Microphysiological systems (MPS) designed to study the complexities of the peripheral and central nervous systems have made marked improvements over the years and have allowed researchers to assess in two and three dimensions the functional interconnectivity of neuronal tissues. The recent generation of brain organoids has further propelled the field into the nascent recapitulation of structural, functional, and effective connectivities which are found within the native human nervous system. Herein, we will review advances in culture methodologies, focused especially on those of human tissues, which seek to bridge the gap from 2D cultures to hierarchical and defined 3D MPS with the end goal of developing a robust nervous system-on-a-chip platform. These advances have far-reaching implications within basic science, pharmaceutical development, and translational medicine disciplines. Microphysiological systems (MPS) designed to study the complexities of the peripheral and central nervous system have made marked improvements over the years and have allowed researchers to assess in two and three dimensions the functional interconnectivity of neuronal tissues. The recent generation of brain organoids has further propelled the field into the nascent recapitulation of structural, functional and effective connectivity which is found within the native human nervous system. Herein, we will review advances in culture methodologies, focused especially on those of human tissues, which seek to bridge the gap from 2D cultures to hierarchical and defined 3D MPS with the end goal of developing a robust nervous system-on-a-chip platform. Rather than provide a comprehensive review on this extensive subject, we have endeavored to highlight a number of important design considerations that are especially important for developing models of the nervous system. We discuss features including substrate and tissue mechanics, inclusion of neuron and glial subtypes, cell-cell interactions, representative histoarchitecture, functional assessments, and the emerging importance of 3D configuration. We then turn to how those design features are being implemented specifically in models of the central nervous system and of peripheral nerve. We then briefly discuss some translational applications of these models and conclude with a discussion of improvements that are expected in key areas with a nod toward future development. These advances have far-reaching implications within basic science, pharmaceutical development, and translational medicine disciplines.et al. Millions of Americans suffer from neurological disorders such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) and novel therapeutics are necessary to treat said conditions. Globally, in 2016, neurological disorders were the leading cause of disability-adjusted life years (276 million) and second leading cause of deaths (9 million)  approaches, jointly termed microphysiological systems as they replicate some organ architecture and physiology Figs.  and 2. Tin vitro study. Extracellular matrix proteins are integral to creating biological niches, which promote the differentiation . And while not necessarily a barrier-forming cell, satellite glia within the periphery envelope dorsal root ganglion somata and perform a litany of functions related to pain processing  is widely the most studied barrier and has been reviewed extensively prior  are the emerging gold standard for et al. et al. et al. in vitro and in vivo  can show functional connectivity wherein “an observable phenomenon… can be quantified with measures of statistical dependencies” Friston . This alet al. Efforts to use microfabrication techniques to control the organization and connectivity of CNS cells in vitro date back at least several decades to the invention of the eponymous Campenot chamber by Robert Campenot  Campeno. These cet al. Brain organoids are made by differentiating hiPSCs or embryonic stem cells through a neural lineage to generate the major cells that make up the human brain . Co-localization of neuronal neurofilament-heavy protein (NF-H) with MBP immunostaining suggested evidence of myelin formation as early as 4wk into differentiation and up to 40% myelinated axons by 8wk of development. Transmission electron microscopy confirmed the presence of compact myelin microstructure by 8wk of development and enabled measurement of G ratios, which may serve as a metric for modeling myelin diseases. This approach may lend itself for use in studying demyelination and remyelination. Cuprizone and lysophosphatidylcholine (LPC) treatment  morphology with a single axon extending from the soma in the spinal cord to the periphery or else a pseudo-bipolar (sensory) morphology that branches towards the periphery and the dorsal horn of the spinal cord. Merely plating peripheral neurons on planar surfaces does not allow for recreation of this morphology; therefore, a myriad of engineering techniques have been employed to generate MPSs that can appropriately induce polarized and parallel-aligned axon growth mimicking nerve structure. 3D printed microchannels have been able to guide DRG axon outgrowth and co-culture with Schwann cells has shown successful induction of myelination and Schwann cell proliferation , are able to be manually manipulated and placed within tissue constructs composed of various substrates, such as methacrylated gelatins or more ubiquitous ECM scaffolds such as Matrigel. Notably, these spheroids can be cultured for many weeks without losing functionality. These long-term culture conditions allow for extensive neurite outgrowth in all dimensions with growth-restrictive hydrogels being able to confine dense axon beds to specific areas for electrophysiological recordings. These constructs can then be used for electrophysiological assessment and exhibit peaks that are able to be defined by treatment with drugs  and neuronal  cell functions and be able to record electrophysiological signals with high signal-to-noise ratios. As within any cellular system, maintaining high viability is crucial. Thick tissue sections and large organoids lack vasculature and therefore do not have the ability to supply oxygen deep into tissue. To overcome the formation of necrotic cores, it is then important to maintain a tissue volume that does not exceed a radius or depth of roughly 200μm . Compound action potentials were able to be recorded with conduction velocity and G ratios able to be quantified. Further development of this system is geared towards the fabrication of peripheral sensory neuronal systems with the promotion of Schwann cell migration being a critical goal to enable myelination of greater length scales.Primary embryonic rat tissue has long served as the basis for peripheral nerve studies and has elucidated mechanisms of myelination by Schwann cells dating back to the 1980s  hold the capacity to elucidate many basic science inquiries and are entering nascent stages of allowing for higher throughput capacity for drug screening. By integrating these neural MPSs with the target tissue, their innervation of or providing reception for et al. in vitro  enables 3D systems to study how drugs and pathogens cross these barriers and affect neural and glial tissue alike. Finally, being able to faithfully record electrophysiological outcomes must move away from planar electrodes found on MEAs and not rely on tissue-disruptive field recordings. While the automation of patch clamping via robotics (Holst et al. et al. et al. et al. Carrying these ideas forward to different distinct loci within the brain, such as the


The further development of balanced multimodal anesthesia, combining two or more drugs with complementary modes of action helps to shape and maintain specific brain states and relevant aspects of murine physiology. Functional connectivity and its dynamic repertoire as assessed by fMRI can be used to make inferences about cortical states and provide additional information about whole-brain functional dynamics. Based on this, a simple and comprehensive functional neurosignature pattern can be determined for use in defining brain states and anesthetic depth in rest and in response to stimuli. Such a signature can be evaluated and shared between labs to indicate the brain state of a mouse during experiments, an important step toward translating findings across species.In recent years, technical and procedural advances have brought functional magnetic resonance imaging (fMRI) to the field of murine neuroscience. Due to its unique capacity to measure functional activity non-invasively, across the entire brain, fMRI allows for the direct comparison of large-scale murine and human brain functions. This opens an avenue for bidirectional translational strategies to address fundamental questions ranging from neurological disorders to the nature of consciousness. The key challenges of murine fMRI are: (1) to generate and maintain functional brain states that approximate those of calm and relaxed human volunteers, while (2) preserving neurovascular coupling and physiological baseline conditions. Low-dose anesthetic protocols are commonly applied in murine functional brain studies to prevent stress and facilitate a calm and relaxed condition among animals. Yet, current mono-anesthesia has been shown to impair neural transmission and hemodynamic integrity. By linking the current state of murine electrophysiology, Ca Allen Brain ProjectBlue Brain ProjectMouse ENCODE ProjectMuch of our understanding of human brain functions comes from murine studies. The ease of genetic