults and metabolic wastes affecting fetal programming. We then discuss the role of nutrient-sensing signals linking the disturbed metabolism to hypertension programming. This review also summarizes current evidence to give directions for future studies regarding how to prevent hypertension via reprogramming strategies, such as nutritional intervention, targeting nutrient-sensing signals, and reduction of metabolic wastes. Better prevention for hypertension may be possible with the help of novel early-life interventions that target altered metabolism. Hypertension is nowadays a top risk factor for cardiovascular disease (CVD) ,2. ThougHuman and animal evidence reveals that hypertension could have its origin in prenatal life and in early childhood ,6. NowadThe major functions of metabolism are: energy production; the conversion of nutrients to carbohydrates, proteins, and lipids; and the elimination of metabolic wastes. Hypertension is connected to impaired metabolic homeostasis , althougThe aim of our review was to provide insight into how maternal nutritional insults and metabolic wastes impact offspring hypertension, what are the mechanisms behind hypertension programming, and what is our potential strategy for targeting metabolic changes to prevent hypertension.Maternal nutrition has substantial implications for fetal development. It not only affects the maternal metabolic adjustment capacity to the hormones secreted by the placenta but it is also the only way for the fetus to get the required nutrients. Requirements for quite a lot of nutrients rise during gestation to meet maternal and fetal demands, which require an increased consumption.During gestation many metabolic alterations occur in the mother that are created for supporting fetal development. For example, the mother becomes less reactive to insulin, resulting in increased glucose availability to the fetus in late gestation. Dietary proteins perform a broad spectrum of metabolic and biological functions. In addition to being the basic building blocks of proteins, amino acids are involved in the regulation of blood pressure (BP), lipid metabolism, food intake and immune function . In earlHypoaminoacidemia happens in gestation during fasting, especially glucogenic amino acids ,14. The Moreover, fetal metabolic wastes are transferred into the maternal circulation via the placenta and eliminated by maternal urination. Accordingly, neonates born to mothers with chronic kidney disease (CKD) are at risk for preterm birth, low birth weight, small size for gestational age, stillbirth and neonatal mortality .Both undernutrition and overnutrition during pregnancy have increased risk for hypertension in later life. Macronutrients are nutrients that people require in large quantities to generate energy, mainly carbohydrates, proteins and fats. Unlike macronutrients, micronutrients are vitamins and minerals which are consumed in small quantities, but are nonetheless essential for physical function. Emerging human and animal evidence supports the idea that excess or deficits in specific nutrients are related to hypertension of developmental origins.Overnutrition refers to a type of malnutrition caused by consuming too much of a certain nutrient, particularly in an imbalanced ratio. Today, only a few human studies have surveyed the impact of excessive intake of a certain macronutrient during gestation on adverse offspring outcomes. Prior work revealed that a high protein diet in gestation is associated with hypertension in adulthood ,24,25. AVarious animal models have been established using insufficient or excessive intake of a specific nutrient during gestation and/or lactation to validate the associations between maternal malnutrition and offspring hypertension found in human observational studies. Here, we summarize current knowledge on maternal malnutrition-induced offspring hypertension in various rodent models  26,27,2,53,54,55There are different methods used for inducing malnutrition in pregnancy and fetus. The most well-established are 2 models of maternal under-nutrition  and some models of maternal over-nutrition. These maternal over-nutrition models, which are typical of the Western diet , result in a disturbed fetal nutritional environment and metabolism . This inCaloric restriction refers to a reduction in caloric intake without incurring deprivation of essential nutrients. Similar to prior research on the effects of famine in humans, restricting caloric intake to 30–70% of normal in pregnant rats caused hypertension in their adult offspring ,27,28,29On the other hand, over-nutrition arising from excessive intake of specific nutrients can lead to hypertension programming . FeedingWorthy of note is that hypertension programming can be induced by maternal malnutrition and disturbed metabolism in a variety of animal models. No matter what type of nutritional imbalance, they produce the same end result–hypertension. These observations reveal there might be common mechanisms