Advances in molecular tumour diagnostics and the number of targeted therapies increase rapidly. Molecular tumour boards (MTBs) are designated to interpret these data and provide clinical recommendations. Not all patients with cancer have access to advice of an MTB. We aimed to determine the current status, opportunities, and challenges of the organisation of MTBs in the Netherlands. We interviewed several stakeholders about their experiences with an MTB, using template analysis. Most clinicians and patient representatives underscore the significance of an MTB, because it can stimulate rational treatment options, enrolment in clinical trials, and interdisciplinary knowledge transfer. Health insurance companies and financial managers are concerned about increasing costs. Registries to assess the clinical benefit of MTBs, guidelines on quality control, financial agreements, and logistical resources are lacking. The national organisation of MTBs and a registry of molecular and clinical data are important issues to address. To aid medical specialists in the highly complex field of molecular biology and clinical care, molecular tumour boards (MTBs) discuss the clinical relevance of genetic aberrations with detailed genomic explanation and treatment options. However, a recent survey shows that the advice of an MTB is not accessible for all patients in the Netherlands and that MTBs vary greatly in composition, tasks, tools, and workflow.We interviewed different stakeholders in the Netherlands about their experiences with an MTB, using a qualitative approach, applying template analysis  Improvement of patients’ outcomes by providing a multidisciplinary tailored-based treatment advice. (2) Continuous interdisciplinary knowledge transfer. (3) Cost-saving by predictive diagnostics preventing ineffective therapy. (4) Facilitation of scientific output. The patient federation encourages early referral to an MTB, as this can provide personalised (extra) treatment options and improve enrolment in clinical trials.Some medical oncologists are more sceptical about the current significance of an MTB. (1) Most of their patients are discussed with late stage disease, which can limit treatment possibilities. (2) In contrast to many lung tumours, treatment options for other solid tumours are more limited. (3) Many current medical oncologists in training have not attended an MTB yet and do not have a clear vision of the potential of an MTB. (4) Appropriate palliative care can be delayed while waiting for an MTB advice. (5) Most clinicians from non-MTB centres and medical oncologists in training experience off-label prescription based on an actionable tumour mutation as an undesirable situation. However, others regard an MTB as a suitable forum to centralise and regulate off-label prescriptions and the patient federation experiences off-label prescription as an act of bravery of their treating physician.Interdisciplinary collaboration is regarded as crucial and participation of a clinical scientist in molecular pathology is considered indispensable. In many MTBs, the treating clinician of the patient who is discussed is absent and relevant clinical information can be insufficient. Some MTB-centres favour more regional collaboration in order to increase the patient number of their MTB, while other MTB-centres with extensive regional collaboration do not have time for further expansion.For the future of MTBs, some respondents propose to maintain tumour non-selective MTBs in every specialised cancer centre and design only one central MTB in the Netherlands for high-complex cases. Alternatively, molecular expertise may be integrated more within the existing tumour-specific oncology boards.All respondents agree that evaluating the quality of an MTB is crucial to gain maximal clinical benefit. The following items warrant regulation and evaluation: (1) the goals of an MTB, including which patients will be referred, (2) the composition of an MTB, (3) registration of clinical outcomes, (4) type, quality, and validation of molecular diagnostic procedures used.Financial managers in the hospitals and representatives of health insurance companies are concerned about increasing costs of diagnostics and medication and stress the importance of evidence for the benefits of MTBs. Respondents did not express need for financial compensation for the time spent on the MTB. In community hospitals prescription of medication off-label often is not possible due to financial constraints. Health insurance companies are willing to reimburse (part of) the costs of molecular diagnostics and treatment, provided that certain conditions are satisfied: (1) criteria for referral to an MTB, (2) insight in the clinical outcomes, and (3) adherence to diagnostic quality demands and the composition of the MTB. Furthermore, in their opinion, pharmaceutical companies should contribute to reimbursement, as they benefit from an increase in the prescription of therapeutic agents. Ultimately, decisions on finances should be made on a national political level.Logistical support is required for coordination of the MTB, facilities, and reports. A simple and widely accessible registration procedure is important. Most respondents believe an MTB report should have a description of the molecular method, a conclusion of the data with a treatment advice, and reference to supporting scientific literature. Some physicians from non-MTB centres prefer to attend the MTB to discuss their patient through teleconsulting, while others prefer referral of the patient. Clinicians feel the urge to discuss possible genetic unsolicited findings prior to the application of molecular diagnostics but differ in preferences on the details of this procedure.The most important points of tension as described are summarised in Table 2 Several studies support evidence for the benefits of precision medicine.7 The first randomised study, the SHIVA trial, comparing precision medicine versus conventional therapy, was negative, although this study has considerable limitations. In the Netherlands, the DRUP study (NCT02925234), and in the United States the TAPUR study (NCT0269353), examine the efficacy of targeted agents based on specific mutations and correlate treatment outcome with data on whole gene sequencing. Furthermore, experiences with MTBs have been described by several other centres.12 Our study included five out of seven MTBs in the Netherlands; it would be of interest to extend this research to other countries. We included representatives of the patient federation. Yet, we acknowledge the difference in education concerning current developments in health care compared to many other patients.Most clinicians value the MTB, primarily for the possible extra treatment options it provides for their patients. To improve MTBs, first, an easily accessible national or international registry is needed that collects molecular, treatment and follow-up data. Second, guidelines are needed concerning the molecular diagnostic methods, the provided clinical information, and the composition and organisation of the MTB. Third, financial arrangements for off-label drugs are a prerequisite to enable financial sustainability. Finally, regional collaboration is crucial in order to assure accessibility to an MTB for every eligible cancer patient. The large variety we observed in MTBs is in agreement with other studies.In conclusion, a well-designed MTB contributes to more extensive personalised treatment options for patients, and furthermore, guides clinicians in their decision-making based on ongoing biotechnological advances. For financial reimbursement of MTB-guided care by insurance companies and governmental organisations, the implementation of quality guidelines and evidence of the clinical benefit of MTB-guided treatment are crucial.Supplementary material


The annual deep brain stimulation (DBS) Think Tank aims to create an opportunity for a multidisciplinary discussion in the field of neuromodulation to examine developments, opportunities and challenges in the field. The proceedings of the Sixth Annual Think Tank recapitulate progress in applications of neurotechnology, neurophysiology, and emerging techniques for the treatment of a range of psychiatric and neurological conditions including Parkinson’s disease, essential tremor, Tourette syndrome, epilepsy, cognitive disorders, and addiction. Each section of this overview provides insight about the understanding of neuromodulation for specific disease and discusses current challenges and future directions. This year’s report addresses key issues in implementing advanced neurophysiological techniques, evolving use of novel modulation techniques to deliver DBS, ans improved neuroimaging techniques. The proceedings also offer insights into the new era of brain network neuromodulation and connectomic DBS to define and target dysfunctional brain networks. The proceedings also focused on innovations in applications and understanding of adaptive DBS (closed-loop systems), the use and applications of optogenetics in the field of neurostimulation and the need to develop databases for DBS indications. Finally, updates on neuroethical, legal, social, and policy issues relevant to DBS research are discussed. Neuromodulation of brain structures and functions is an evolving field. Ongoing scientific and technological advancements have facilitated an improved understanding of brain networks and the neural signals involved in the signs and symptoms of a number of neuropsychiatric conditions. Novel methods of electrical current delivery have been recently applied to existing neuromodulation techniques in order to improve the understanding and the ability to more precisely affect mechanisms, function and to influence cortical and subcortical structures. The deep brain stimulation (DBS) Think Tank is an annual forum that facilitates discussion and debate about the latest scientific, technological, ethico-legal issues, social innovations, challenges, and opportunities in the field. The Sixth Annual DBS Think Tank was held in Atlanta, GA, United States from 6 to 8 May, 2018. The meeting focused on the use of novel modulation techniques and emerging areas of scientific, technological, ethical, and policy development. Specifically, the meeting addressed issues and possibilities of modulating different neuronal networks; expanding capabilities of responsive (closed-loop) DBS systems; and the therapeutic potential of targeted brain network modulation. Particular emphasis was placed upon advances and gaps in knowledge of and capabilities to affect brain electrophysiology, interface optogenetics and DBS, and on the multiple  factors that can limit and/or de-limit these domains. We divided current proceedings in seven separate sections discussing advances in the field as follows: connectomic and network neuromodulation, advances in neurophysiological signals for DBS, new neuromodulation techniques, applications of optogenetic techniques in DBS, databases for DBS, and neuroethical, Legal and social issues in DBS.Different stereotactic techniques are commonly used to assure proper localization of subthalamic (STN-DBS) leads in Parkinson’s disease (PD), including anatomical neuroimaging and indirect stereotactic methods. However, therapeutic benefits are likely the result of engagement and modulation of other brain regions that are interactive with specific stimulation sites and networks . An imprn = 1,030) and PD patients (n = 90)] Recent works highlight the importance of modulating the hyperdirect pathway (connecting the STN to cortex) in the effectiveness of STN-DBS . UtiliziSimilarly, this technique can be used to explore or refine DBS targets and theoretically to avoid or reduce side effects of neuromodulation . CognitiThis technique can also be used in DBS treatment of other conditions. For example, chronic-progressive gait ataxia in patients with essential tremor (ET) can be