modification and other practical and financial issues have made the mouse the best-explored mammalian model organism in neuroscience. A multitude of murine protocols and repositories provide reliable benchmarks in today’s brain research (including the 3). This permits direct comparisons of large-scale murine and human brain functions, and opens up opportunities to use a plethora of genetically engineered models to clarify a wide range of clinical and basic neuroscience issues—from the pathogenesis of neurological disorders to fundamental questions about consciousness.In recent years, technical and procedural advances have brought functional magnetic resonance imaging (fMRI) to the field of murine neuroscience. The unique capacity of fMRI to measure functional brain activity non-invasively and across the entire brain relies on tight neurovascular coupling, in which increased neural activity triggers local elevations in cerebral blood flow (CBF), cerebral blood volume (CBV), and blood oxygenation  humans, a mouse has no interest in participating in an fMRI study. Head fixation, body restraint, and habituation to the acoustic noise produced by the MR gradients (up to 115 dB sound pressure) cause enormous stress to this remarkably rousable creature, which is far less amenable to training than rats , and second, to maintain hemodynamic integrity (see “Murine fMRI and Hemodynamic Integrity” section).Low-dose anesthetic protocols are commonly applied in mouse fMRI to address these problems and to alleviate potential suffering due to stress, fear, and pain. The goal is to achieve high-quality translational data from sedated, i.e., calm, relaxed, and undistracted subjects. However, anesthetics have been shown to impair neural transmission , local field potentials (LFP), or calcium (Ca2+) imaging, yielding distinct spatiotemporal profiles that can be considered as signatures of distinct brain states.In the murine as in the human brain, neural information is processed against a background of spontaneous, ongoing activity generated by the promiscuous firing of neurons or structured patterns of neural populations. These oscillatory dynamics can be assessed cortical activation  is positively correlated to the level of general arousal, which is mediated by modulatory input from subcortical cholinergic and monoaminergic  nuclei  nuclei . These aSensory stimuli are processed differently against the background of diverse cortical states  receptor agonists including volatile ethers, α2 adrenoreceptor (α2AR) agonists, and N-methyl-d-aspartate (NMDA) receptor antagonists. Each class exerts its sedating effects based on one of three key principles: (1) top-down by inhibiting cortical neurons directly (NMDA receptor antagonists); (2) bottom-up by suppressing subcortical arousal nuclei that affect cortical states (α2AR agonists); or (3) both, by inhibiting neurons across the entire brain  and excitatory (depolarizing) inputs that are required to exceed the threshold for rebound spiking. These inputs can be differently modulated by distinct anesthetic types and dosages. The resulting spiking patterns reverberate in recurrent neuronal circuits and can synchronize large networks of cortical neurons by reciprocal coupling, which manifests as cortical oscillations on EEG. These oscillations are generated either within the cortex or the thalamus, or between these two densely interconnected regions . All anesthetics exert their sedating effects by acting on specific target receptor types , leading regions .Thalamic key players of rhythm generation are excitatory thalamocortical (TC) cells in intralaminar and medial thalamic nuclei  are produced within the cortex  waves has been shown to be a more reliable marker for stable sedation  requires the driving input of higher-order TC nuclei . Since tThis causal relationship unifies two central hypotheses of consciousness, which had previously assumed a dependence on either cortical feedback or higher-order TC loops , which coincides with a sudden rise in slow-delta power; i.e., delta oscillations (1–4 Hz) primarily in the frontal areas, and slow waves (<1 Hz) across the entire cortex . Slow-deThe exact phase-amplitude coupling of slower and faster waves is a function of the anesthetic depth  and are robust to various experimental perturbations  clearly dominate the EEG . Slow wavia recurrent TC projections  of local endogenous sleep-promoting cells that send inhibitory projections to other key arousal nuclei in the midbrain and pons . This cahibition .cerveau isolé  in rodent fMRI—a well-established behavioral measure of anesthetic depth for volatile ethers Steffey, . BrieflyAnesthetic depth can be monitored by behavioral markers and pupil dilation diameter to assess the level of arousal , which occurs earlier, approximately with the appearance of frontal alpha oscillations and before slow waves dominate the EEG . At thisA Agonists Suppress Neural Activity Across the Central Nervous System” section; reviewed in Pennartz et al., This offers not only a direct link between introspective reports, behavioral and neuroimaging markers, but also a vivid example of how the examination of large-scale networks using fMRI can complement models of LOC that are based on the suppression of feedback or feedforward information transfer along the cortical hierarchy  is added to the inspiratory gas  stimuli, like subcutaneous electrostimulation  lead either to bilateral patterns or to no response at all  compared to medical air (21%). This has been explained by a decrease in lung volume for pure oxygen based on alveolar collapse, known as absorption atelectasis  that were highly correlated with transient MABP surges induced by methods of controlled pharmacological vasoconstriction , which coincide with homeostatic and behavioral responses . Notably, the majority of murine resting-state studies have been conducted under anesthesia  promote FC that can span extensive cortical networks in humans and rats, occasionally reaching into the basal ganglia and thalamic structures . Each time-shifted segment then undergoes a correlation analysis, which gives access to dynamic aspects of FC, which have been reported to be well conserved across rats, monkeys, and humans  disrupt FC in a bottom-up manner . DisinhiKetamine, on the other hand, which acts primarily in a top-down manner in the cortex, mediates LOC by direct suppression of fronto-parietal and further cortico-cortical FC . In contCombining isoflurane and medetomidine at levels roughly half their mono-anesthetic dosages . Comparing FC matrices for medetomidine-isoflurane against propofol with reference to the “ground truth” of an awake habituated rat gives an immediate impression of what we are heading for . With reSince brain states during wakefulness alter with the level of arousal, such a “ground truth” is still prone to reflect stress and restraint rather than the resting state, which becomes critical when comparing results with human volunteers  to induce and maintain brain states that correspond with those of calm and relaxed human volunteers; and (2) to assure hemodynamic integrity—in other words, to preserve neurovascular coupling and physiological baseline conditions. Up to this point, we have discussed the general principles of anesthesia and have highlighted the need to recognize and overcome the shortcomings of current anesthetic protocols. This will require strategies to shape, maintain, and unambiguously identify distinct brain states in fMRI that meet the above criteria, to conduct reliable, reproducible studies and translate findings from mice to humans.Preclinical fMRI aims for an animal that is sufficiently sedated, yet with a fully functional brain. This challenge puts high demands on anesthetic protocols to induce and maintain an intermediate brain state that closely approximates an awake, calm, relaxed, and undistracted state during the fMRI task. Current standard practices involving simple mono-anesthesia are outdated. Balanced multimodal anesthesia, in which two or more drugs are combined to balance their complementary effects, has come into use in the clinic  identifying a brain state and the integrity of its qualifiers; and (2) comparing this state across subjects, trials, scanners, labs, and species. We will refer to this identifier of a specific brain state as a maintained, intermediate neurophysiologically-determined (MIND) signature.Among these qualifiers, we choose one A number of qualifiers have the potential to illuminate characteristics of brain states and the functional implications that accompany them. The set of such qualifiers is growing rapidly through new findings and the development of novel analytical tools  or invasive electrophysiological recordings of SEP and Ca2+ signals in primary, secondary sensory, and higher-order cortical areas. Multichannel recordings .Another advantage of FC in fMRI is that it can be acquired simply in the form of a resting-state scan without any additional equipment. This makes it a strong candidate measure for determining a MIND signature in translational fMRI. fMRI tasks can be flanked with brief resting-state scans that permit the brain state to be identified at regular points throughout an experiment. Such flanking approaches of FC have previously been shown to reveal valuable information on anesthetic effects on murine fMRI tasks  are adjusted to functionally approximate the awake state and (2) indicate the integrity of a defined set of functional qualifiers. This concept assumes a mechanistic connection between FC and the other qualifiers, so