underlying hypertension programmed by maternal nutritional insults.The biochemical parameters of waste products in the form of blood creatinine and urea demonstrated a significant drop from the pre-pregnancy values by 24 weeks of pregnancy, but the values later rise in the third trimester in contradistinction to the basically expected trends . The excThe prevalence of CKD in women of childbearing age is around 3%–4% . HoweverMammalian cells have various ways of sensing energy and essential cellular nutrients such as amino acids, glucose, and lipids. The sensing of nutrient signals is the key factor for whole-body metabolic homeostasis . MaternaTo ensure cellular metabolism, the ATP level must be tightly regulated within a proper range. AMP-activated protein kinase (AMPK) appears to achieve this coordination . AMPK isEmerging evidence suggests that dysregulated AMPK signaling pathway is connected to developmental programming of hypertension, whereas AMPK activation in early life helps prevent offspring’s hypertension . In sponMammals depend on several approaches to maintain glucose concentrations within a narrow physiological range. Multiple mechanisms of glucose sensing exist to tightly regulate the intake, storage and breakdown of glucose by different organs. Additionally, a network of hormone signals, exemplified by glucagon and insulin, seek to coordinate orderly responses to systemic glucose concentrations in distant organs. AMPK is known to participate in controlling glycogen and glucose metabolism.Unlike glucose, fructose is specifically and passively transported by the facilitative glucose transporter 5. So far, the role of glucose transporters in hypertension remains largely unknown. Despite the similarity in their structures, fructose and glucose are metabolized in different ways. Using the maternal high-fructose diet model, we utilized RNA next-generation sequencing (NGS) technology to investigate the transcriptome expression in several organs ,80,81. WAmino acids are the building blocks for proteins. Placental amino acid transporters regulate their exchange from the maternal to the fetal circulation ,83. As rThe availability of amino acids is highly dependent on the mechanistic target of rapamycin (mTOR) . mTOR fuLipid metabolism refers to activities from uptake of lipids in the gut to cellular uptake and transport to compartments such as mitochondria. Phosphoinositides are lipid signaling molecules that act as master regulators of cellular signaling. The phosphoinositide signaling system is common to many vasoconstrictor agents and as such is influential in the regulation of BP . HoweverSod2, Sirt7, Ren, Nrf2, Nos2, Nos3 and Sgk1 [Several nuclear hormone receptors are lipid-sensing factors that influence lipid metabolism . The livand Sgk1 . Additioand Sgk1  and mateand Sgk1 . ConsideThe sensing of free fatty acids is through G-coupled protein receptors (GPRs), also referred as free fatty acid receptors (FFARs) . Short cIn a maternal high fructose diet model, the elevation of offspring’s BP was accompanying by decreased renal GPR41 and GPR43 expression . AnotherIt is well-known that supplementation with long-chain omega-3 polyunsaturated fatty acids (PUFAs) is associated with reduced cardiovascular risk . PUFAs fIn addition to nutrient-sensing signals, several molecular mechanisms involved in hypertension programming have been proposed based on prior research, covering oxidative stress , nitric As detailed descriptions of these mechanisms are beyond the scope of this paper, readers are referred elsewhere for more in-depth information. A schematic summarizing the dysregulated nutrient-sensing signal and its interconnected molecular mechanisms linked to developmental programming of hypertension is presented in Emerging evidence reveals a highly disturbed metabolism in different pathways in response to multiple maternal insults, resulting in programmed hypertension. These data point to new potentially causal mechanisms behind metabolic programming, which can be further investigated in the search for new ways of preventing hypertension.As for our current understanding of the DOHaD theory, it turns out that control and prevention of hypertension can be initiated early before the onset of hypertension in early life stage-fetal periods, namely reprogramming . ParticuIt is well known that optimal maternal nutrition is essential for supporting fetal growth and development. Accordingly, the above-mentioned risk factors regarding maternal malnutrition illustrated in Nutritional supplementation interventions starting during gestation as a reprogramming intervention to avert developmental programming of hypertension in rodent models are listed in G-nitro–L-arginine methyl ester (L-NAME) administration [2S), early-life cysteine supplementation is a way to produce endogenous H2S and prevent the developmental programming of hypertension [First, taurine has several potentially beneficial effects against hypertension that include the