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

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

Neuromodulation: selected approaches and challenges.

The brain operates through complex interactions in the flow of information and signal processing within neural networks. The 'wiring' of such networks, being neuronal or glial, can physically and/or functionally go rogue in various pathological states. Neuromodulation, as a multidisciplinary venture, attempts to correct such faulty nets. In this review, selected approaches and challenges in neuromodulation are discussed. The use of water-dispersible carbon nanotubes has been proven effective in the modulation of neurite outgrowth in culture and in aiding regeneration after spinal cord injury in vivo. Studying neural circuits using computational biology and analytical engineering approaches brings to light geometrical mapping of dynamics within neural networks, much needed information for stimulation interventions in medical practice. Indeed, sophisticated desynchronization approaches used for brain stimulation have been successful in coaxing 'misfiring' neuronal circuits to resume productive firing patterns in various human disorders. Devices have been developed for the real-time measurement of various neurotransmitters as well as electrical activity in the human brain during electrical deep brain stimulation. Such devices can establish the dynamics of electrochemical changes in the brain during stimulation. With increasing application of nanomaterials in devices for electrical and chemical recording and stimulating in the brain, the era of cellular, and even intracellular, precision neuromodulation will soon be upon us.

Global health, global surgery and mass casualties: II. Mass casualty centre resources, equipment and implementation.

Trauma/stroke centres optimise acute 24/7/365 surgical/critical care in high-income countries (HICs). Concepts from low-income and middle-income countries (LMICs) offer additional cost-effective healthcare strategies for limited-resource settings when combined with the trauma/stroke centre concept. Mass casualty centres (MCCs) integrate resources for both routine and emergency care-from prevention to acute care to rehabilitation. Integration of the various healthcare systems-governmental, non-governmental and military-is key to avoid both duplication and gaps. With input from LMIC and HIC personnel of various backgrounds-trauma and subspecialty surgery, nursing, information technology and telemedicine, and healthcare administration-creative solutions to the challenges of expanding care (both daily and disaster) are developed. MCCs are evolving initially in Chile and Pakistan. Technologies for cost-effective healthcare in LMICs include smartphone apps (enhance prehospital care) to electronic data collection and analysis (quality improvement) to telemedicine and drones/robots (support of remote regions and resource optimisation during both daily care and disasters) to resilient, mobile medical/surgical facilities (eg, battery-operated CT scanners). The co-ordination of personnel (within LMICs, and between LMICs and HICs) and the integration of cost-effective advanced technology are features of MCCs. Providing quality, cost-effective care 24/7/365 to the 5 billion who lack it presently makes MCCs an appealing means to achieve the healthcare-related United Nations Sustainable Development Goals for 2030.

High efficient electrical stimulation of hippocampal slices with vertically aligned carbon nanofiber microbrush array.

Long-term neuroprostheses for functional electrical stimulation must efficiently stimulate tissue without electrolyzing water and raising the extracellular pH to toxic levels. Comparison of the stimulation efficiency of tungsten wire electrodes (W wires), platinum microelectrode arrays (PtMEA), as-grown vertically aligned carbon nanofiber microbrush arrays (VACNF MBAs), and polypyrrole coated (PPy-coated) VACNF MBAs in eliciting field potentials in the hippocampus slice indicates that, at low stimulating voltages that preclude the electrolysis of water, only the PPy-coated VACNF MBA is able to stimulate the CA3 to CA1 pathway. Unlike the W wires, PtMEA, as-grown VACNF MBA, and the PPy-coated VACNF MBA elicit only excitatory postsynaptic potentials (EPSPs). Furthermore, the PPy-coated VACNF MBA evokes somatic action potentials in addition to EPSPs. These results highlight the PPy-coated VACNF's advantages in lower electrode impedance, ability to stimulate tissue through a biocompatible chloride flux, and stable vertical alignment in liquid that enables access to spatially confined regions of neuronal cells.

Nanotechnology and neurosurgery.

Various nanotechniques will make substantial contributions to the advancement of neurosurgery in the near future. We here review nanotechniques relevant to (1) nanomanipulation, (2) nanoimaging, (3) non-surgical nanorepair, and (4) nanoneuromodulation. Nanomanipulation includes several techniques for performing what might be called 'surgery' on the nervous system at the level of the neuron, neuronal processes, or intracellularly. Nanoimaging refers to viewing the nervous system (and its disorders) at the cellular or subcellular level. Non-surgical nanorepair considers substances (usually manufactured rather than naturally occurring) with impressive properties to promote axonal regeneration, halt deleterious processes (e.g., hemorrhaging), and extend neuronal (and organ to organism level) lifespan. Nanoneuromodulation refers to interacting with the nervous system at the nano/neuronal level-either monitoring or stimulating-in order to affect the nervous system's electrical and/or electrochemical (e.g., neurotransmitter) function.