that specific functional properties can be inferred from the detection of a specific MIND signature . Such a Defining a MIND signature that could indicate the cortical state, stimulus–response properties, their hemodynamic translation, and dynamic FC in the form of one unique identifier would be extremely useful. The unambiguous identification of brain states during fMRI would also substantially improve the process of developing (and communicating) novel anesthetic protocols. A verifiable linkage between these qualifiers requires the simultaneous assessment of neural and hemodynamic readouts (see below). However, a large fraction of qualifiers can be assessed in separate measurements. It is reasonable to perform initial anesthetic adjustments outside the MR scanner, based on electrophysiological and behavioral responses to stimuli and cortical signatures during rest , while under a tight control of physiological parameters. It is therefore important to select conditions under which the qualifiers measured outside the scanner can be linked to others obtained during fMRI.via sophisticated design of hardware and pulse sequences . In fact, fMRI at high levels of sound pressure substantially boosts BOLD responses to subcutaneous electrostimulation of the rat under α-chloralose, compared to silent fMRI protocols or after deafening by cochleotomy  anesthetic effects could be referenced against an awake, but calm and relaxed volunteer—even within the same subject; (2) introspective reports could link specific MIND signatures to LOC and to the overall experience; and (3) determining precise translational limitations in general brain functions and specific anesthetic effects, to assess the scope for murine transgenic and optogenetic applications to explore human cognition and consciousness.2+ imaging, and other modalities to probe brain functions. In clinical practice, balanced multimodal anesthesia is common and increasingly being used as a substitute for opioids, especially in light of the current opioid crisis in the US (Brown et al., The need for effective anesthetic protocols and a better comprehension of their underpinnings is not exclusive to translational fMRI, but is equally important for preclinical researchers studying electrophysiology, CaYet accessing knowledge on anesthetic effects is not always straightforward. Much valuable information is buried in publications that focus on biological research questions and use anesthesia only as an experimental tool. Many anecdotal observations of crucial effects remain unpublished “lab lore” and are not available to the community. Having access to this information could substantially accelerate our progress in detailing anesthetic effects to develop multimodal protocols for a stable sedation with the best possible preservation of brain functions. A community-driven open database of key observations—collected from publications and lab notes—would make this information more accessible, promoting reproducibility and preventing research groups from running into the same “dead ends” already discovered by others. We are currently developing a web-based infrastructure for such an open initiative across neuroimaging communities, to facilitate the exchange of this information. We invite anyone interested in this initiative to contact the corresponding author.Within the fMRI community, the additional assessments of resting-state fMRI at selected points throughout the experiment would help to specify the actual brain state and make comparisons of data across labs more reliable. The concept of the MIND signature could support this process by defining a set of qualifiers and one identifier readout that permits a reliable indication of a specific brain state and its related functional properties. Our future work is dedicated to further refining and establishing the MIND signature in a collaborative effort.To make proper use of translational fMRI for a direct, non-invasive comparison between large-scale brain functions in humans and mice, it is essential to understand the impact of anesthesia on neural physiology. The animal is usually anesthetized to avoid variations due to stress and distraction, with the ultimate aim of achieving stable sedation while maintaining a functional brain state close to that of an awake, resting subject. Maintaining functional brain states and neurovascular coupling are the two major challenges of preclinical fMRI. Most anesthetics affect neural and hemodynamic integrity in different ways, based on their target receptors, which typically assigns them to one of the three main classes of anesthesia. Despite addressing different pathways, all classes exert their effects by spoiling the phase-frequency relationships of remote neuronal populations, which eventually leads to a breakdown of information transfer along the cortical hierarchy and thus LOC. The resulting disruption of higher-order circuits is reflected in FC, although the specifiability of markers for discrete functional stages remain to be clarified. Better knowledge of the mechanisms of action allows to balance different compounds in order to develop multimodal anesthetic protocols for translational fMRI, ideally revealing mainly species-specific variations and not the influence of anesthesia. The concept of the MIND signature has been proposed as an approach to determine and re-identify specific brain states and related functional properties induced by different anesthetic drugs and levels across studies, laboratories, and species.HR: conceiving and drafting the article, agrees 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. TN: revising the article critically, final approval of the submitted version.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.


Mucopolysaccharidosis (MPS) consists of a group of 11 enzymatic defects which result in accumulation of undegraded glycosaminoglycans (GAG) in lysosomes. MPS is a severe metabolic disease for which only bone marrow/hematopoietic stem cell transplantation and enzyme replacement therapy are current therapeutic options. However, they are available for only a few of MPS types, and are ineffective in treatment of central nervous system. Recent studies indicated that the autophagy process can be impaired in MPS, but various contradictory conclusions have been published in this matter. Nevertheless, stimulation of autophagy has been proposed as a potential therapeutic option for MPS, and very recent results suggest that such approach might be effective in improving MPS symptoms. Still the mechanisms of autophagy changes in MPS are not clear, and efficiency of autophagy activation in clearing the storage material requires further investigation. These problems are summarized and discussed in this review. Mucopolysaccharidosis (MPS) is a common name for the group of lysosomal storage diseases (LSD), characterized by accumulation of undegraded glycosaminoglycans (GAGs) Fig. . These cThe lack of effective therapy for MPS which would correct all the disease symptoms  was found to cause extremely high levels of heparan sulfate (one of GAGs) in plasma and urine of patients who developed severe MPS-like symptoms. Thus, it was proposed to classify this disorder as a new MPS type. Intriguingly, the VPS33A protein is involved in autophagy, while the c.1492C > T mutation did not alter this process  might indicate either enhanced autophagosome formation or decreased autophagic flux. In the latter case, the autophagy process is impaired rather than stimulated. Therefore, we suggest that discrepancies in published conclusions on the efficiency of autophagy in MPS could arise from various interpretations of obtained results. Despite these differences, it appears that in most cases, significant changes in autophagy were found in MPS cells which indicate that this process in affected by accumulation of GAGs. According to the arguments presented above, we favor the hypothesis that autophagy is generally impaired in MPS, while opposite conclusions might arise from ambiguous interpretation of the results and/or from considering only gene-expression patterns rather than actual changes in cellular processes. Nevertheless, we cannot exclude that autophagy might be differentially affected in various types or subtypes of MPS.Since autophagy leads to degradation of accumulated compounds in cells, one might assume that stimulation of this process could be assessed as a potential strategy to develop novel treatments for diseases caused by storage of various macromolecules. Such a strategy has been proposed, and has been discussed recently  occurs in MPS, having an important role in the development of various symptoms, including neurodegeneration. Therefore, one might predict that even reduction of only secondary storage material should also be beneficial for MPS patients.The first indication that enhanced lysosomal biogenesis might be profitable for MPS patients came from studies on genistein, a natural isoflavone, which was previously demonstrated to impair synthesis of GAG, thus, being considered in substrate reduction therapy for MPS (Piotrowska et al. Despite indication that genistein can activate autophagy, it was not known if such activation can be of therapeutic potential in MPS. However, very recent studies demonstrated that trehalose, another autophagy stimulator, could improve symptoms of MPS IIIB mice (Lotfi et al. Recent studies indicated that the autophagy process may be impaired in MPS, and that its stimulation could be a promising therapeutic approach in this group of LSD (summarized in Fig.