regulation of NO, oxidative stress, and the RAS . Previoustration . Moreovestration ,123,124.stration . As cystrtension .Although current hypertension guidelines recommend the adoption of dietary modifications in patients with elevated BP , whetherDuring pregnancy and lactation, milk and dairy products consumption is a major source of source of protein and other nutrients. A systematic review of 20 studies indicated that maternal milk and dairy products intake during pregnancy is positively associated with fetal outcome . Due to Several types of lipids have been utilized as reprogramming interventions for programmed hypertension in experimental studies. Conjugated linoleic acid is a microbial metabolite coming from dietary PUFAs. Conjugated linoleic acid supplementation in gestation and lactation protected adult rat offspring against high-fat diet-primed offspring hypertension . AnotherThere are some carbohydrates being utilized to prevent offspring’s hypertension as reprogramming interventions. Some known prebiotics (inulin or oligosaccharides) are low digestible carbohydrates . PerinatSeveral vitamins and trace elements show cardiovascular benefits . Unlike Dietary sodium and potassium intake is also involved in the regulation of BP. Prior work revealed that a diet that reduces salt intake while enhancing potassium consumption is able to control or prevent hypertension . NeverthThere are several functional foods that can improve hypertension as well as metabolic abnormalities ,144. ForAdditionally, plants produce polyphenols, which are considered essential functional foods in our diet. As we reviewed elsewhere , severalMalnutrition and disturbed metabolism in early life can impair nutrient-sensing signals that have a fundamental impact on fetal metabolism and development. Interventions targeting AMPK or PPARs signaling have been reported to avert the development of hypertension in a variety of developmental programming models.Both indirect and direct AMPK activators have been examined in developmental programming of hypertension. Indirect AMPK activators refers to modulators that cause AMP or calcium accumulation without a direct communication with AMPK . Some inOf note, resveratrol recently received great attention as a reprogramming intervention not only against hypertension but also metabolic syndrome ,153,154.A growing body of evidence indicated that PPARs have a key role in the pathogenesis of many metabolic disorders, and their ligands have therapeutic potential in restoring these metabolic disorders ,156,157.Uremic toxins are metabolic wastes that accumulate in subjects with impaired kidney function. The major uremic toxins contributing to hypertension programming are TMAO, ADMA, and tryptophan-derived metabolites ,163,164.TMAO is a gut microbiota-derived uremic toxin and its level correlates with CVD mortality . TMAO prAnother uremic toxin is ADMA. ADMA is increasingly recognized as a biomarker of CKD and hypertension ,171. We Maternal treatment with melatonin , aliskirTryptophan-derived uremic toxins, mostly derived from the kynurenine and indole pathways, have been closely linked to cardiovascular risk in patients with CKD . IndoxylConsidering that tryptophan-derived uremic toxin are ligands for AHR and that AHR activation is associated with hypertension programming ,179, AHRCurrent evidence has indicated the impact of maternal metabolic disturbance in the developmental programming of hypertension. This review sought to highlight potentially causal mechanisms behind underlying disturbance of metabolism during fetal development and adulthood hypertension. Reflecting current knowledge, our review further opens new avenues for prevention of hypertension via targeting disturbed metabolism underlying hypertension programming.While prior work has generated ample evidence on the impact of disturbed metabolism during fetal development on the development of adulthood hypertension, it is still uncertain whether and why restoration of metabolic imbalance occurring early in life would benefit offspring outcomes, especially hypertension.In the future, we recommend bridging the gap between human and animal research through a focus on reprogramming strategies targeting metabolism-modulated metabolites and nutrient-sensing signals. There is presently scant information on how various reprogramming strategies obtained from animal research might be used in pregnant women. Longitudinal analysis of metabolites, nutrient-sensing signals-related biomarkers and detailed background data are of the greatest importance in studying the time window effects of maternal metabolic disturbance on offspring hypertension; this research can aid in design of hypothesis-driven interventions and ideal timing of their administration.These are imperative questions to answer, considering early-life preventative interventions targeting restoration of metabolic disturbance might provide novel therapeutic opportunities to reduce the global burden of hypertension.