reversed following prolonged DBS washout, and is likely due to a stimulation-induced vestibulo-cerebellar network dysfunction . Using vDeep brain stimulation of the subcallosal cingulate (SCC) has recently shown promise for the treatment of therapy-resistant depression , acting As previously stated, it is becoming increasingly evident that the benefits of DBS for disorders such as ET and PD depend on the connectivity of the site of stimulation with other brain networks and regions . InsightMethods for evaluating connectivity include both anatomical (diffusion tensor imaging and tractography) and functional techniques . One of the earliest demonstrations of such DBS targeting was the application of connectivity-based thalamic segmentation, which revealed discrete thalamic regions with distinctive connectivity patterns with cortical regions . SubsequWhile the use of tractography-guided thalamic targeting for ET has been a powerful proof of concept, an additional practical utility lies in the potential of using such approaches to either optimize therapies that have been inconsistent to date, or to develop novel applications. For example, thalamic DBS for pain is associated with inconsistent efficacy, possibly due, in part, to the lack of optimized targeting. To gain insight to the potential value of tractography-guided thalamic DBS targeting for pain, a small retrospective analysis of five patients was performed. It was shown that the pain patients who derived benefit from thalamic DBS for their pain had DBS leads that co-localized with those thalamic regions with maximal connectivity with the post-central gyrus . LookingOther studies have investigated DBS targets other than the thalamus. Investigators have mapped the hyperdirect pathway from the primary motor cortex to STN, based on the hypothesis that the optimal site of STN stimulation is the site of hyperdirect pathway input. To further explore this hypothesis, hyperdirect pathways and associated STN target maps generated by two different tractography approaches  were compared . Both idBrain networks can also be evaluated using both non-invasive and invasive neurophysiologic methods . There hNeuropsychiatric disorders are increasingly being viewed as node and network-level brain dysfunctions. Apropos such a perspective, there is renewed enthusiasm for understanding the complex anatomical and functional bases of particular neuropsychiatric states and conditions. Extant, simplistic classifications of neuropsychiatric disorders based solely upon patient signs and symptoms have been limited, at best, and clinically ineffective and inefficient as worst, and therefore a taxonomy based on orthogonalized axes of psychological constructs and neural circuit dysfunction may be better suited  in affording a more rational (and testable) basis for developing new therapeutic methods and approaches, inclusive of DBS.A number of brain networks have been implicated in depression, including those subserving the default mode, salience, and negative affect . The conThe study included the use of directional current steering DBS and individualized network targeting; with the aims of demonstrating that this approach to targeting was feasible and safe, and could possibly reduce depressive symptoms. Targeting networks – instead of specific structures – might prove to be crucial to individualizing therapies aimed at modulating specific brain networks important to depression (and other neuropsychopathologies). In this light, specific network modulation may also be viable and of value in treating obsessive compulsive disorder (OCD) . PreviouGiven mounting evidence to support the possibility of obtaining good clinical outcomes in the absence of neurophysiological mapping – and multi-dimensionally ; an important question is what the future of intracranial neurophysiology portends in an era of increasing use of real-time MRI-guided and CT-verified DBS implantation in asleep patients. One possibility is that network mapping, rather than mapping of a single target structure, will be important to improve the efficacy – and ultimate clinical effectiveness and value of DBS. For instance, as evidence emerges for separate networks that may be therapeutically responsive to differential stimulation  , techniqOpportunities for multi-scale, high-resolution neurophysiological data collection are most robust intraoperatively, but assessments are limited by available time and by the physical constraints that restrict the complexity of behavioral tasks which can be engaged . The useNew techniques in tractography are being investigated as methods which can be used to identify aberrant brain networks and potential foci of epilepsy . Using tResting state LFP neural recordings from the PD STN in intra- or peri-operative studies have demonstrated exaggerated oscillatory neuronal activity and synchrony in both the alpha (8–12 Hz) and beta (13–30 Hz) bands . The ext® PC + S, Medtronic, Inc., FDA IDE approved). It has been demonstrated that the transition from the resting state to a moving state  is associated with a change in the LFP spectrum, which was more prominent in the akinetic rigid versus the tremor dominant PD phenotypes  is also an important locus in the pathological network of PD, and is commonly targeted for the treatment of refractory motor symptoms . InvestiThus, current studies aim to improve the closed loop algorithm and to analyze smaller windows of data to test different refresh rates. Detector sophistication will be critical to acquiring and assessing signals, and several critical questions remain regarding whether to employ single threshold or center frequency; the ideal rate of signal updates; ramp and onset times, and the potential for energy savings, technical sources of variance, long term benefit and signal reliability and reproducibility afforded by this technique. Moreover, the increasing complexity of these signals will likely require computerized or algorithmic programing to mitigate long programing visits, and this prompts questions and concerns about capability and use of bio-informatic systems to facilitate these approaches .FOG affects approximately 78% of PD patients and is a major cause of falls, and determinant of quality of life. Animal research suggests that the GPi and PPN contribute to the FOG in advanced PD . DespiteClosed-loop stimulation has similar efficacy to open-loop, and in some contexts, closed-loop stimulation might be better than traditional DBS . ChronicThe Medtronic Activa PC + S device enables the use of a cortical strip for sensing/recording and a DBS electrode for stimulation in the treatment of patients with refractory tremor. The need for tremor control fluctuates greatly during the day and theoretically, a closed loop system could minimize concerns about side effects related to over- and/or under-stimulation . InvestiAlthough DBS treatment of PD is an active field of research, many of the initial challenges and limitations of these treatments continue to be investigated. Meta-analysis of multiple DBS studies showed great variability in lead location . About oThus, it becomes important to ask whether we really know where the target is, and if it is the “best” target. For example, in treating PD, tremor might be more responsive when the STN is stimulated in one subregion, and bradykinesia may improve more with stimulation of another subregion. In a recent study, researchers attempted beta-triggered closed- loop DBS in primates that were engaged in an acute reaching task. It was found that greater improvements in rigidity were obtained using closed- loop DBS , and that rigidity improved more during certain aspects of the movement . These rin vivo by stimulating neurons in the mouse hippocampus without recruiting neurons of the overlying cortex. By altering the currents delivered to a set of immobile electrodes, different motor patterns in living mice could be ‘steerably’ evoked  (DA circuits) ] and the dopaminergic neurons of the dorsal raphe nucleus (DRNDA) . The useircuits) . BidirecDA neurons play a key role in this process  is a key contributor to motor suppressing pathways in the basal ganglia, yet its neuronal heterogeneity has not been engaged as a resource for therapeutic interventions. Optogenetic techniques may enable cell specific identification and stimulation of GPe networks that can be modulated by DBS . The indAddiction can be regarded – at least to some extent – as a neural circuit disorder; functional imaging has identified the cortico-accumbal-pallidal network as a locus of altered resting state connectivity in patients with addiction, and the nucleus accumbens (NAc) has been proposed as a target for DBS . NAc-DBSUnderstanding mechanisms underlying altered functional connectivity in addiction could be leveraged to design targeted neuromodulation protocols to normalize circuit function and abolish behaviors associated with addiction. For example, cocaine exposure potentiates prefrontal cortical inputs to the NAc via the insertion of calcium-permeable AMPA receptors, and optogenetically driving these inputs between 10 and 15 Hz triggers a signaling cascade that reverses this synaptic potentiation and abolishes drug sensitization and seeking . Based oWhile neural stimulation has opened up a new class of therapeutics for a number of neurological and psychiatric diseases, there has been little work to examine how such stimulation could be used to treat Alzheimer’s disease (AD), the most common form of dementia. The lack of research on neural stimulation in AD likely stems from the fact that little is known about how neural activity fails in AD or how neural activity affects molecular pathology. Therefore, to determine how brain stimulation could potentially be used to treat AD, we identified deficits in neural activity in mouse models of AD and determined the effects of neural stimulation on molecular and cellular pathology .Because spatial navigation deficits are one of the earliest symptoms of AD and the hippocampus is one of the neuroanatomical areas first affected by the disease, we examined how hippocampal neural activity changes in AD . Using aTo achieve the same effects non-invasively, we harnessed the neural circuits’ natural tendency to respond to sensory stimuli. While extensive prior work has shown that flickering lights and sound stimuli drive neural activity at specific frequencies in sensory cortices, we have found such flickering sensory stimuli can also drive specific frequencies of neural activity in deeper brain structures, including the hippocampus, albeit with more modulatory effects . Using tThe use of complex, heterogeneous, multi-level and -dimensional data is -and will increasingly be – crucial to realizing the potential of a number of neurotechnologies and their use in clinical practice . RapidlyDropBox model, the Cranial Cloud system is capable of integrating information with currently available and widely used electronic medical record systems . Clinical assessments and anatomical/imaging data can be collected in a standardized method in order optimize compatibility with various atlases and programs. The overall goal is to maintain and advance normalized, consistent and efficient data collection, sharing and analysis soas to both reduce (if not eliminate) constraints imposed by existing systems, and to avoid the time and economic costs of duplicative analyses. Questions remain about the funding source of such an endeavor, but it will likely require collaboration between academic, corporate and government institutions. Concerns about data sharing with third parties will be a challenge for ensuing technologies.Cranial Cloud engages this opportunity by providing a platform to standardize data collection and storage . This pr1. In keeping with this policy, the Blackfynn Scientific Platform functions to standardize data collection in DBS patients, and to make these data more accessible in accordance