Nonetheless, the group recognized the public health importance of resolving this question and suggested good practice guidelines for future studies.Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection (LRTI) and hospitalization in infants and children globally. Many observational studies have found an association between RSV LRTI in early life and subsequent respiratory morbidity, including recurrent wheeze of early childhood (RWEC) and asthma. Conversely, two randomized placebo-controlled trials of efficacious anti-RSV monoclonal antibodies (mAbs) in heterogenous infant populations found no difference in physician-diagnosed RWEC or asthma by treatment group. If a causal association exists and RSV vaccines and mAbs can prevent a substantial fraction of RWEC/asthma, the full public health value of these interventions would markedly increase. The primary alternative interpretation of the observational data is that RSV LRTI in early life is a marker of an underlying predisposition for the development of RWEC and asthma. If this is the case, RSV vaccines and mAbs would not necessarily be expected to impact these outcomes. To evaluate whether the available evidence supports a causal association between RSV LRTI and RWEC/asthma and to provide guidance for future studies, the World Health Organization convened a meeting of subject matter experts on February 12–13, 2019 in Geneva, Switzerland. After discussing relevant background information and reviewing the current epidemiologic evidence, the group determined that: (i) the evidence is inconclusive in establishing a  The current evidence supporting a causal association between RSV and RWEC/asthma is mixed. Understanding whether prevention of RSV LRTI can lead to reductions in rates of RWEC and asthma will contribute important information to policy decisions regarding RSV vaccines and mAbs.meta-analysis that will be reported separately. Third was a convening of subject matter experts on February 12–13, 2019 in Geneva, Switzerland (Agenda and Participants in Appendix A). The objectives of the meeting were: (i) to evaluate the strength of the current evidence for a causal association between early life RSV LRTI and subsequent RWEC/asthma, (ii) to evaluate the evidence that future RSV vaccines/mAbs can reduce rates of RWEC/asthma, and (iii) to provide methodological guidance for future studies. This report summarizes the meeting.To shed light on this important question, the World Health Organization (WHO) undertook three activities. The first comprised an analysis of the sample size required to estimate the potential impact of RSV prevention by vaccines or mAbs on the subsequent development of RWEC in RCTs 2Epidemiological studies have shown that more than half of children experience their first RSV infection in the first 12 months of life and almost all will have had an infection by two years of age 3Wheeze, which can refer to both a clinical sign and a reported symptom, is an intrathoracic sound and a sign of airflow limitation According to the Global Initiative for Asthma, asthma can be challenging to diagnose in children less than six years of age for the following reasons: (1) many young children experience viral-associated recurrent wheezing in the absence of asthma, and (2) measurements of airway obstruction using spirometry are challenging to perform in this age group and can be normal between symptomatic episodes Asthma is believed to be caused by complex interactions between genes and the environment. Heritability estimates for asthma range from 25 to 95% and numerous markers of asthma risk have been identified, most notably polymorphisms at the chromosome 17q21 locus 4An association between infant bronchiolitis and later development of asthma was first hypothesized in the late 1950 s prior to any LRTI event, and found lower lung compliance and higher resistance to be associated with increased risk for both RSV hospitalization and number of days with subsequent wheeze in the first year of life It is not well understood why some otherwise healthy infants develop severe LRTI when infected with RSV. Potential explanations include infection with a more virulent RSV strain (37–39), an aberrant host immune response 55.1Most of the evidence for an association between early life RSV LRTI and subsequent RWEC and asthma comes from observational studies, of which only two have been conducted in LMICs The first type of prospective study is referred to here as a “medical event cohort study,” which defines exposure as an RSV LRTI inpatient or outpatient medical event, usually occurring within the first 1–2 years of life. Eligibility for enrollment into medical event cohort studies is therefore defined based on the known RSV LRTI exposure status. When studies compare this exposed group to those without RSV LRTI medical events, or to individuals hospitalized for a non-respiratory condition, many find a positive association between RSV LRTI and subsequent RWEC with odds ratios ranging from 3 to 36 The second type of prospective study is a birth cohort study in which participants are enrolled in early infancy and prospectively surveilled for respiratory illnesses and RWEC/asthma outcomes. These include high-risk birth cohorts that enroll infants born preterm and/or with a family history of asthma or atopy A third type of prospective observational study follows non-randomized infants who received RSV mAbs The association between RSV and RWEC/asthma can also be evaluated retrospectively, using administrative databases such as medical records. Administrative database studies have consistently shown associations between RSV LRTI hospitalization or unspecified bronchiolitis in early life and RWEC/asthma medical events in later life 5.2Two placebo-controlled randomized controlled trials (RCTs) of RSV mAbs have assessed RWEC and/or asthma outcomes. The first trial was an RCT of palivizumab conducted in healthy preterm Dutch infants that showed a decrease in the number of days with parent-reported wheezing in the first year of life and parent-reported current asthma at six years of age in the intervention group, but no difference in physician-diagnosed asthma or lung function at six years of age 5.3meta-analyses meta-analysis was published in 2017 as a part of a series of publications from the REGAL  study. It included 74 publications from the United States, Canada, and Europe (including Turkey and the Russian Federation) meta-analysis published in 2013 included 20 publications from 15 unique studies and found that children with RSV LRTI in early life had significantly higher relative odds of wheeze and asthma in later life compared to those without RSV LRTI  meta-analysis, published in 2019, included 41 observational studies and excluded immunoprophylaxis studies meta-analysis of epidemiologic and clinical trial data that will examine testable implications from both causal and non-causal models for the association between early life RSV LRTI and subsequent wheezing illness. A limitation of all meta-analyses on this topic is that it is challenging to compare results across studies given the use of different exposure and outcome definitions and underlying differences in the populations being studied.Several systematic reviews 66.1Selection bias, information bias, and confounding can each affect observational studies of RSV and RWEC/asthma. Selection bias can occur if children with severe RSV disease are more likely than those with less severe RSV LRTI to be enrolled and retained in a cohort through the study period. Information bias can occur via differential misclassification if children with a history of RSV LRTI are more prone to be diagnosed clinically with RWEC/asthma and/or undergo testing for asthma, or if children in the comparator group have RSV LRTI that is not detected. Misclassification bias can also be introduced if parents of children with RSV LRTI are more likely to report or remember wheezing episodes, and likewise, if parents of children with asthma more readily recall early RSV illness. Another potential source of misclassification bias is that many studies do not define a clear ‘washout’ period after the acute RSV illness, raising the possibility that some wheezing associated with the acute primary RSV disease episodes are misclassified as respiratory sequelae.Confounding can be another source of bias in observational studies. Studies that do not adequately control for risk factors for both RSV LRTI and RWEC/asthma such as age, prematurity, access to health care, co-morbidities, exposure to indoor air pollution and secondhand smoke, and genetic susceptibility may be subject to a confounding bias that overestimates the association. Insufficient understanding of the shared genetic susceptibility for RSV LRTI, RWEC and asthma (e.g. specific immune markers or genes) limits the possibility to control for genetic confounding in observational designs. One approach to control for genetic confounding is to study twins. Although their statistical power is limited by their small size, studies of monozygotic twins discordant for RSV hospitalization in infancy have not shown evidence of differences in asthma prevalence or lung function Another consideration in interpreting observational studies is the choice of comparison group. As noted earlier, a positive association between RSV LRTI and subsequent RWEC/asthma is consistently observed in studies that compare this exposure group to a comparator group without any LRTI medical event, but not when comparing to individuals with an LRTI caused by a pathogen other than RSV. This could be interpreted as meaning that multiple respiratory