Global health, global surgery and mass casualties. I. Rationale for integrated mass casualty centres.

It has been well-documented recently that 5 billion people globally lack surgical care. Also well-documented is the need to improve mass casualty disaster response. Many of the United Nations (UN) Sustainable Development Goals (SDGs) for 2030-healthcare and economic milestones-require significant improvement in global surgical care, particularly in low-income and middle-income countries. Trauma/stroke centres evolved in high-income countries with evidence that 24/7/365 surgical and critical care markedly improved morbidity and mortality for trauma and stroke and for cardiovascular events, difficult childbirth, acute abdomen. Duplication of emergency services, especially civilian and military, often results in suboptimal, expensive care. By combining all healthcare resources within the ongoing healthcare system, more efficient care for both individual emergencies and mass casualty situations can be achieved. We describe progress in establishing mass casualty centres in Chile and Pakistan. In both locations, planning among the stakeholders (primarily civilian and military) indicates the feasibility of such integrated surgical and emergency care. We also review other programmes and initiatives to provide integrated mass casualty disaster response. Integrated mass casualty centres are a feasible means to improve both day-to-day surgical care and mass casualty disaster response. The humanitarian aspect of mass casualty disasters facilitates integration among stakeholders-from local healthcare systems to military resources to international healthcare organisations. The benefits of mass casualty centres-both healthcare and economic-can facilitate achieving the 2030 UN SDGs.

Clinical Cell Therapy Guidelines for Neurorestoration (IANR/CANR 2017).

Cell therapy has been shown to be a key clinical therapeutic option for central nervous system diseases or damage. Standardization of clinical cell therapy procedures is an important task for professional associations devoted to cell therapy. The Chinese Branch of the International Association of Neurorestoratology (IANR) completed the first set of guidelines governing the clinical application of neurorestoration in 2011. The IANR and the Chinese Association of Neurorestoratology (CANR) collaborated to propose the current version "Clinical Cell Therapy Guidelines for Neurorestoration (IANR/CANR 2017)". The IANR council board members and CANR committee members approved this proposal on September 1, 2016, and recommend it to clinical practitioners of cellular therapy. These guidelines include items of cell type nomenclature, cell quality control, minimal suggested cell doses, patient-informed consent, indications for undergoing cell therapy, contraindications for undergoing cell therapy, documentation of procedure and therapy, safety evaluation, efficacy evaluation, policy of repeated treatments, do not charge patients for unproven therapies, basic principles of cell therapy, and publishing responsibility.

Neuroprotection at the nanolevel--Part I: Introduction to nanoneurosurgery.

Nanoneurosurgery demands a departure from the traditional "excise what you can see and touch" role of neurosurgeons. Moreover, there is a conceptual leap necessary for neuroscientists as well as neurosurgeons in developing and applying nanotechniques to neurosurgery at the nanolevel. After introducing the realm of nanotechnology and some unique properties of nanomaterials, I review several of the nanotechniques in development that are most likely to affect neuroprotection at the nanolevel. These techniques include quantum dot "nanobarcode" labeling of cellular and subcellular entities, as well as nanotechniques for following enzymatic reactions in real time. Nanoscaffolds offer mechanical enhancement of neurorepair; carbon nanotube electrode arrays can provide nanolevel electrical and chemical enhancement. Even traditional "cut and sew" surgery is being taken down to the micron, if not nano, level for single axon repair, and the technology can use capillaries to deliver therapeutics to virtually any portion of the nervous system with greater than pinpoint accuracy. In this report, I use these nanotechniques to introduce the multiplex nanodevices under development.

Neuroprotection at the nanolevel--Part II: Nanodevices for neuromodulation--deep brain stimulation and spinal cord injury.

Nanotechniques presented in this article's companion report are being multiplexed into nanodevices that promise to greatly advance our understanding and treatment of many nervous system disorders. Current neuromodulation techniques for deep brain stimulation have major drawbacks, such as large size (in comparison with ideal of small neuron group stimulation), lack of feedback monitoring of brain electrical activity, and high electrical current needs. Carbon nanotube nanoelectrode arrays address these drawbacks and offer the possibility of monitoring neurotransmitter levels at the synapse/neuronal level in real time. Such arrays can monitor and modulate electrochemical events occurring among neural networks, which should add greatly to our understanding of neuronal communication. A multiplex nanodevice for studying (and enhancing) axonal regeneration after spinal cord injury is also being developed. The nanotechniques described in the companion piece are combined in a micron-sized neural growth tube lined with nanodevices through which the regenerating axon extends--allowing continuous monitoring and modulation of the axon's electrochemical environment plus directional guidance with a biodegradable nanoscaffold. Multifunction nanodevices provide opportunities for neuronal (and subneuronal) monitoring and modulation that will enhance neuroprotection and neurorepair far beyond the micro- and macrolevel techniques used heretofore.