with existing regulations for data sharing2. As well, this platform can maintain data that would otherwise be lost due to cessation of funding. Blackfynn aims to develop a strong business model to sustain the database independently of short-term funding. This database will enable improved workflow and medical record integration that will appeal to clinicians and researchers. A major feature of the program is its web-based, high performance computing capability, which allows users to maintain possession of their data while simultaneously using the platform for data analysis.National Institutes of Health policy states that data should be widely and freely available, while still maintaining privacy and confidentialityOne example of such successful data collection, storage and sharing is the Parkinson’s Progression Markers Initiative (PPMI), which facilitates rapid exploration and data-driven analysis, rather than exclusively utilizing a hypothesis-driven approach. This database can also be combined with other backgrounds and datasets to examine biomarker overlap and/or to integrate genetic or physiologic data, and can facilitate cooperation and collaboration between the academic and corporate sectors, and can positively impact and be implemented by a variety of stakeholders, including foundations and advocacy groups. These collaborations are – and will be ever more – essential given the resource demands for the sustenance and iterative expansion and improvement of such a large database.The neurosurgical implantation of DBS systems requires a high degree of accuracy in placing electrodes at the identified target sites, and clinical outcomes greatly depend upon the precise localization of special leads and contacts . For exaUltra-high field (UHF) MR acquires images using a generated magnetic field that is equal to or greater than 7T . 7T MRI At the most fundamental level, the aim of development and use of brain implants has been to enable successful intervention against treatment-resistant neurological and psychiatric disorders. Although the underlying rationale and goals of invasive neuromodulation were and remain benevolent, implantation of these devices exposes patients to both the inherent risks of neurosurgery and to the burden and risks incurred through the use of novel technology . There iTo date, such issues have been addressed on a case-by-case basis. In the United States there is no legal obligation to provide continued access to DBS devices or resources. Yet, given that the majority of DBS implantation is undertaken as either a large scale clinical trial, or as a component of investigator initiated research (IIR) studies, the constructs of the Declaration of Helsinki could be utilized to support and reinforce continuity of care under as a component obligation of protecting the best interests of the patient/subject – both during and as a consequence of the research study – as constituent to the conduct of responsible research , 2016. TIndeed, costs of establishing, and supporting continued care could substantially constrain certain sponsors’ ability to pursue research. In turn, such constraints could negatively impact both a sponsor’s engagement in and support of further research, and the potential benefits that such research could provide to the extant and future recipient patient populations at-large. Recent requests for proposals (RFPs) issued via the National Institutes of Health’s programs within the US Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative have mandated that researchers describe the plan for the patient at the end of the study period, and the ethical principles supporting an extended  limited duty of care beyond the research protocol. More specific language is being considered for incorporation into current and future RFPs. But any meaningful discussion of ethics must acknowledge and address economic issues, and so consideration of continued care as a constituent of responsible research must be inclusive of cots and coverage of provision and access, time period of extended care, availability of treatment options and alternatives, development of novel treatments, and the systems in place and operational in order to accommodate the fiscal burdens of such needs and demands.Perhaps one of the more provocative, if not contentious ethico-legal questions is whether DBS “changes” personality, the “self” and in these ways, impairs patient individual autonomy . As wellMoreover, defining “advancement” and “improvement” to establish the groundwork for ongoing research, development and use-in-practice will be essential to a prudent approach to DBS in this era of personalized medicine, global health initiatives, healthcare and technological inequalities, and the expansion of multi-national research and medical tourism opportunities. In this light, such discourse must be international and sensitive, if not responsive, to differing cultural perspectives, needs, philosophies, values, and capabilities . We haveThe field of neuromodulation continues to evolve and ongoing research will shape the scientific landscape. This manuscript represents the views of the participants of the think tank and does not consider all the literature on the topics discussed. As in prior years’ meetings, an anonymous 40 question poll was sent online to evaluate participants’ perspectives and attitudes toward the current and near-term future developments and applications in neuromodulation. Sixty six participants responded. Individual studies were approved by the local Institutional Review Board of participating institutions in this technical report and written informed consent was obtained from all participants.AR-Z, JG, EB, VG, AG, PS, SS, CM, MF, JV, VV-M, UA, LA, HB-S, HM, NP, AHG, AS, MC, GL-M, MR, MAR, LC-Z, P-FD, WC, RG, HC, AK, KB, JW, WD, NH, WD, KF, and MO fulfilled the authorship criteria by substantial contributions to the conception of the work, providing data for the work, revisiting it critically for important intellectual content, approving the final version, and agreeing to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer VV-V declared a past co-authorship with one of the authors MO to the handling Editor.


Health care is optimized when the best evidence base (BEB) is translated into policies whose effectiveness can be verified. Bioinformationdisseminates BEB and is critical to translational health care. The survival of all prokaryotes and eukaryotes, including mammals, andultimately our species, depends upon their ability to adapt to changes in their micro-environmental milieu and to the challenges of theirsurrounding macro-environment. Disturbances in the organism's macro-environment, such as the stressful stimuli derived fromenvironmental changes akin to the current climate crisis, alter its physiological, cytological, biological, epigenetic and molecularmicroenvironment, and trigger concerted allostatic responses to regain homeostasis. Individual patient data analysis advocates theallostasiome as the specific pattern of biological events and pathways each individual organism undergoes to regain a balanced state ofhomeostasis following macro-environmental insults. Translational Environmental Restoration (TER) is the translation of BEB in climatechange research into effective and efficacious policies for restorative renewal of our macro-environment. Patient-centered translationalhealth care in the current climate crisis depends upon defining and characterizing the allostasiome as a complex systemic processintertwined with TER. Bioinformation is timely and critical to climate crisis research in general and to TER specifically, because it informsand disseminates the best available evidence for each subject's allostasiome. Concerted research must define and characterize BEB of themulti-dimensional medical emergency produced by the current climate crisis. Novel lines of investigation, including allostasione research,increasingly depend on bioinformation for dissemination, and are foundational for TER, one plausible solution to this complex health carecrisis. Bioinformation  refers to the collection,analysis and interpretation of a range of physio-biologicalcharacteristics of an organism under study. Group and individualdata from prokaryotes and sub-prokaryotic particles to eukaryoticorganisms, from the lowest invertebrates to human subjects, areprocessed and disseminated as bioinformation. Bioinformation datamay include genomic molecular fingerprints and physiological data, which together define, characterize, constitute andregulate the subject's microenvironment. Bioinformation findingsalso pertain to the situational environment  in which the subject finds it, which has adetermining impact upon the subject's physiological regulation.Bioinformation is the cornerstone of dissemination of new finding in the biomedical sciences. Therefore, Bioinformation is possibly themost timely and critical aspect of translational health care, whichintegrates the best evidence base (BEB) from translational researchinto treatment interventions that maximize effectiveness  .Bioinformation is obtained by a variety of tools and instruments,from individual meetings to other traditional means of data sharing, and othercontemporary modalities .The peer-reviewed written word remains the best approachthe scientific community has to review and disseminate biomedicalresearch findings, and to submit them to the rigorous evaluationdesigned to generate BEB. This journal, Bioinformation, has playeda critical role in this process for over a decade, and continues to beas timely as it is critical to concerted progress and advances inbiology in general and translational health care particularly.A common neologism in the scientific community, particularly inthe biological and the medical sciences, is to add the suffix 'ome' torefer to the totality of a specific domain of study, exclusive ofothers. The origin of this terminology is traceable to Germanphysician Dr. Hans Winkler, who defined, in 1920, the "das Genom" as the haploid chromosome set "...which, togetherwith the pertinent protoplasm, specifies the material foundation ofthe species..." [We can expand this terminology even further in the context ofstudy of the specific elements in the microenvironment that alter,for example the immune surveillance to certain tumors .SimilarHeat stress, breathable air and water - fresh and sea - acidityincrease due to raised CO2 levels, clean water deprivation anddrought, release of toxic gases are but a few of the consequences tothe climate change crisis all living organisms are experiencing atevery latitude. It matters not what the weather is in any given siteon any given day: climate patterns have changed widelyworldwide; and the situation is growing worse by the day. Expertsdo not speak of climate change any longer, but of climate crisis: aserious, aggressive, existential and extreme crisis that threatens allspecies - vegetal and animal, human beings included - and ourplanet as a whole. This is not an overstatement: climate data BEBconvincingly show the precipitating downward pattern of life onearth as a direct consequence of climate change.The macro-environmental stressors associated with climate changeimpact the disease-health trajectory of each individual patient. Thatis to say, the allostasiomic pattern of response to the variety ofclimate change-associated health threats is different and distinct ineach individual patient. Consequently, to provide patient-centeredhealth care, it is timely and critical to elucidate these allostasiomicpatterns, and to disseminate this novel bioinformation. Concertedresearch on the systemic complexity of climate change informspolicies directed at countering, salvaging and restoring our healthysurvival on our planet. Translational Environmental Restoration(TER) refers to the translation of the best evidence base (BEB) in theclimate change crisis, as one on the principal drivers of our macroenvironment,into effective and efficacious policies. The science ofTER follows the same principles of finding BEB, translating BEB,testing the effectiveness of BEB and disseminating BEB astranslational healthcare .The climate crisis causes serious threats to biological system, aboveand beyond the aforementioned macro-environmental stressors ofheat challenge, de-oxygenation and carbon dioxide pollution ofpotable and sea water sources with consequential poisoning ofplanktons and fish, air particulates and their impact on depressingcellular immune surveillance to a variety of blood and solid tumorsacross vertebrate species, worsening lung disease, emphysema andasthmatic conditions, and psycho-cognitive and sleep disturbances.As serious is the outcome of the climate crisis on ocean and aircurrent , which pushes temperateclimatic zone towards the pole. Consequently, the ice caps showdangerous melting patterns, and torrid humidity and heatspreading wider from the equatorial band. With that expansion ofthe tropical zones, mosquito-borne diseases spread wider and fasterinto heavily inhabited cities. Novel infectious diseases, includingEbola , Zika 77 and otBioinformation is timely and critical for translational health care. Tobe clear, bioinformation has a central role in TER as well because itinforms the allostasiome, which is essential for patient-centeredcare and individual patient data research and analysis , 10.Bio