viruses are causal agents for RWEC/asthma, that LRTI itself is a causal agent, or that the susceptibility to develop LRTI when infected with any respiratory virus is a marker of underlying predisposition for RWEC/asthma.Finally, although some non-randomized studies of RSV immunoprophylaxis in high-risk infants have found a reduction in RWEC or better lung function in treated compared to untreated infants 6.2The greatest advantage of RCTs is that confounding by a shared predisposition for both the exposure and outcome should be eliminated. However, RCTs can be subject to misclassification bias, particularly if unmasking of the treatment assignment occurs before the end of follow up. There may have been such bias in the Dutch palivizumab RCT that showed a decrease in parent-reported asthma at six years of age after unmasking had occurred, but no difference in more objective measures including physician-diagnosed asthma or lung function A limitation of RCTs of RSV mAbs and vaccines is that they require very large sample sizes to detect an association with most RWEC/asthma outcomes. A recent analysis used systematic reviews and expert opinions to test 81 sample size assumption scenarios, with risk ratios between maternal vaccination and recurrent wheezing ranging from 0.9 to 1.0 for 70% of the scenarios 7This report summarizes many of the methodologic challenges faced by studies that aim to assess (1) whether there is a causal association between early life RSV LRTI and subsequent RWEC and asthma, or (2) whether an effective RSV preventive product could be expected to reduce the risk of subsequent RWEC/asthma. Recognizing these limitations, the participants discussed good practices for designing and analyzing future studies in order to maximize their contribution to the evidence base. This guidance is presented in Observational studies: Additional observational studies using conventional designs were considered to be of little value in further elucidating the causal link between RSV LRTI and RWEC/asthma, with a few exceptions. Observational studies that would be of value are those that incorporate measures of neonatal immune function or pre-exposure lung function assessments, and those that involve quasi-random exposure to RSV in specific geographical settings.Randomized controlled trials: RCTs were considered to be the least biased study design to assess both the questions of causal association and whether RSV preventive products can reduce subsequent RWEC/asthma, but they require investment in sufficiently powered individual trials and/or the use of standardized measures of exposure and outcome to allow pooling of data across multiple studies for meta-analyses.Post-introduction studies: Given the large sample sizes required by RCTs, post-introduction studies conducted after RSV vaccines/mAbs are licensed and introduced into national programs were considered to be promising strategies to address these questions. Examples include pre-post ecological studies, case-control studies, and phased introduction studies. Pre-post studies, where population-level rates of RWEC/asthma before and after vaccine introduction are compared, offer a straightforward approach but are not recommended to address these questions due to important limitations. In addition to requiring high quality pre-introduction surveillance data, they are susceptible to bias due to temporal trends in disease prevalence. This is a particular risk for asthma outcomes because asthma prevalence is not constant within communities over time and secular trends in risk factors such as diet, antibiotic use, urbanization and air pollution can be difficult to control for Given the limitations of each approach, a combined strategy incorporating evidence from long-term follow up of randomized trials in addition to post-introduction data will likely be required to determine whether vaccines and mAbs reduce RWEC/asthma. A challenge of all prospective study designs is retaining participants throughout the 3–5 years of follow up that are required before outcomes can be assessed. Regardless of design, all studies conducting long-term follow up should assess the comparability of those who remain in the study to those who are lost to follow-up.Finally, the meeting participants identified key variables, definitions and measurements that future studies assessing these questions should consider . The parThere was agreement that the primary long-term outcomes of early life RSV LRTI that are of public health interest are RWEC, measured until at least three years of age, and asthma, measured at six years of age or later, and that studies should prioritize medically attended outcomes using standard definitions. FOT is a promising tool for objective measures of lung function in infants and young children and can be considered for use in all settings, including LMICs Potential confounders are important to measure in observational studies to the extent possible but some, such as genetic susceptibility, are very difficult to control for. Simple, standardized data collection methods for all co-variates of interest are preferred, with birth weight, preterm birth, and family history of asthma and atopy identified as the highest priority. Finally, although studies are unlikely to be powered to detect effect modification, information about preterm birth, Down syndrome, and congenital heart disease should be collected if available.8The meeting participants agreed that, given the current knowledge of the potential public health benefit, RSV vaccine policy decisions should be based on the efficacy and impact against the spectrum of acute illness caused by RSV LRTI in infants and young children, with the primary focus being prevention of severe disease. Definitive data on the impact of RSV vaccines/mAbs on subsequent RWEC and asthma are unlikely to be available at the time vaccine policy recommendations are made. If high-quality, robust evidence does eventually support a preventive role of RSV vaccines/mAbs for RWEC/asthma, the additional longer term health and economic benefits related to RWEC/asthma prevention could contribute to policy-making in some countries.9meta-analysis This WHO-sponsored meeting was convened to evaluate the current evidence for a causal association between RSV LRTI in young children and subsequent development of RWEC/asthma, to assess the potential for RSV vaccines and mAbs to reduce the risk of RWEC and asthma, and to provide guidance for future studies that are poised to address these questions. The evaluation of the evidence was focused on the body of epidemiological literature rather than the experimental data from animals and humans. Moreover, the application of causal modelling techniques to the epidemiologic data were not considered, but will be addressed in the forthcoming WHO commissioned systematic review and causal association between RSV LRTI and RWEC/asthma, (ii) the evidence does not establish that RSV mAbs and vaccines are likely to have a substantial effect on these outcomes and (iii) the prevention of severe, acute RSV disease in young children, a well-established, substantial public health burden, should continue to be the highest priority for policy-setting bodies deliberating on RSV vaccine and mAb recommendations, regardless of their impact on subsequent RWEC and asthma  the current epidemiological evidence is inconclusive in establishing a d asthma . RSV vacNonetheless, the participants considered that the high burden of RWEC and asthma justifies the continued study of the association between these two conditions, and that a better understanding of the association could contribute to establishing the public health value of RSV vaccines and mAbs. Regardless of whether a causal association exists, the burden of RWEC/asthma in LMICs needs to be elucidated and benchmarked to other public health priorities. Future epidemiological studies that examine the association should follow good practice guidance  using stBoth RSV associated LRTI and RWEC/asthma confer a substantial disease burden in children globally. To identify a single intervention, such an RSV vaccine or mAb, that lessens the burden of both diseases would be a fortuitous public health success. Efforts should continue to better understand whether this can be achieved. Nonetheless, lack of conclusive evidence for a dual preventive impact should not slow the pursuit of new preventive approaches independently targeting each of these important diseases of childhood.The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: LB has regular interaction with pharmaceutical and other industrial partners. He has not received personal fees or other personal benefits. He is the founding chairman of the ReSViNET Foundation. JAE has served as a consultant to Sanofi Pasteur and Meissa Vaccines and her institution receives support from Novavax, AstraZeneca, Merck, and GlaxoSmithKline. LLH reports research grants to her institution from Novavax, Merck, GSK, and Pfizer. TVH receives funding relevant to the submitted work from the National Institutes of Health and the WHO and served on the Pfizer RSV Infant/Maternal Health External Advisory Board in 2019. HN has received grant funding from Bill and Melinda Gates Foundation, Sanofi Pasteur, World Health Organization and Innovative Medicines Initiative. HN has received honoraria and speaker fees from Sanofi Pasteur, Abbvie and Janssen. EAFS reports grant support and personal fees in the last 36 months from Astra Zeneca Inc., Merck & Co., Regeneron Inc., and Pfizer Inc.; grant support from Novavax; and personal fees from Roche Inc. AbbVie Inc., and Alere Inc.