Post-allograft transplant antirejection regimens  may trigger or aggravate hyperglycemia or hyperlipidemia. Post-transplant medication management must balance immune suppression and glucose and lipid control because the existence of glucose or lipid imbalance is associated with shorter times of useful allograft function. We review the underlying mechanism of relationships between glycemia/lipidemia control, transplant rejection and graft aging.Although solid organ transplantation in persons with diabetes mellitus is often associated with hyperglycemia, the risk of hyperlipidemia in all organ transplant recipients is often underestimated. The diagnosis of diabetes often predates transplantation; however, in a moderate percentage of allograft recipients, perioperative hyperglycemia occurs triggered by antirejection regimens. Post-transplant prescription of glucocorticoids, calcineurin inhibitors and mTOR inhibitors are associated with increased lipid concentrations. The existence of diabetes mellitus prior to or following a liver transplant is associated with shorter times of useful allograft function. A cycle involving Smad, TGF beta, m-TOR and toll-like receptors has been identified in the contribution of rejection and aging of allografts. Glucocorticoids (prednisone) and calcineurin inhibitors (cyclosporine and tacrolimus) induce hyperglycemia associated with insulin resistance. Azathioprine, mycophenolate and prednisone are associated with lipogenesis. mTOR inhibitors (rapamycin) are used to decrease doses of atherogenic agents used for immunosuppression. Post-transplant medication management must balance immune suppression and glucose and lipid control. Concerns regarding rejection often override those relative to systemic and organ vascular aging and survival. This review focuses attention on the underlying mechanism of relationships between glycemia/lipidemia control, transplant rejection and graft aging. Despite diabetes mellitus being the most prevalent underlying condition requiring transplantation, all solid organ recipients are subject to hyperlipidemic vascular complications. Underlying mechanisms explaining vascular risk associated with immunosuppressive antirejection medication have not been widely disseminated.Type 2 diabetes mellitus, predominantly a state of insulin resistance with increased lipogenesis, is initially associated with hyperinsulinemia that may decrease with time. We now recognize subtypes of type 2 diabetes that may be characterized by remission: gestational remitting with delivery, obesity-related remitting with bariatric surgery and steroid or immunosuppression related remitting with therapy cessation. In some patients, the appearance of hyperglycemia exposes a trait that may lead to the well-known complications of diabetes . However, in others, prolonged follow-up does not result in these complications. The prognostic impact of these subtypes within the transplant population is unknown.In the 50 years of genetically non-related kidney transplantation, there was a gradual acceptance of recipients with diabetes mellitus, followed by awareness that hyperglycemia and infection were important side effects of immunosuppression . The US Individuals with type 1 diabetes mellitus were younger, demonstrating higher survivals at these time intervals . Among over 10,000 persons with native kidneys, diabetes and hypertension, modulation of medication dosages for control of hyperglycemia was noted to be related to the estimated glomerular filtration rate . ModulatMammalian target of rapamycin (mTOR) is a complex of protein kinase signal molecules that promote kidney disease. Located in the glomerular podocyte and mesangial cell, mTOR is involved in the generation of diabetic nephropathy . The mTOThree excellent articles introduce the topic of medications for immunosuppression with the timeline of post-transplantation hyperglycemia ,18,19. TThe medication most often associated with hyperglycemia or the concept of “new onset diabetes after transplantation” in the years after kidney transplantation is prednisone . MechaniAs a result of the mechanisms listed in Rapamycin and other mTOR inhibitors eliminate the insulin resistance associated with protein kinase-related hypertriglyceridemia . This meThe Banff Human Organ Transplantation study identified the peritubular portion of the capillary as the target for antibody attack in chronic active transplant rejection of kidney allografts ,39. The Investigators have described a cascade: Smad → TGF Beta → mTOR → mesangial collagen fibrosis inhibited by rapamycin . This raFurther investigation into the role of the important member of mTOR, the protein kinase PKC, was centered upon early diabetic nephropathy  in the STZ diabetic rat. At this early stage, innate immunity (toll-like receptors) was activated along with cytokines of inflammation (interleukin 17). Inhibition of Protein Kinase C by rapamycin was associated with the blockade of progression of nephropathy in this experimental model of Type 1 diabetes mellitus . There iPericardiac and perirenal fat are predictors of atherosclerotic pathology affecting cardiovascular outcomes and renal function. When perirenal fat volume was studied, live donor renal grafts with higher fat volume resulted in lower estimated GFR than those with lesser perirenal fat volume .Cholesterol is essential for the structure of the glomerular podocyte diaphragm, which functions to select molecules for excretion versus those to be retained. Excess