Single institutional review board (IRB) review of multisite research increased in frequency over a decade ago with a proliferation of master IRB reliance agreements supporting statewide and regional consortia and disease- and population-specific networks. Although successful, the increasing number of agreements presented significant challenges and illuminated potential benefits of a single, nationwide agreement. Anticipated changes in federal regulations highlighted the need to systematize and simplify IRB reliance. To address these challenges, the NIH National Center for Advancing Translational Sciences funded a project to establish a national IRB reliance network that would support national adoption of single IRB (sIRB) review. The Streamlined, Multisite, Accelerated Resources for Trials (SMART) IRB Platform launched in July 2016 to facilitate dissemination, adoption, and implementation of a collaboratively developed master IRB reliance agreement and supportive tools and resources. More than 580 institutions have joined SMART IRB’s Master Common Reciprocal Institutional Review Board Authorization Agreement and begun using the SMART IRB platform to support sIRB arrangements. Here, we describe the tenets of the agreement and operational benefits and challenges of its use. SMART IRB’s early success affirms the utility of collaborative, flexible, and centralized approaches to supporting sIRB review while highlighting the need for further national harmonization. In multisite studies, the burden and expense of conducting multiple, duplicative ethics reviews by several institutional review boards (IRBs) has been cited as a major barrier to research, delaying research conduct without demonstrable benefit to the protection of human subjects ,2. SinglTo address these challenges, in September 2014, the National Institutes of Health (NIH) National Center for Advancing Translational Sciences (NCATS) funded a projectIn July 2016, NCATS funded the Streamlined, Multisite, Accelerated Resources for Trials (SMART) IRB Platform  to facilTraditionally, all institutions involved in a master IRB authorization agreement would sign a single agreement and keep copies of the signed agreement on file. This approach was untenable on a national scale; therefore, a new approach to enable institutional sign-on was developed. SMART IRB’s Master Common Reciprocal Institutional Review Board Authorization Agreement (the SMART IRB Agreement) , the fouBy joining SMART IRB, Participating Institutions eliminate the need to review, negotiate, and sign a new IRB reliance agreement for each study, a review that is often a lengthy process involving institutional legal counsel and requiring the signature of the appropriate institutional official. For each study, Participating Institutions need only document use of the SMART IRB Agreement, the specific reliance arrangements , and any conditions specific to the oversight of that study. The SMART IRB Agreement provides for a certain amount of flexibility in the implementation of study-specific reliance arrangements. Three key areas of flexibility are: (1) who will serve as the Privacy Board for institutions when the HIPAA Privacy Rule applies to the study, with the default expectation being that the Reviewing IRB will serve in this capacity; (2) whether the Reviewing IRB will require a combined or separate approach to HIPAA authorizations, with the default being a combined consent and HIPAA authorization form; and (3) whether the Reviewing IRB will be solely responsible for reporting to federal agencies and sponsors, such as in the case of a finding of an unanticipated problem or serious and/or continuing noncompliance, or will provide a joint report, or delegate the reporting to the affected Relying Institutions, with the default being sole reporting by the Reviewing IRB. SMART IRB has developed a template implementation checklist to assist institutions in documenting how these flexible terms will be implemented for a given study .Institutions join the SMART IRB Agreement individually. In developing the eligibility criteria, consideration was given to how best to build trust between Participating Institutions and promote the protection of human subjects. To be eligible to join the Agreement, an institution must: (1) have an active FWAhttps://ohrp.cit.nih.gov/search/fwasearch.aspx?styp=bsc).The rationale for requiring an FWA was that maintenance of an FWA indicates an institution’s commitment to human research protections and its accountability for the compliance of its HRPP with federal standards. IRB organizations (IORGs) do not need an FWA; however, these organizations must register with the OHRP and thus demonstrate their knowledge of and compliance with US federal regulations. The status of a Participating Institution’s FWA or IORG registration may be verified via the OHRP website  their existing reliance relationships, or those going forward, there is no requirement to do so. However, institutions must communicate with one another in advance of ceding review for any research study to clarify which agreement they are using and document the reliance for that research.The SMART IRB Agreement includes some default requirements that the Reviewing IRB may agree to waive. For example, when using the SMART IRB Agreement, the default requirement is that all Participating Institutions (1) maintain, implement, or have access to a human subjects research quality assurance/quality improvement process, function, program, or service that can conduct and report to the Participating Institution the results of for-cause and not-for-cause audits and (2) maintain sufficient insurance coverage – or self-funded liability coverage in the case of state institutions – to cover the research activities related to a given reliance arrangement. Institutions are encouraged to use the SMART IRB SOPs  for studUnder the SMART IRB Agreement, a Reviewing IRBIn executing its responsibilities and in performing its review and oversight, the Reviewing IRB must consider local requirements that have been communicated by a Relying Institution. These might include: (1) applicable state or local laws, regulations, institutional policies, standards, or other local factors, including ancillary reviews, relevant to the research that would affect the conduct or approval of the research at the Relying Institution; (2) site-specific information requested/identified in the customizable sections of the Reviewing IRB’s consent form; (3) conflict of interest (COI) determinations, prohibitions, and management plans; and (4) local requirements and restrictions on use and disclosure of protected health information (PHI) that could prevent the Reviewing IRB from approving a request for waiver or alteration of HIPAA authorization with respect to the Relying Institution.The Reviewing IRB ensures any COI management plan is incorporated into its initial review or other deliberations, as applicable, such as including disclosures to subjects in informed consent forms, and may impose additional prohibitions or conflict management requirements more stringent or restrictive than those proposed by a Relying Institution. However, a Reviewing IRB may not modify or change any management plan or mandated disclosure to participants without discussion with and acceptance by the Relying Institution.The Reviewing IRB makes its policies and procedures available to Relying Institutions, when applicable and upon request. When informed consent is required, the Reviewing IRB provides approved informed consent templates to the Relying Institutions and the Site Investigators (either directly or through a designee), permitting customization of limited site-specific sections . There is flexibility in how Reviewing IRBs communicate institutional requirements for consent forms to the Reviewing IRB . The RevThe Reviewing IRB promptly notifies the Overall Principal Investigator (PI), Site Investigator(s), and the Relying Institutions of determinations , review decisions , and lapses in IRB approval and any applicable corrective action plans. The Reviewing IRB also promptly notifies the Overall PI, Site Investigator(s), and Relying Institution(s) about findings of and actions related to apparent or actual serious or continuing noncompliance, including any steps necessary for remediation of the noncompliance at the Relying Institution; unanticipated problems involving risks to subjects or others; subject injuries related to research participation; significant subject complaints ; and suspension or termination of IRB approval of the research.A Reviewing IRB can conduct audits of the research, request a Relying Institution to conduct an audit or investigation and report back its findings, or work cooperatively with a Relying Institution to conduct an audit or investigation. The Reviewing IRB notifies a Relying Institution in advance if it determines that reporting to a regulatory agency, sponsor, funding agency, and/or other oversight authority is required. Typically, the Reviewing IRB will draft the report and provide the involved Relying Institution(s) the opportunity to review the draft report before sending to external recipients, with a minimum of five business days for review; the Reviewing IRB is under no obligation to adopt comments of a Relying Institution. The involved Participating Institutions may agree on an alternate arrangement, whereby the Relying Institution drafts and makes the report or the Reviewing IRB and Relying Institution jointly develop the report. The Reviewing IRB will also promptly notify the Relying Institutions of any communications received from the FDA, OHRP, and/or other regulatory agencies relevant to the ceded research.While a Relying Institution cedes IRB oversight of a study, the institution retains responsibility for the protection of human subjects; for compliance with applicable laws, regulations, and ethical standards; and for compliance with the terms of its FWA  that would affect the conduct or approval of the research at the Relying Institution. A Relying Institution will also provide site-specific information in the customizable sections of the Reviewing IRB’s consent form. Relying Institutions must maintain and share COI policies, and, unless an alternative arrangement is made, perform COI analyses, communicate its COI determinations to the Reviewing IRB, and abide by the Reviewing IRB’s COI determinations.With regard to the HIPAA Privacy Rule, Relying Institutions work with the Reviewing IRB to establish