Treatment decisions with curative intent for patients with stage III non-small cell lung cancer (NSCLC) often require a complex decision process, and benefit from continuous communication of expertise among, and between, lung cancer teams. In stage III NSCLC that is deemed unresectable, and in some resectable cases, the ongoing consensus is that concurrent chemoradiotherapy (cCRT) is the most appropriate treatment. Despite this, there are still low numbers of patients with stage III disease who undergo multi-modality cCRT treatment in the United Kingdom, in comparison with other parts of the Europe. The poor outcomes and lack of access to optimal treatment is a call to arms for UK lung cancer teams to improve patient outcomes, through prehabilitation and rehabilitation, to ensure that patients have the best physiological reserve for multi-modality treatment. An experienced multi-disciplinary team is required to assess patient eligibility and deliver cCRT to ensure maximum access for this potentially curative strategy.▼; AstraZeneca UK Limited), when their disease had not progressed following the completion of platinum-based cCRT. Based on these results, durvalumab offers a standard of care as consolidation therapy for such patients. Pembrolizumab and nivolumab are approved for the treatment of patients with stage IV NSCLC and are being investigated in ongoing Phase II and III trials, in patients with stage III disease. Nivolumab was being investigated in a randomised controlled Phase III trial following cCRT ; however, this study was terminated in February 2019 because other treatments have been found to be efficacious, while pembrolizumab following cCRT demonstrated promising efficacy in an open-label Phase II trial in the same setting .Radiotherapy is a modulator of the immune response and tumour microenvironment; emerging evidence suggests that radiotherapy triggers the patients’ immune system to recognise the increase in T cell diversity. The synergistic effect between radiation and immune check point modulations has been demonstrated in multiple pre-clinical studies and has now been confirmed following the results of the Phase 3 PACIFIC trial, which demonstrated a significant improvement in progression-free survival and overall survival for adult patients with stage III unresectable NSCLC, whose tumours express PD-L1 on ≥1% of tumour cells, who received durvalumab (Imfinzi®In summary, the rapidly expanding role of immunotherapy for metastatic stage IV NSCLC has provided lung cancer teams with the expertise to apply their knowledge to curative stage III NSCLC, offering a more positive outlook for patients, and clinicians, with the introduction of durvalumab for eligible patients with stage III NSCLC.


Point-of-care ultrasound (POCUS) is nowadays an essential tool in critical care. Its role seems more important in neonates and children where other monitoring techniques may be unavailable. POCUS Working Group of the European Society of Paediatric and Neonatal Intensive Care (ESPNIC) aimed to provide evidence-based clinical guidelines for the use of POCUS in critically ill neonates and children.Creation of an international Euro-American panel of paediatric and neonatal intensivists expert in POCUS and systematic review of relevant literature. A literature search was performed, and the level of evidence was assessed according to a GRADE method. Recommendations were developed through discussions managed following a Quaker-based consensus technique and evaluating appropriateness using a modified blind RAND/UCLA voting method. AGREE statement was followed to prepare this document.Panellists agreed on 39 out of 41 recommendations for the use of cardiac, lung, vascular, cerebral and abdominal POCUS in critically ill neonates and children. Recommendations were mostly (28 out of 39) based on moderate quality of evidence (B and C).Evidence-based guidelines for the use of POCUS in critically ill neonates and children are now available. They will be useful to optimise the use of POCUS, training programs and further research, which are urgently needed given the weak quality of evidence available. The incorporation of Point of Care Ultrasound (POCUS) has represented a transformative change in clinical practice, challenging the traditional diagnostic and procedural “art” of medicine, especially in acute care environments. It has emerged as “the new” clinical tool and it has displaced, in some way, the classical stethoscope. It is performed and interpreted by the bedside clinician with the intent of either answering a focused question or achieving a specific procedural goal.The use of POCUS by critical care providers has increased significantly in recent years and adult emergency medicine had pioneered this field with the publication of guidelines for implementation of structured POCUS training –7. TheseBedside goal-directed echocardiography has been the first POCUS application in paediatric practice with guidelines for implementation. An expert statement was published in 2011, followed by the United Kingdom Expert Consensus Statement on Neonatologist Performed Echocardiography (NPE) and recommendations for NPE in Europe –10. The As more acute care providers invest in POCUS technology, it is critically important to define POCUS main purposes, establish formal training and develop accreditation guidelines, in order to maximise POCUS benefits and reducing risks.Therefore, the European Society for Paediatric and Neonatal Intensive Care (ESPNIC) assembled a group of international paediatric POCUS key opinion leaders to create evidence-based guidelines for the use of current and emerging POCUS applications in the neonatal (NICU) and paediatric intensive care units (PICU) by any clinician working in these units.Three lead authors, one neonatologist (YS), one paediatric intensivist (DDL) and one paediatric cardiologist (CT), identified expert colleagues who significantly contributed with publications in the POCUS field and/or have developed POCUS training courses in the last 10 years, similarly to what had been done with previous ESPNIC guidelines . PanelliA.strong agreement . The goal of cardiac POCUS is to obtain physiological and haemodynamic information to aid in clinical decision making. If any structural abnormality are suspected or diagnosed while performing cardiac POCUS, a formal echocardiogram should be performed by a paediatric cardiologist —ing (FS) , 15. In ing (FS) –45. Howestrong agreement . In the presence of tricuspid regurgitation, pulmonary artery systolic pressure (PASP) can be reliably estimated using bedside POCUS. In the absence of right outflow tract obstruction, the regurgitation velocity represents the difference in pressure between the right atrium and the right ventricle. PASP is derived using a modified Bernoulli equation training , 52.Recommendations for use of cardiac POCUSA total of 41 recommendations on the use of POCUS in neonatal and paediatric critical care were discussed. There was strong agreement on 22 recommendations after first-round voting. Following the discussion in an in-person meeting among the experts ), 19 recommendations were re-worded and re-voted in the second round . RDS is characterised by a poorly aerated lung with the absence of A-lines, presence of small “subpleural” consolidations and diffuse white lung (confluent B-lines). Conversely, in TTN, the interstitial pattern alternates with areas of near-normal lung (with A-lines). Pleural line thickening might be seen in late preterm and term babies —by POCUS , 152.agreement . A renal ultrasound is useful to easily detect the presence of hydronephrosis even by novices [POCUS may detect obstructive uropathy in neonates and children [although for a definite diagnosis a detailed assessment should be performed by a paediatric radiologist]— novices –154. Uriagreement . Bowel POCUS may be used to assess peristalsis [POCUS may assess bowel peristalsis in neonates and children—istalsis  but insuistalsis .disagreement [POCUS may recognise hypertrophic pyloric stenosis [although for a definitive diagnosis a detailed assessment should be performed by a paediatric radiologist]—dence D )strong agreement . A paracentesis may be required for either diagnostic or therapeutic purposes. POCUS should be used for pre-procedural planning, identification of epigastric vessels and real-time ultrasonographic guidance. In adult studies, the use of ultrasound has been shown to decrease both bleeding complications and the overall cost of care for patients undergoing in-hospital paracentesis —nclusive , 160. Funclusive , 162. POerfusion , 163–166erfusion . These wthis end .Recommendations for abdominal POCUSSemi-quantitative systolic ventricular function measures that may be used in POCUS have been summarised in Table in general, is indeed important.POCUS is increasingly being utilised in neonatal and paediatric critical care as a valuable adjunct to clinical examination. The use of POCUS by the clinician is different than a complete diagnostic study by the specialist and its role is dynamic—the same provider can perform and interpret the study, rapidly integrate this information within the current clinical setting, and then repeat the study to identify changes associated with the intervention. POCUS involves a focused assessment to answer a specific question, and it provides anatomical and/or physiological information to be integrated with clinical and laboratory data and make timely and accurate decisions possible. The statements on which panellists disagreed concerned two particular indications (endocarditis and hypertrophic pyloric stenosis), whose diagnosis should be done by a detailed ultrasonography in the hands of an expert paediatric cardiologist or radiologist. The role of POCUS  for these indications is not clear, while the role of ultrasound, There remains a significant variation in clinical practice—in indications, training program and clinical governance. The application of POCUS in clinical practice is dependent on many factors including availability of ultrasound machines, providers, hospital setting, local patient population and specialty. Even within a unit, practice varies among clinicians and their expertise. We subdivided POCUS recommendations according to the estimated level of training required for their use Fig. , and thiDefining a scope of practice is fundamental for POCUS, and these ESPNIC guidelines have been developed for the targeted use of ultrasound in NICU and PICU by any neonatologist or paediatric intensivist. For most diagnostic  and procedural (line placement and fluid drainage) POCUS applications, these