levels of ceramide, a sphingolipid, can be destructive to the ability to discriminate solutes critical for excretion from those appropriate for retention . IncreasIt stands to reason that some of these pre-transplantation mechanisms will be operating after transplantation, depending upon the choice of immunosuppression . The proAlthough liver insufficiency does not commonly occur after a kidney transplant, renal insufficiency may occur after a liver transplant. Among twelve liver allograft recipients studied before and after transplant, an observed fall in the glomerular filtration rate (GFR (27%) was not due to dehydration or heart failure as evidenced by increases in both somatic blood flow (RBF) and oxygen utilization following transplantation .Follow-up of recipients of liver allografts indicates significantly better results for those without a diagnosis of diabetes mellitus compared to those with diabetes mellitus . PretranSince some of the mechanisms of lipogenesis are associated with excess nutrition or elevated glucocorticoid dose, there is a chance for recurrence of the process after transplantation. Excessive caloric intake or toxic ingestion results in steatosis/fibrosis of the allograft. There is no evidence for allograft-related lipogenesis .Glucocorticoids contribute to lipogenesis by the conversion of skeletal muscle amino acids through acetate to glycogen via glycogen synthase. Similarly, glucocorticoids organize the conversion of skeletal muscle amino acid through acetate to palmitate with the stimulation of fatty acid synthase ,62,63. NMinimal to moderate hyperglycemia following solid-organ transplantation may not require treatment and may not ordinarily be called post-transplant diabetes mellitus ,68. A keWhen kidney allograft function falls below an estimated glomerular filtration of 60 mL/minute , there iSince the estimated glomerular filtration rate (eGFR) may change rapidly with unrelated kidney allografts, doses of antihyperglycemic medications may require rapid change. Insulin is metabolized and excreted by the kidney, and levels rise with deceasing allograft function. C-Peptide, also renally excreted, is a more reliable measure of circulating insulin that is removed in part with hepatic passage through the liver. The glucose/C-Peptide ratio is useful in decisions of doses of medications for glucose control, especially when eGFR is changing . The norIn rare instances, all doses of medications for glucose control are discontinued as eGFR is falling , leadingPost-transplant prescription of glucocorticoids (prednisone and dexamethasone), calcineurin inhibitors (cyclosporin and tacrolimus) and mTOR inhibitors (sirolimus and everolimus) is associated with increased lipid concentrations. Glucocorticoids increase triglycerides through the inhibition of lipoprotein lipase, calcineurin inhibitors also inhibitors lipoprotein lipase . Lower lIn addition to the well-known adverse cardiovascular outcomes of long-term hyperlipidemia and their reduction with lipid-lowering agents, there is now significant research linking elevated lipids to allograft rejection and vasculopathy ,81,82,83Hyperlipidemia following solid organ transplant is a consequence of the interaction of immunosuppressive agents, genetic predisposition and diet/obesity . Each grDespite significant animal model and human research linking adverse cardiovascular outcomes to hyperlipidemia, there are no allograft-recipient-specific guidelines for the control of hyperlipidemia.Generally, kidney and liver transplant candidates are chosen because their risk of cardiovascular events is low. For this reason, trials of preventive therapies often do not have sufficient cardiovascular events to produce meaningful statistical differences in benefits . For patThe presence of diabetes or hyperlipidemia of either long duration or accompanying the requirement for organ replacement therapy is associated with elevated risk to allograft function ,87. GlycIncreased risk for kidney allograft rejection is partially due to increased activity of the inflammation cascade. Activation of the pathway known as mammalian target of rapamycin occurs in persons with diabetes mellitus. This leads to increased inflammation, which contributes to allograft rejection. The Banff Transplantation Study has identified the capillary pericyte as the most sensitive site for antibody attack in chronic, active allograft rejection. We can conclude that a diagnosis of diabetes mellitus, before or after the initiation of immunosuppression, contributes to the risk of loss of allograft function, with the capillary pericyte as a major focus of pathogenesis. A cascade combining several factors in kidney fibrosis included sMAD → TGF Beta → mTOR → mesangial collagen. Rapamycin was protective by blocking the process of fibrosis, but the rapamycin effect could be over-ridden by the over-expression of HIF .Beyond the scope of this review are gestational diabetes , obesity