whether a separate authorization form or combined consent/authorization will be used for the research, provide any institution-specific language, and notify the Reviewing IRB of any specific local requirements and restrictions on use and disclosure of PHI that could prevent the Reviewing IRB from approving a request for a waiver or alteration of HIPAA authorization for the Relying Institution.A Relying Institution must have an institutional mechanism by which local research participants or others may convey complaints about the research to a local contact and must ensure that the approved protocol and consent form address financial coverage for research-related injury and be able, either through applicable grant, contract, or other arrangements, to uphold the coverage commitments.If the Reviewing IRB requests an audit or investigation, a Relying Institution must provide research records and related information, meet with representatives from the Reviewing IRB, report any of its own findings to the Reviewing IRB within a reasonable time frame, and help carry out and comply with all corrective actions required by the Reviewing IRB. When reporting to regulatory agencies is required, Relying Institutions must promptly provide any comments on the draft report of the Reviewing IRB or, if requested, promptly prepare the draft report and provide the Reviewing IRB an opportunity to review and comment. As noted above, the involved institutions may agree on an alternate arrangement, whereby the Relying Institution drafts and makes the report or the Reviewing IRB and Relying Institution jointly make the report. A Relying Institution may elect to make its own additional report, in which case, it must provide a copy to the Reviewing IRB. Relying Institutions must promptly notify the Reviewing IRB of any reporting-related communications received from regulatory agencies.As noted above, when the advent of a national IRB authorization agreement eliminated the need to negotiate and sign study-specific agreements, a mechanism was required to identify which institutions qualify to join and have agreed to the terms of the master agreement and to allow institutions to attest to using the agreement on a study-by-study basis.https://smartirb.org/participating-institutions/). Within the first 4 months, over 100 institutions joined SMART IRB, including all 62 then-current CTSA program hubs; as of May 31, 2019, more than 580 institutions had joined, including universities, academic medical centers, community hospitals, cancer centers, patient-powered research networks, and independent/commercial IRBs , notices; and the institutional official (IO)) to generate an institution-specific Joinder Agreement to the SMART IRB Agreement; the Joinder platform allows SMART IRB personnelSign-on was encouraged by the SMART IRB team deploying a team of regional ambassadors to reach out to institutions about joining the Agreement and answer questions about the terms of the Agreement and process for joining. SMART IRB ambassadors are IRB experts and HRPP professionals from across the country, who provide guidance on eligibility criteria, assist institution in the process of joining, and provide local training and support to enable sign-on to and implementation of the SMART IRB Agreement. Regional ambassadors were joined in their efforts by representatives from the National Patient-Centered Clinical Research Network and the Research Centers in Minority Institutions Translational Research Network, and the ambassador team as a whole has been key to the dissemination and adoption of the SMART IRB Agreement. Over time, some ambassadors have taken on broader roles, providing support in education and other key focus areas.https://smartirb.org/resources/.In addition to facilitating sign-on to and implementation of the Agreement, Ambassadors also support the creation, testing, dissemination, and adoption of tools and resources to aid institutions in the implementation of sIRB review. Recognizing that institutions and investigators vary significantly in their experience with, and established infrastructure and resources to support, sIRB review, the SMART IRB team has developed resources that target three key roles in a sIRB arrangement: study teams, Reviewing IRBs, and Relying Institutions. Resources included: template for documenting reliance arrangements; a checklist to allow institutions to document how they implement the flexible provisions of the SMART IRB Agreement; communication plan for sIRB review, which documents key communication roles; template description of SMART IRB and template IRB letter of support for grant applications; local context survey; and investigator responsibilities checklists. All resources are freely available at Additionally, to provide support related to documenting study-specific reliance arrangements, establishing a Reviewing IRB, and facilitating communication between institutions, a central, workflow-based, online platform termed the SMART IRB Online Reliance System (ORS) was developed. The system provides a mechanism for investigators and IRB/HRPP and other institutional administrators to request, track, and document study-specific reliance arrangements under the Agreement. ORS provides research teams with a standard mechanism to initiate sIRB requests, ensuring that the investigator’s home institution is aware of the reliance request, and automatically notifying designated representatives from all engaged sites so that they may collaborate efficiently in determining suitable arrangements. The system identifies for investigators the information and documents needed by the institutional representatives to consider reliance arrangements and, upon submission of a request, ensures this information is routed to the appropriate parties. ORS uses tailored informatics workflows to maximize communication and coordination throughout the reliance determination process. In the case of Reviewing IRBs and Relying Institutions, the ORS provides a robust communication platform that allows the institutions – with security and specificity – to track the status and outcome of reliance requests, thus ensuring compliance with federal regulations governing sIRB review.First launched in betaThe ORS and other supportive resources may be accessed via SMART IRB’s open-access online compendium, which provides frequently asked questions (FAQs), best-practice templates, checklists, guidance, and other tools to aid in implementation of sIRB review. Users can filter resources for a specific role  or topic . Periodic webinars help institutions get started with SMART IRB and the ORS, implement the SMART IRB Agreement, understand the roles and responsibilities of a Relying Institution or a Reviewing IRB, and introduce how and when to use SMART IRB’s available resources. Recordings of past webinars are available to provide users just-in-time information to support their reliance needs. Ambassadors and SMART IRB team members have attended regional and national events to present and answer questions about SMART IRB specifically and sIRB review more generally. In April 2019, SMART IRB hosted an sIRB boot camp for IRB and HRPP professionals to help these individuals and their institutions successfully implement sIRB review by leveraging the SMART IRB Agreement and supportive resources. This day-long session was attended by more than 100 regulatory professionals from 21 universities, medical centers and hospitals, private companies, and organizations throughout the USA, including the NIH.As institutions increasingly use sIRB review of multisite research protocols, inconsistencies among local policies and processes relevant to IRB review and the conduct of research have become apparent. Some variation reflects institutional differences in contracting, such as different policies and approaches to indemnification; these differences do not touch the participant or the study team, and while inconvenient and a cause of delay do not impact research conduct. However, variations in institutional policies, requirements, and procedures that impact the conduct of the research, the expectations of the investigators and their teams, and the treatment of the participant make it challenging for a well-meaning study coordinator or investigator to remember and comply with the specifics for each study. These variations are often trivial, such as the age of assent being 12 or 13, or the days allowed for reporting of an unanticipated problem; compliance with the requirements of the Reviewing IRB may render the investigator noncompliant with the policies of their own Relying Institution. Disparate local policies and differing SOPs frustrate – and unnecessarily burden – those who are charged with implementing single site review of multisite studies.https://smartirb.org/harmonization/. Current working groups are developing (1) a reciprocal, comprehensive, harmonized indemnification agreement; (2) additional FAQs to address HIPAA issues that arise in reliance agreements; and (3) recommendations on processes for and communication of changing investigators and their study staff after study approval.To begin the long process of institutional alignment, the SMART IRB team and NCATS convened the Harmonization Steering Committee (HSC) composed of a broad array of stakeholders, including representatives from NIH, OHRP, Food and Drug Administration (FDA), Veterans Affairs (VA), AAHRPP, Federal Demonstration Partnership, NCATS Trial Innovation Network, and independent and institutional IRB and HRPP professionals, to develop, demonstrate, and disseminate unified policies, processes, and procedures for sIRB review. Meeting monthly, the HSC focuses on standardizing methodologies, processes, and infrastructure critical to support multisite studies. Initially, five working groups, each with 8–9 members from academia, independent IRBs, government, and industry, were charged with addressing: (1) institutional and local/state responsibilities, (2) institutional versus IRB responsibilities, (3) sIRB fees and charging models, (4) reportable events, and (5) standard consent templates. Building upon current practices, working groups sought to define common elements, identify differences, and aggregate successful workflows; each deliverable was reviewed by the HSC, posted for public comment for a period of 45 days, amended, revised, and finalized. As of May 31, 2019, five harmonized policies or templates are available for broad adoption: (1) Fees and Costing Models under NIH sIRB Policy, (2) Institution versus IRB Responsibilities Guidance, (3) Institutional Profile, (4) Protocol-Specific Requirements Document, and (5) Reportable Events Recommendations. To access the documents and learn more about the development process, see In response to external pressures catalyzing and now mandating the shift to sIRB review, SMART IRB has sought to connect IRBs, HRPPs, and research administration professionals to provide a sounding board for questions, to address challenges, and to communicate best practices. Starting with the development of the SMART IRB Agreement, SMART IRB has relied upon a wide range of stakeholders to ensure that its resources reflect and support the breadth and depth of multisite research. Indeed, the active engagement and support of CTSA leadership, institutional officials, human research professionals, and IRB administrators throughout the USA made this work possible. Through established outreach efforts and collaboration, SMART IRB is poised to facilitate nationwide adaptation to changes in policy and regulations or other changing research needs.Looking ahead, the incipient changes in the Final Common Rule will require revision of the SMART IRB Agreement, revisions that may be significant but that nevertheless afford the opportunity to introduce additional changes, should they be recommended by the stakeholder community and deemed essential to the continued growth of the