guidelines can be used at all ages in children or neonates. However, while using cardiac POCUS in neonates, clinicians should be aware that undiagnosed critical congenital heart defects can present just during this period. They should acknowledge the limitations of skills, and it should not be used as a screening tool for diagnosing or excluding congenital heart defects. A patient with a suspected critical congenital heart defect should be quickly referred to a paediatric cardiologist, even if this implies out-of-hospital patient’s transportation. However, in cases of suspicion of a non-critical defect or for patients with low pre-test probability a more expectative management can be provided. Moreover, the use of pulse-oximetry screening for congenital heart defects is useful and should be integrated into the clinical decision-making process, as internationally recommended , 169.These guidelines may help in standardising clinical practice across acute care settings and physicians. It is not meant to be prescriptive, but rather to outline the important features of structured POCUS applications in clinical practice. The use of these guidelines often will not have any cost implication for the equipment, as ultrasound machine is almost always available in most neonatal and paediatric intensive care units. ESPNIC will promote the diffusion of these guidelines by appropriate advertisement, links and presentation in the society congresses and training events.These guidelines have strengths and limitations as any other. Strengths are represented by 1) the fairly subdivided multidisciplinary panellists’ group , and (2) the use of a standardised methodology. In several fields, these recommendations are based upon a few studies with moderate/low evidence or based upon experts’ opinions and this is a striking difference compared to similar guidelines in adult critical care. In fact, authors answered to following PICO questions: “Does point-of-care ultrasound for heart/lung/line placement/abdomen/brain provide any clinical advantage in neonatal or paediatric intensive care practice?” (supplementary methods). These questions were purposely quite general, as POCUS is not a therapeutic intervention, but rather a diagnostic and monitoring technique and we expected few randomised controlled trials or high-quality diagnostic accuracy studies about POCUS specifically aiming to improve any particular paediatric/neonatal outcome. Moreover, some of the POCUS applications may not be immediately used in all intensive care units as in ours, because of the specific expertise required in some particular contexts (such as the extremely preterm neonates or non-sedated and non-collaborative patients). However, the existence of formal guidelines may help to improve the local expertise and foster new studies to expand knowledge in this field and refine future recommendations. This is extremely important as further studies are warranted to demonstrate that POCUS actually improves patients’ management and outcome, similar to what has been demonstrated in adult critical care  the fair, 55. AnoThese guidelines may provide a substrate to develop a POCUS curriculum and structured training programs, which are urgently needed for quality assurance. This guideline paper is not a training statement: requirements and methods of POCUS training should be a sensible follow-up article to this one.Despite the lack of published evidence-based guidelines specifically for its use in the neonatal and paediatric intensive care units, POCUS is increasingly being used. ESPNIC POCUS guidelines provide the substrate to optimise POCUS use in neonatal and paediatric critical care and guide future research steps according to currently unmet needs. Guidelines may help in making the clinical practice standardised and clinical governance robust.Additional file 1. Online supplementary material.


Efficient information coding (EIC) is a universal biological framework rooted in the fundamental principle that system responses should match their natural stimulus statistics for maximizing environmental information. Quantitatively assessed through information theory, such adaptation to the environment occurs at all biological levels and timescales. The context dependence of environmental stimuli and the need for stable adaptations make EIC a daunting task. We argue that biological complexity is the principal architect that subserves deft execution of stable EIC. Complexity in a system is characterized by several functionally segregated subsystems that show a high degree of functional integration when they interact with each other. Complex biological systems manifest heterogeneities and degeneracy, wherein structurally different subsystems could interact to yield the same functional outcome. We argue that complex systems offer several choices that effectively implement EIC and homeostasis for each of the different contexts encountered by the system. The incredible similarity between pearl white and cotton white and the consequent inability to choose one can be discomforting. Nonetheless, an experienced painter who has been regularly exposed to the palette of colors can distinguish them unmistakably well. Such adaptation in responses dependent on the statistical prevalence of specific stimuli can be explained by a fundamental principle called efficient information coding (EIC)  critically govern their ability to generate specific patterns or rates of action potentials. Alterations to single neuron properties result in massive changes to information transfer across individual neurons, even if the afferent information impinging on their synapses remain unchanged ,38,48,49At the neuronal scale, EIC implies a match between single-neuron response properties and the statistics of different attributes of the impinging network activity ,52–56. IExtensive studies involving the EIC framework at the molecular scale –27,59–68Degeneracy is a ubiquitous biological phenomenon involving the interactions between structurally distinct components yielding similar function . The manDegeneracy in EIC could manifest as system-to-system variability or as an individual system employing distinct context-dependent routes at different instances. A simple illustration of efficient information transfer occurring with these different manifestations is visualized with human communication involving written and verbal forms of different languages, dynamical gestures, and different contexts . The avaDegeneracy as a substrate for simultaneously achieving both EIC and homeostasis is particularly appealing because biological systems continually adapt to noisy dynamical stimuli exhibiting context-dependent natural statistics. Specifically, as the external stimuli is continually changing, there is a need to simultaneously maintain several variables within physiologically plausible levels. The availability of disparate routes ensures that the system has several degrees of freedom to simultaneously achieve these outcomes without cross-interferences. Degeneracy also favors evolvability of efficient coding by virtue of disparate structural components adapting differently to environmental changes, together offering a substrate for adaptive innovations in achieving EIC in a perpetually changing environment ,22.Degeneracy forms a reliable substrate to achieve similar information transfer efficiency through several non-unique routes. At the behavioral scale, animals are required to dynamically rely on and effectively use information from various sensory modalities to achieve functional goals such as mate attraction  and findThe transformation of synaptic inputs to single-neuron responses is a critical step in the cascade of transformations required for EIC of sensory stimuli by neural responses. Therefore, sensory information transfer is governed by cellular—scale parameters that mediate the input—output characteristics of individual neurons. However, efficient coding studies exploring degeneracy with reference to the impact of cellular—scale parameters on neural responses to external stimuli have been far and few. There is evidence for degeneracy in the expression of efficient spatial information transfer through rate or phase codes in hippocampal neurons . These sIn the molecular-scale parametric space involving receptor identity, downstream signaling motifs, post-translational modifications on receptor subunits, information typically relates to the abundance and dynamics of agonist molecules ,26,60,79Heterogeneity is an inescapable reality in biological systems. Heterogeneities in the brain span molecular diversity, cell-to-cell, circuit-to-circuit, and animal-to-animal variability in characteristic properties. There are also pronounced functional distinctions in encoding and decoding strategies as well as behavioral and perceptual differences. The relationship between EIC and heterogeneities has been explored from three perspectives across scales. The simplest perspective considers heterogeneities in the parametric space as a natural consequence of the manifestation of degeneracy in the functional space of EIC. Specifically, if different individuals within a population achieve EIC through disparate parametric combinations, pronounced inter-individual heterogeneity in underlying parameters are naturally expected. The manifestation of degeneracy and heterogeneities implies that a mechanism that enhances information transfer in one individual might be detrimental in another owing to distinctions in mechanisms that yielded EIC.A second perspective, through the lens of reducing information redundancy ,71,80,81vs. I cells) in the electrosensory lobe of electric fishes  balance at the network scale, firing rate and voltage levels at the cellular scale, and calcium levels at the molecular scale –99. A unOur synthesis spanning several species and multiple scales demonstrates EIC as a generalized biological principle. We argued that biological complexity and ensuing degeneracy are central cogs in the concurrent emergence of EIC and homeostasis. We emphasized the critical roles for parametric heterogeneities as well as dynamics (associated with the stimulus and the response spaces) in improving information transfer. We postulate the interplay between EIC and homeostasis as a universal repeating motif whose balance governs biological systems across scales. The recognition of the ubiquitous nature of these governing principles and explorations focused on degeneracy as a substrate for their concurrent emergence would pave the way for deducing the beneficiary roles of complexity across all biological systems .