Vertically aligned carbon nanofiber architecture as a multifunctional 3-D neural electrical interface.

Developing biomaterial constructs that closely mimic the natural tissue microenvironment with its complex chemical and physical cues is essential for improving the function and reliability of implantable devices, especially those that require direct neural-electrical interfaces. Here we demonstrate that free-standing vertically aligned carbon nanofiber (VACNF) arrays can be used as a multifunctional 3-D brush-like nanoengineered matrix that interpenetrates the neuronal network of PC12 cells. We found that PC12 neuron cells cultured on VACNF substrates can form extended neural network upon proper chemical and biochemical modifications. The soft 3-D VACNF architecture provides a new platform to fine-tune the topographical, mechanical, chemical, and electrical cues at subcellular nanoscale. This new biomaterial platform can be used for both fundamental studies of material-cell interactions and the development of chronically stable implantable neural devices. Micropatterned multiplex VACNF arrays can be selectively controlled by electrical and electrochemical methods to provide localized stimulation with extraordinary spatiotemporal resolution. Further development of this technology may potentially result in a highly multiplex closed-loop system with multifunctions for neuromodulation and neuroprostheses.

Planning and Executing the Neurosurgery Boot Camp: The Bolivia Experience.

BACKGROUND: The neurosurgical boot camp has been fully incorporated into U.S. postgraduate education. This is the first implementation of the neurosurgical boot in a developing country. To advance neurosurgical education, we developed a similar boot camp program, in collaboration with Bolivian neurosurgeons, to determine its feasibility and effectiveness in an international setting. METHODS: In a collective effort, the Bolivian Society for Neurosurgery, Foundation for International Education in Neurological Surgery, Solidarity Bridge, and University of Massachusetts organized and executed the first South American neurosurgical boot camp in Bolivia in 2015. Both U.S. and Bolivian faculty led didactic lectures followed by a practicum day using mannequins and simulators. South American residents and faculty were surveyed after the course to determine levels of enthusiasm and their perceived improvement in fund of knowledge and course effectiveness. RESULTS: Twenty-four neurosurgery residents from 5 South American countries participated. Average survey scores ranged between 4.2 and 4.9 out of 5. Five Bolivian neurosurgeons completed the survey with average scores of 4.5-5. This event allowed for Bolivian leaders in the field to unify around education, resulting in the formation of an institute to continue similar initiatives. Total cost was estimated at $40 000 USD; however, significant faculty, industry, and donor support helped offset this amount. CONCLUSION: The first South American neurosurgical boot camp had significant value and was well received in Bolivia. This humanitarian model provides a sustainable solution to education needs and should be expanded to other regions as a means for standardizing the core competencies in neurosurgery.

Neuroprotection trek--the next generation: the measurement is the message.

Animal trials of many pharmacological neuroprotective agents have been quite successful, whereas trials in humans have been uniformly disappointing. A major difference between laboratory research in animals and clinical research in humans is the amount and/or quality of data obtained. The goal of this presentation is to argue that when clinical studies consist of more valid, objective data--that is, as our measurement capabilities in clinical research become as robust as they are in laboratory research--we are likely to gain new insights into both (1) injury to the nervous system and (2) neuroprotective treatment strategies. Technological advances (in data acquisition and analysis)--often novel even in the laboratory--will be the "scale" that will enable progress in measurement. As examples of such technological advances, two projects initiated at NASA Ames Research Center are cited. The NASA Smart Probe Project, with the goal of combining multiple microsensors and neural networks for real-time tissue identification (e.g., for tumor detection), has recently moved into the clinical realm, with a prototype being used to diagnose breast cancer in women "on the spot". The NASA Nanoelectrode Array Project has fabricated nanoscale devices that can simultaneously monitor electrical activity and neurotransmitter concentrations, while providing electrical stimulation focally and precisely (and potentially in a closed-loop fashion based on the input from the nanosensors). The large amounts of data that such techniques can acquire and analyze--separated spatially and temporally throughout the nervous system, if necessary--will provide insights not only into neuroprotective strategies, but also into the workings of the nervous system itself.