SMART IRB network and use of the SMART IRB Agreement. The SMART IRB team is in the process of soliciting input from representatives of Participating Institutions and from the public; the process is transparent. If it is deemed necessary, there will be time for a facilitated sign-on process to an updated agreement to ensure Participating Institutions are able to transition without a gap in participation.new master agreements has been mitigated and Participating Institutions will determine the appropriate time frame to transition completely to the SMART IRB Agreement. As with the work of the HSC, great benefit is to be found in further alignment of processes across institutions, including the use of a common master reliance agreement. That said, the work of facilitating sIRB review is not done: many institutions and investigators are still learning the impact of IRB reliance on the execution of multisite studies and how local processes and resources must adapt to accommodate the shift in research oversight. SMART IRB has and will continue to support IRBs, institutions, and study teams as they successfully transition to and thrive in sIRB review of multisite research.Pending changes to federal regulations requiring sIRB review for multisite human research studies, scheduled to be effective in 2021, along with the existing, though relatively new, NIH sIRB policy, require institutions to substantially re-engineer their HRPPs, conceiving and implementing changes to infrastructure, policies, and procedures, while educating and reorienting regulatory personnel and study teams. SMART IRB presents opportunities for efficiencies and expedited processes in conducting IRB oversight and review. Since its introduction, the SMART IRB Platform  has been widely adopted, with many institutions having retired or in the process of retiring other existing master reliance agreements and fully transitioning to the SMART IRB Agreement. As noted above, the Agreement does not preclude the use of other reliance agreements, and institutions may reasonably determine that continued use of existing agreements may, in certain cases, be preferable to the use of the SMART IRB Agreement . However, it is our expectation that, with the continued growth of the SMART IRB network, the need to develop


Liver diseases pose a serious problem for national health care system all over the world. Liver regeneration has profound impacts on the occurrence and development of various liver diseases, and it remains an extensively studied topic. Although current knowledge has suggested two major mechanisms for liver regeneration, including compensatory hyperplasia of hepatocytes and stem or progenitor cell-mediated regeneration, the complexity of this physiopathological process determines that its effective regulation cannot be achieved by single-target or single-component approaches. Alternatively, using traditional Chinese medicine (TCM) to regulate liver regeneration is an important strategy for prevention and treatment of liver disorder and the related diseases. From the perspectives of TCM, liver regeneration can be caused by the disrupted balance between hepatic damage and regenerative capacity, and the “marrow”-based approaches have important therapeutic implications for liver regeneration. These two points have been massively supported by a number of basic studies and clinical observations during recent decades. TCM has the advantages of overall dynamic fine-tuning and early adjustment, and has exhibited enormous therapeutic benefits for various liver diseases. Here, we review the recent advances in the understanding of liver regeneration in TCM system in the hope of facilitating the application of TCM for liver diseases via regulation of liver regeneration. The mechanism of liver regeneration has long-termly been an important host factor for the development of liver diseases. After nearly a century of efforts, especially with the rapid development of stem cell-centered regenerative medicine, mechanistic understanding of liver regeneration progresses rapidly . HoweverIt has currently been known that the regulation of liver regeneration is not only the partial function of the liver, but also the overall comprehensive effect of dynamic changes of human body. Therefore, regulation of liver regeneration must be based on the overall dynamic regulation. The treatment using one-sided therapeutic method will fail to meet the needs of various aspects and ever-changing regulation of liver regeneration, and the curative effect must be limited ,3. Due t2Current paradigm generally describes two mechanisms of liver regeneration: hepatocyte compensatory hyperplasia, and stem or progenitor cell-driven regeneration . It is aFor the alternative regeneration mechanism, blood-borne cells of the bone marrow origin also play a role, in addition to the resident liver cells –13. Hepa33.1Having experienced the research hotspots, including anti-virus, anti-liver fibrosis, anti-hepatoma and immune-regulation for the treatment of liver diseases, a new research hotspot of regulating liver regeneration by TCM has been emerged. Many past studies have paid attention to studying the effects of TCM on liver damage or liver regeneration and to elucidating the underlying mechanisms . With th2-induced hypoxia injuries in SK-HEP-1 cells, and meanwhile significantly improved the NO content and NOS activity concomitant with a decrease in reactive oxygen content [The therapeutic practice of TCM or integrated Chinese and Western medicine for hepatic failure has demonstrated the scientific and advanced nature of reducing the mortality of liver failure, alleviating complications, and improving the quality of life by regulating the imbalance between liver damage and liver regeneration –27. TCM  content . Studies content . Specifi content . In addi content .3.2Nei Jing [“Marrow engenders liver” is an important academic thought of Nei Jing ,40. ReceNei Jing . “MarrowNei Jing . TherefoRecently, some studies have found that the increasingly severe liver cirrhosis causes hematopoietic dysfunction and loss of hematopoietic stem cells, leading to dysfunction of blood and immunity and reduced regeneration potential . Thus, t4Because of the extremely complex and verified nature of the process and mechanism of regeneration and repair, in order to maintain or promote the regeneration of the stem cell microenvironment, it is necessary to use the mode of action of overall dynamic fine-tuning early adjustment to comprehensively regulate with multiple targets and multiple pathways. Obviously, single-target chemical medicines cannot meet such requirements. Therefore, there is currently no single-target chemical medicine that can regulate liver regenerative repair effectively. TCM has the comprehensive adjustment advantages of complex composition and overall dynamic fine-tuning features, which fully meet the needs of regulating regeneration and restoration. TCM utilizes the natural healing ability of viscera tissue to regenerate and repair the damage of viscera tissue, and rebuild and restore the structure and function of visceral tissue, which possesses the characteristics of being natural, making the best use of circumstances, dynamic changes, reversing the disease, overall adjustment, high security, and being affirmative in maintaining or improving the regenerative repaired stem cell microenvironment . It has Proliferation and activation of HSCs are thought to be the key steps of liver fibrosis, and the attention of treatment has always been focused on how to inhibit the proliferation and activation of HSCs . HoweverCurrent studies have confirmed that the oval cells are one kind of important hepatic stem cells for liver regeneration and repair ,69. When5The rapid progress of liver regeneration research, the lack of specific technologies and methods for regulating liver regeneration, and the effective functional characteristics and advantages that the TCM has to regulate liver regeneration, have collectively brought great opportunities for the basic and clinical researches of preventing and curing liver diseases and related diseases by regulating liver regeneration. Many efforts have been made to improve the ability and level of TCM or integrated Chinese and Western medicine to prevent and cure liver diseases and related diseases. However, faced with the more complex interaction mechanism between the components of TCM and the complex mechanism of liver regeneration, and with the insufficiency of clinical standard system for clinical application, insurmountable challenges for basic and clinical application research of regulating liver regeneration with TCM are proposed.Normal and abnormal liver regeneration are difficult to be distinguished clinically. It is difficult to establish an index system suitable for clinical application to objectively evaluate the normal or abnormal liver regeneration, which is a key scientific problem that hinders the clinical application of TCM to regulate liver regeneration. TCM regulates liver regeneration mainly through inartificial or natural methods to adjust the internal mechanism of liver regeneration and to normalize liver regeneration. The main mechanism of action is to transform the pathological imbalance mechanism into the normal equilibrium mechanism, so the criterion for therapeutic effect evaluation is “expectation of balance”. The complex composition in TCM, the use of natural therapy, the overall dynamic fine-tuning and early adjustment, and the characteristics of individualized diagnosis and treatment exactly meet the complex and ever-changing needs of liver regeneration regulation, which is of realistic and potential advantages. Furthermore, there are needs to investigate how the physical liver regeneration and pathological liver regeneration are regulated by TCM, given that many Chinese herbs medicines have food function and are commonly used in diets of healthy people. In short, the continuous improvement and development of various systems biology technologies can provide ways and hope to solve the above-mentioned complex problems. The combination of evidence-based medical evidence and the real-world big data can also promote clinical research and application of TCM for regulating liver regeneration.The authors declare that there is no financial or other relationship that might lead to a conflict of the present article. All authors have reviewed the final version of the manuscript and approved it for publication.