The rhizobiome typically consists of microbiota  and small soil animals (nematodes and microarthropods), which all directly or indirectly interact with plants and affect plant performance , and the endosphere. Their results demonstrate that, as expected, rhizosphere communities are a subset of bulk soil communities, but rhizoplane communities consist of both rhizosphere and endosphere microbes. They further demonstrate that endosphere bacterial communities are most influenced by environmental variables such as phosphorous (P), potassium and nitrogen, while endosphere fungal communities are mostly driven by plant genetic variables.Studies examining plant-rhizobiome interactions mostly focus on biotic communities occurring either inside or outside the roots. In their study, Huang et al. studied how two species of ectomycorrhizal truffles (Tuber) affected the growth and physiology of Castanopsis rockii seedlings and bacterial communities in the rhizosphere. Their study shows that colonization by both fungi improved key leaf traits  and increased bacterial richness in the rhizosphere. Yet, the authors also observed species-specific effects of truffle species on plant physiology, in line with their distinct effects on bacterial communities, indicating that ectomycorrhizal fungi play an important role in shaping rhizosphere communities.In addition to understanding how the rhizobiome is shaped by the plant, it is important to examine the impacts of key rhizobiome members on plant physiology, as changes in plant traits may in turn reshape rhizobiome community composition. Huang et al., Han et al. demonstrated species-specific effects on plant-microbe interactions, when studying arbuscular mycorrhizal (AM) fungi in the roots of poplar (Populus) species. They demonstrated that in parallel with changes in soil nutrient levels, AM fungal communities in roots changed within a year, being more species-rich and diverse in fall than in spring. They also reported that AM fungal communities vary between poplar species and between life stages within species. The authors suggest that this variation can be related to the variation in root structures, but this needs further research. Additionally, it needs to be considered, that as poplar species are simultaneously colonized by arbuscular mycorrhizal fungi, understanding the dynamics of entire fungal communities can be key for unraveling plant-microbe interactions with these host plants.Similarly to Persea americana) production, Villar-Moreno et al. studied the potential of synthetic community assembly of bacterial Pseudomonas chlororaphis strains to protect avocado roots against the phytopathogenic fungus Rosellinia necatrix. Combining in vitro and in vivo experiments, they showed that a synthetic community of three P. chlororaphis strains, extracted from avocado rhizospheres, successfully colonized avocado roots and suppressed R. necatrix infection. However, pathogen suppression by the synthetic community was as strong as that of an already-known pathogen-suppressive P. chlororaphis strain, leaving the question whether synthetic communities can provide additional pathogen suppression effects, open for now.Knowledge on which rhizobiome members promote plant performance may be used to modify rhizobiome communities and enhance plant health. Aiming for more sustainable avocado (Ji et al. looked at the transcriptional changes in roots and leaves of wheat plants treated with beneficial rhizobacteria Bacillus velezensis JC-K3 and Bacillus subtilis HG-15 in ambient conditions and under salt stress. The authors reported that the genes that were differentially expressed in treatments with bacteria are associated with the metabolism of carbohydrates, amino acids, secondary compounds and signal transduction pathways. They suggest that the rhizobacteria used in their study may have ameliorative effect on wheat in case of salt stress, by promoting growth and improving disease resistance, as seen by the expression of specific genes important for these functions.The importance of understanding how we can use microorganisms to promote plant performance under abiotic stressors is more important than ever. To advance this knowledge, Abbasi discussed different adaptations that plants have evolved to scavenge for P under drought. Abbasi also discussed different abiotic and biotic factors that improve or reduce P uptake by the plant, pointing out that soil fungal communities play an essential role in P availability to the plant, sometimes leading to increased plant pathogen resistance. Moreover, the author summarized the evidence for contributions of P-solubilizing bacteria to plant P acquisition and the effects of other rhizobiome members on the establishment of these bacteria. Abbasi proposed that future studies should focus on exploring the putative role of P-solubilizing bacteria in plant adaptation to arid environments, which become more widespread under climate change.In areas where soil moisture is limited, plant access to nutrients, especially P, is particularly challenging. In a review article, As seen from the variety of studies in this Research Topic, plant performance is indisputably affected by many factors that shape the rhizobiome. In accordance with the nature and specificity of plant-rhizobiome interactions, studies in natural ecosystems such as forests are more focused on exploring the importance and drivers of microbial interactions with the plants, while studies in agricultural settings are focused on exploring the application of microbial communities to enhance plant performance. We believe that each of these study types is important to enhance our understanding on different aspects of plant-rhizobiome interactions and encourage research to combine the knowledge obtained from natural and agricultural systems to advance current understanding in host-microbe interactions in the rhizosphere.OT: Writing – original draft, Writing – review & editing. KK: Writing – original draft, Writing – review & editing. RW: Writing – original draft, Writing – review & editing.