All over the world, there is an increase in the overall survival of the population and the number of elderly people. The incidence of allergic reactions is also rising worldwide. Until recently, allergies, and in particular food allergies (FAs), was regarded as a pediatric problem, since some of them start in early childhood and may spontaneously disappear in adulthood. It is being discovered that, on the contrary, these problems are increasingly affecting even the elderly. Along with other diseases that are considered characteristics of advanced age, such as cardiovascular, dysmetabolic, autoimmune, neurodegenerative, and oncological diseases, even FAs are increasingly frequent in the elderly. An FA is a pleiomorphic and multifactorial disease, characterized by an abnormal immune response and an impaired gut barrier function. The elderly exhibit distinct FA phenotypes, and diagnosis is difficult due to frequent co-morbidities and uncertainty in the interpretation of in vitro and in vivo tests. Several factors render the elderly susceptible to FAs, including the physiological changes of aging, a decline in gut barrier function, the skewing of adaptive immunity to a Th2 response, dysregulation of innate immune cells, and age-related changes of gut microbiota. Aging is accompanied by a progressive remodeling of immune system functions, leading to an increased pro-inflammatory status where type 1 cytokines are quantitatively dominant. However, serum Immunoglobulin E (IgE) levels and T helper type 2 (Th2 cytokine production have also been found to be increased in the elderly, suggesting that the type 2 cytokine pattern is not necessarily defective in older age. Dysfunctional dendritic cells in the gut, defects in secretory IgA, and decreased T regulatory function in the elderly also play important roles in FA development. We address herein the main immunologic aspects of aging according to the presence of FAs. Food allergies (FAs) are becoming a relevant public health concern, affecting over 200 million people worldwide and its prevalence is increasing, mainly in developed countries . FAs areFAs are much more common in children than in adults. Most FAs start in early childhood and usually disappear in adulthood. For this reason, FAs are often considered an almost exclusively pediatric disease. However, although its prevalence is greatest in young children, the occurrence of FA reactions is becoming frequent in the elderly ,8. Most It is estimated that the current prevalence of allergic diseases in the elderly reaches 10% but this data is underestimated and also destined to increase . An incrBesides the lack of epidemiological data, very little is known about the peculiar immunopathogenetic aspects and the clinical presentation of FAs in old people .The aim of this review is to analyze the pathophysiological mechanisms underlying food allergy in the elderly, emphasizing the most peculiar aspects in this segment of the population, which form the basis of possible intervention measures.The genetic background controls immunity and inflammation, and influences both the aging process and the development of allergies. Several underlying mechanisms of FAs in the elderly are now recognized, the first of which is immunosensecence, i.e., the peculiar age-related remodeling of the immune system. During senescence, both innate and adaptive immune reactions are deeply changed, favoring the development of FAs .In the elderly, there is an imbalance of lymphocyte sub-populations, characterized by a decrease of naive lymphocytes with an accumulation of memory and senescent lymphocytes. Dysfunctions of immune regulatory cells, thymus involution, hematopoietic stem cell malfunctioning, dysregulation of apoptotic processes, a stress response, and mitochondrial function all contribute to the remodeling of the immune system in the elderly . How theIncreased inflammatory cytokines and antigen-presenting cell dysfunction contribute to allergic sensitization and inflammation in the aging. Dendritic cells, the mainstarter of the adaptive responses, exhibit altered costimulatory molecule expression in frail elderly subjects, conditioning dysfunctional antigen processing and presentation, which can elicit allergic responses .Concerning effector cells of allergic reactions, most studies report a reduction in eosinophil degranulation in response to IL-5 stimulation and a decreased mast cell function notwithstanding a normal number of mast cells in the tissues .A compromised T helper function and defects of the isotype switching leading to impaired immunologic memory and lower response to vaccines have been observed in the elderly . ConversSenescence affects not only the systemic immunity but also the local immune responses, especially on the gastrointestinal mucosa. The induction of mucosal tolerance is of paramount importance in mounting protective responses against new dietary antigens, therefore preventing FAs . The gasInflammaging, the condition of chronic inflammation that drives senescence , increasThe presence of opsonizing secretory IgA antibodies against food antigens is a central mechanism of mucosal immunity by reducing the attachment, penetration, and invasion of antigens across the mucosal wall. Secretory IgA supplied through breastfeeding protect newborns against harmful antigen penetration, leading to transient tolerance/immunity against oral allergens. This mucosal first-line defense mechanism deteriorates with age and orally induced antigen-specific IgA responses weaken . The immIn the elderly, the integrity of the gut epithelial barrier is compromised, contributing to the chronic subclinical inflammatory state. Furthermore, the leaky epithelial barrier promotes Th2-immune responses by allowing allergens to penetrate into tissues where they are processed by dendritic cells and macrophages and presented to T cells . AllergeFood allergens are mostly structurally stable proteins that usually present a greater risk of causing systemic reactions. When digestion is compromised, labile food proteins can also persist partially undigested along the gastrointestinal tract and become food allergens . The gasAlso, age-related changes in organs and systems different from the gut can exert an important role in the development of FAs in the elderly. The skin is one of the main targets of an allergic reaction to food, as well as an important site of primary sensitization. As a result of chronological and environmental factors, the aged skin is characterized by atrophy and dehydration . The proIn addition to the impaired function of the local immunity and increased gastrointestinal mucosa permeability, age associated alterations of the gut microbiota may also favor FA development in the elderly.The gut microbiota is a complex ecological system that exerts a central role in several physiological functions, and its composition changes throughout the host’s life. It is sensitive to environmental influences and the host’s diet, and depends on the host’s genetics, gender, and the aging process per se .The system of the secretory IgA plays a critical role not just for the defense against infections but also for the modulation of local immune responses through the maintenance of the intestinal microbiota. Inflammatory processes are associated with dysregulation of the homeostatic interactions between the intestinal microbiota and the aging host .Intestinal microbiota exhibit significant age-associated changes in composition and diversity, as well as in functional features, mainly caused by the immune system remodeling and low-grade chronic inflammation, which respectively characterize immunosenescence and inflammaging .Immunosenescence exerts a key role by modifying the host’s response to microbiota, triggering inflammaging, and shifting Th1 versus Th2 responses, thus favoring tolerance dysruption and allergic reaction development .Antibiotics are among the most commonly used drugs in the elderly and are often used improperly. They influence the microbiome composition and function interfering with immune homeostasis. In the geriatric age, antibiotics can further disturb the composition of the microbiota ,54. HoweTogether with the peculiar remodeling of the immune system during senescence, the compromised integrity of epithelial barriers and the sub-clinical chronic inflammatory condition commonly observed in the elderly, a central role in sensitization to food allergens is also played by the lack of micronutrients and vitamins .Micronutrients and antioxidants modulate immune responses and it is suggested that their deficits favor the development of Th2 type responses. For example, deficits of iron, zinc, and vitamin D, which are very common in the elderly, may represent additional risk factors for the onset of allergic reactions during senescence .Zinc is an essential trace element that plays a central role regarding the immune efficiency. Zinc intracellular homeostasis, regulated by metallothioneins and specific transporter proteins, is altered in aging, leading to its decreased availability for immune functions. A reduced zinc level, frequently observed in the elderly, could be responsible for a decreased production of Th1 cytokines, whereas this does not affect the production of Th2 cytokines, thus inducing a cytokine imbalance that promotes the development of allergic diseases .Zinc deficiency contributes to thymic atrophy; immature B cell accumulation; and decreased IgM, Ig-G2a, and IgA subclasses. Stress situations, through pro-inflammatory cytokine production, including IL-6 and TNF-α, are often associated withzinc deficiency. Inflammatory cytokines, permanently increased in the geriatric population, bind zinc ions with a consequent reduced zinc bioavailability and altered immune functions. In particular, decreased levels of zinc induce a reduction of Th1 cytokines, such as IFN-γ, IL-2, and TNF-α, while Th2 cytokines, in particular IL-4, are enhanced. Through this mechanism, zinc deficiency could favor the development of FAs in the elderly .Iron deficiency is also frequent in the elderly . The decSeveral studies suggest that vitamin D deficiency is also very common in the elderly, supporting FA development. Immune dysregulation, in addition to an increased parathyroid hormone level and impaired bone health resulting in enhanced risk of fractures, is a serious consequence of vitamin D deficiency in the elderly ,60. The The variable natural history and the complexity of the possible pathogenetic mechanisms, as well as several age-associated factors, make the diagnosis and management of FAs in the elderly difficult. Nutritional abnormalities and vitamin deficiencies, as well as hormonal imbalances and inflammaging, interacting with genetics, may alter the immune responses, leading to FA development. The age-related decline of physiological functions, in addition to the immune system remodeling, which characterizes senescence, contribute to confer peculiar clinical findings to FA in the elderly ,63.Furthermore, despite the normal or increased number of mast cells in the skin of aged subjects with an allergy and a sufficient positive response to prick tests with specific allergens, elderly show weaker cutaneous responses and less intense pomfoid reactions to histamine control . TherefoFrailty, comorbidity, and multi-drug intake are conditions commonly found in the elderly and must be taken into account in the management of aged people affected by FAs. Immunologic reactions to foods can be confused with symptoms of other common age-related diseases or be masked by the use of various drugs. Consequently, the characteristic symptoms of FAs often go unnoticed and this contributes to underestimating FA prevalence in old age . DrynessAnaphylaxis is a severe and life-threatening hypersensitivity reaction that can affect allergic patients at any age . ClinicaThe intake of antiulcer drugs is common in the elderly to cure gastritis, gastroesophageal reflux, gastric ulcers, or in association withcorticosteroids and non-steroidal painkillers to minimize their gastrolesive effects. Gastric hypoacidity and increased permeability of the upper gastrointestinal tract also occur as a result of therapy with acid-suppressive drugs, facilitating the onset of an FA, as well as eosinophilic esophagitis. Elderly patients treated with proton pump inhibitors or H2-receptor blockers are at higher risk for sensitization because dietary proteins both remain incompletely digested and can cross the mucosal barrier more easily due to the increased permeability, thus becoming allergenic ,49.Adverse food reactions show peculiar characteristics in the elderly that concern both the pathogenesis and the clinic. FAs in the elderly are driven by immunosenescence, as well as the cell aging and tissue modifications that characterize advanced age. The aged gastrointestinal mucosa is central in the development of FAs in the elderly through its compromised digestive properties and structural changes, as well as the alteration of its immune functions linked to immunosenescence and age-related microbiota remodeling. Among the risk factors for the sensitization to food allergens in the elderly, in addition to chronic damage and inflammation of gut epithelia due to the aging process, there are chronic alcohol consumption, chronic infections, multimorbility, polymedication, and drug side effects .


Normal aging results in subtle changes both in ACTH and cortisol secretion. Most notable is the general increase in mean daily serum cortisol levels in the elderly, without a noteworthy alteration in the normal circadian rhythm pattern. Glucocorticoid excess seen in the elderly population can have serious consequences in both the structural and functional integrity of various key areas in the brain, including the hippocampus, amygdala, prefrontal cortex, with consequent impairment in normal memory, cognitive function, and sleep cycles. The chronically elevated glucocorticoid levels also impinge on the normal stress response in the elderly, leading to an impaired ability to recover from stressful stimuli. In addition to the effects on the brain, glucocorticoid excess is associated with other age-related changes, including loss of muscle mass, hypertension, osteopenia, visceral obesity, and diabetes, among others. In contrast to the increase in glucocorticoid levels, other adrenocortical hormones, particularly serum aldosterone and DHEA (the precursor to androgens and estrogens) show significant decreases in the elderly. The underlying mechanisms for their decrease remain unclear. While the adrenomedullary hormone, norephinephrine, shows an increase in plasma levels, associated with a decrease in clearance, no notable changes observed in plasma epinephrine levels in the elderly. The multiplicity and complexity of the adrenal hormone changes observed throughout the normal aging process, suggests that age-related alterations in cellular growth, differentiation, and senescence specific to the adrenal gland must also be considered. Normal aging is associated with multi endocrine changes, including those associated with changes in the structure and function of the adrenal gland. The various morphological changes of the adrenal gland that occur during aging are associated with alterations in hormonal output, such as a gradual sustained, increase in glucocorticoid secretion and decline in adrenal androgen levels. The increase in circulating levels of cortisol in aging individuals is of particular interest due to the impact of cortisol on several systems, including cognition, and the inherent relationship of chronic stress, elevated cortisol, and aging.Stress is a constant factor in modern life. The stress response in healthy organisms is aimed at maintaining the balance of biological functions, or homeostasis, when faced with physiological or psychological challenges, that may be real or even perceived. The normal stress response entails a tight orchestration of several adaptive response cascades of the central nervous system and the neuroendocrine systems that are targeted at facilitating homeostasis and ultimately, survival. An integral part of the response entails activation of stress neural circuits, which link brain regions responsible for basic sensory and motor functions for perception and motor response to the stressful challenge, respectively, as well as more intricate autonomic, neuroendocrine, cognitive, and behavioral activities. While activation of these neural circuits is considered part of the normal stress response, chronic stress may deregulate these circuits and responses, resulting in impaired function of these systems.The stress response system is comprised of central and peripheral components. Of these, the hypothalmic-pituitary-adrenal (HPA) axis has been defined as a primary player in the stress response. The HPA axis has been the subject of intense basic and clinical research in the attempt to understand why the primary adrenal hormonal output, glucocorticoids, is critical for life. While the stress system has been widely studied, the magnitude, and complexity of the various interactions between the its primary components remain elusive . Nerve cThe wealth of the available evidence strongly suggests that chronic stress can accelerate aging . In addiAging or senescence has served as a focus for research for several decades. While life expectancy has increased significantly, with the age group consisting of individuals over the age of 85 years being the fastest growing age group, our understanding of the aging process remains unknown. Upon critical examination of numerous theories proposed to explain the aging process, two categories emerge that are not mutually exclusive: (1) those that are based on the notion that aging is programmed; and (2) those that are based on the idea that aging is related to the accumulation of damage at a wide gamma of targets and from various sources . The celThe adrenal gland or suprarenal gland weighs about 5 g consists of two distinct structures, both anatomically and chemically: an inner region, or medulla, that contains catecholamine-producing chromaffin cells and an outer region, or cortex, that is important for synthesizing life-sustaining steroids. The medulla, which produces catecholamines receives sympathetic innervation, while the cortex, which produces life-sustaining steroids is regulated by the pituitary hormones .The cortex is divided into three zones; zona reticularis (amounting up to 7% of the gland mass), zona glomerulosa (15%), and zona fasciculata (50%), where each of the zones secrete different hormones  Figure . All adrThe centrally-located medulla, which constitutes 28% of the gland, is surrounded by the adrenal cortex, and made up of interlacing cords of densely innervated granule-containing cells adjacent to venous sinuses. The cells comprizing the medulla are derived from the nervous system and produce catecholamines . Stimulation of hormone secretion, leads to release of the hormones into the circulation via exocytosis . The medExposure to a stressful stimulus results in activation of both the hypothalamic-pituitary-adrenal (HPA) axis and the arousal/sympathetic system, which comprise primary components, the central and peripheral parts, of the stress system. Of the variety of factors that are produced and released in the stress response, the mediators of the HPA axis, particularly the glucocorticoids, are critical . NormallAs physiologic functions gradually decline during aging, a reduction in activity across the hypothalamic-pituitary-adrenal (HPA) axis occurs. The HPA axis is fundamental to homeostasis, acting as a regulator of stress response . During It has been suggested that aging is related to the loss of balance between the two fundamental process, damage, and repair , as wellThe cortisol secretion pattern by zona fasciculata of the adrenal cortex undergoes several modifications with age. Unlike most hormones whose levels diminish throughout aging, mean cortisol concentrations increase , displayIncreased cortisol levels and diminished axis sensitivity are generally related with inferior cognitive status, dementia of degenerative and vascular cause , depressFrailty has also been associated with elevated diurnal cortisol levels , 48, a sDehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS), produced and secreted by zona reticularis of the adrenal cortex in response to ACTH stimulation, decrease profoundly during aging . AdrenalDHEA/DHEAS secretion is considered of great significance in frailty . Higher The reduction in DHEAS levels with the simultaneous preservation of plasma cortisol, reveal a dissociation of the cortical secretory pattern, which may be caused by selective depletion in zona reticularis cells leading to impairment of androgens, rather than being controlled by a hypothalamic aging pacemaker , 52. In The concentration ratio of glucocorticoids to DHEAS is closely tied to aging, with a gradual increase. Cortisol has neurotoxic effects by stimulating neuronal degeneration through increased susceptibility to metabolic and vascular injuries, reduction of dendritic length, and cell death possibly associated with apoptosis . On the Aldosterone secretion and release from the adrenal cortex declines with aging . Basal lRegarding adrenal medullary function, basal adrenaline secretion decreases with age . EpinephThe circadian rhythm is regulated by the hormone melatonin which shows a decrease in levels throughout aging . The decAging involves a gradual decline in all human functions, including adrenal deterioration. Inevitable clinical sequelae include alterations in body composition, such as loss of density of bone minerals, muscle mass loss, and fat mass increase. These changes may also be related to the endocrine system adjustment to aging . SpecifiCertain characteristic changes in body composition are observed in older persons. These include a decline in total body weight, gradual loss of fat mass , loss of muscle mass, and accumulation of visceral fat , 77. CumDuring the aging process, significant changes of glucose homeostasis include lower levels of insulin and gradually increased resistance to its action . Total bCortisol as a catabolic hormone significantly affects glucose metabolism. Higher cortisol concentrations are associated with insulin resistance and increased fasting glucose . It was One of the most apparent and inescapable effects of aging is a decline in bone mineral density, leading to osteopenia, osteoporosis, and increased risk of fractures. Bone density increases until adulthood, followed by a stable period and thereafter a gradual age-related decline . AdvanciMost body systems and organs, including that responsible for immune function, undergo slow, and continuous changes throughout the aging process that ultimately compromises their normal function . Among t+ cells and this counters the changes in CD8+ produced by glucocorticoids , prefrontal cortex (PFC), and amygdala (AMYG) are highly interconnected key brain regions implicated in stress. Stress induces profound behavioral changes that are paralleled by structural and plastic changes in these areas. HC serves as an important connection between the cortex and hypothalamus, regulating in part, cortisol diurnal rhythm. The HC has an overall inhibitory effect HPA axis activity, serves as a primary central target of stress hormones, and is extraordinarily vulnerable to stress. A key function of the PFC includes the transient storage and manipulation of information to guide subsequent behavior. Dysfunction of the PFC is noteworthy in several psychiatric disorders. The dorsolateral PFC (DLPFC) is important in the conscious regulation of emotion to reduce fear responses and is involved in negative feedback HPA axis regulation. The medial (m) PFC has been implicated in the pathogenesis of MD and SZ and influences HPA axis activity. It has a central role in regulating emotions, reward encoding, and goal directed learning. The mPFC is tightly connected with the DLPFC and limbic areas, particularly the AMYG, which has a central role in the detection of threat and fear. In contrast to the HC and PFC, which decrease in volume after chronic stress, the AMYG increases, which is associated with enhanced anxiety. During emotional challange, the PFC exerts control over the AMYG; successful emotion regulation is associated with increased PFC activity and decreased AMYG activity –30.Stress is a risk factor that affects the physical, mental and social health of individuals through lifespan , 96. It Aging is accompanied with decrease of and deficiencies in autonomy, health, and social status which entail elevated stress . There iNotwithstanding the correlational and not causal relationship between stress, HPA axis and aging, evidence revealed that age-related HPA axis changes affecting the health outcomes of older adults mainly via the diurnal cortisol secretion pathway . ElevateTrauma and injury are well-known factors of homeostasis disruption that cause stress to living organisms. Surgical trauma is a controlled and standardized injury in the sterile environment of the operating theater on a patient receiving pharmacologic treatment for pain control with or without anesthesia. Despite this, surgery is a major stressor causing an inflammatory reaction with activation of numerous cytokines, mobilization of cellular response, and a well-defined hormonal response . The twoResearchers have discovered from the early eighties that surgery produces changes in the cortisol circadian rhythm. McIntosh et al demonstrated that in a small group of 10 patients, serum cortisol levels had significantly increased in the second postoperative day after upper abdominal surgery. They also found that this increase was influenced by the type of surgery; high trauma surgery patients had two times greater increase of their serum cortisol levels on postoperative day two in comparison to low trauma patients . Ten yeaIn general, basal ACTH secretion, as well as basal and stimulated, cortisol release does not change in the elderly . Regardl5 of the geriatric population that is six times greater than that observed in the general population. Most of these patients have severe comorbidities, infectious and pulmonary diseases, fluid and electrolyte disorders, and complicated diabetes mellitus (Old age is not synonymous with incapacity and frailty. Frailty is associated with an increased vulnerability to stressful stimuli, with a decreased ability to maintain a controlled, normal response to intrinsic and environmental stressors, and decreased ability to maintain both physiological, and behavioral homeostasis. Almost 20–30% of the population over 75 years of age is associated with geriatric frailty, which increases notably with advancing age . Empiricmellitus . Sepsis/mellitus . A plausBoth normal aging and chronic stress appear to affect the body via shared mechanisms related to glucocorticoid function. The chronicity of both the aging process, particular in relation to alterations in the structure and function of the adrenal gland, and stress can be detrimental to an individual's general well-being. The available evidence supports that the synergy of aging and chronic stress, via their common end-point effector cortisol, can adversely affect the function of numerous vital systems, leading to neural and cognitive changes, osteopenia, diabetes mellitus, visceral obesity, altered immunocompetence, among others.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.