Autophagy is considered a cytoprotective function in cancer therapy under certain conditions and is a drug resistance mechanism that represents a clinical obstacle to successful cancer treatment and leads to poor prognosis in cancer patients. Because certain clinical drugs and agents in development have cytoprotective autophagy effects, targeting autophagic pathways has emerged as a potential smarter strategy for cancer therapy. Multiple preclinical and clinical studies have demonstrated that autophagy inhibition augments the efficacy of anticancer agents in various cancers. Autophagy inhibitors, such as chloroquine and hydroxychloroquine, have already been clinically approved, promoting drug combination treatment by targeting autophagic pathways as a means of discovering and developing more novel and more effective cancer therapeutic approaches. We summarize current studies that focus on the antitumor efficiency of agents that induce cytoprotective autophagy combined with autophagy inhibitors. Furthermore, we discuss the challenge and development of targeting cytoprotective autophagy as a cancer therapeutic approach in clinical application. Thus, we need to facilitate the exploitation of appropriate autophagy inhibitors and coadministration delivery system to cooperate with anticancer drugs. This review aims to note optimal combination strategies by modulating autophagy for therapeutic advantage to overcome drug resistance and enhance the effect of antitumor therapies on cancer patients. A number of agents in development and even clinical drugs for cancer treatment have cytoprotective autophagy effects that contribute to drug resistance.Combination treatment with an autophagy inducer and inhibitor is a good opportunity for discovery and development of more novel and effective therapeutic approaches for cancer treatment.Macroautophagy (hereafter termed autophagy) is a physiological and dynamic process dependent on the formation of double-membrane vesicles to maintain metabolic homeostasis by capturing intracellular constituents, including redundant or unnecessary proteins, injured or aged organelles, and later degrading them in lysosomes. Basal autophagy is widely accepted as a mechanism of cell survival under conditions of nutrient deprivation because the lysosome-released breakdown products are recycled into metabolic and biosynthetic pathways . AutophaAutophagy in cancer treatment is also context-dependent and complicated. There are generally two effects of autophagy in response to anticancer drugs or ionizing radiation treatment in cancer cells . One effThe other effect is the cytoprotective function, which is a drug resistance mechanism resulting in a clinical obstacle to successful cancer treatment and leads to a poor prognosis of the patients. The cancer cells initiate autophagy to escape from the damage of drugs or radiation. Efforts to inhibit treatment-induced autophagy has therefore attracted great interest to improve cancer therapy efficiency . By combMultiple agents in development in preclinical and clinical trials and even many clinical drugs have been found to trigger cytoprotective autophagy, including mTOR inhibitors, kinase inhibitors, natural products, and antiangiogenic agents . Meanwhivia genomic interference against autophagic genes  or pharmacological inhibitors of key components within the autophagy pathway in cancer resistance , LY294002, and Bafilomycin A1 (Baf A1) are common autophagy inhibitors that function in early autophagy by PI3K inhibition and in late autophagy by blocking vacuolar-type H(+)-ATPase, respectively . ChloroqExcept the classical autophagy inhibitors mentioned above, more agents with function of autophagy inhibition in certain cases have been proved. This kind of autophagy inhibitors may have multiple biological activities and exhibit promising inhibitory effect of therapy-induced cytoprotective autophagy that facilitate overcoming acquired resistance to antitumor therapy. The Bcl-2 family of proteins are not only regulators of apoptosis signaling, but also involved in autophagy processes . The BclAccumulating evidence has shown that targeting autophagy in combination with antitumor agents has been effective at enhancing cell death and improving the efficacy of cancer therapies in various cancer types. The antitumor agents are currently under investigation with a cytoprotective autophagy effect that is mainly classified into several types according to distinct characteristic  is an anthracycline antibiotic derived by chemical semisynthesis from bacterial species and works by intercalating DNA for the treatment of various cancers. EGCG, one of the highest catechins from green tea, promisingly showed the capability to augment the antitumor efficacy of DOX in HCC and osteosarcoma treatment involving autophagy inhibition . As a clvia necrosis and significantly augments the combination antitumor effect with sorafenib and the HDAC inhibitor vorinostat in hepatocellular carcinoma cells  and exhibited remarkable efficacy in solid tumor malignancies treatment, including the first-in-class proteasome inhibitor bortezomib and second-in-class proteasome inhibitors carfilzomib and oprozomib . Howevert manner . Moreovet manner . MLN9708pression .2+ entry (SOCE) inhibitor SKF-96365 exhibits potent antineoplastic activity, but its antitumor capacity is often limited by cytoprotective autophagy that delays apoptosis. HCQ could significantly augment the anticancer effect of SFK-96365 in colorectal cancer  followed by significant autophagy inhibition and enhanced antitumor effect of sorafenib in HCC  for several cancers. Therefore, targeting autophagy regulation is also a strategy to enhance SDT efficiency. For breast cancer, a biomimetic nanoplatform exhibited capability in restoring cells' sensitivity to SDT coating” . For thecoating” .in vitro studies, the toxicity of them showed different in vivo. High peak concentrations of CQ may result in infant deaths in case reports that associated with single-tablet ingestions indicated the significant toxicity of CQ. However, people survived suicide attempts taking HCQ, demonstrating HCQ is safely dose-escalated in cancer patients. Moreover, clinical trials showed that autophagy is unable to be completely inhibited by CQ in vivo. These warrant us that searching more potent autophagy inhibitors is critical for promoting an opportunity to apply the combination therapeutic strategy in clinical studies , Project of Wuhan Municipal Health Commission (WZ18Q02) and National Natural Science Foundation of China (81903101).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.


Without new approaches to improve child survival, these countries are also likely to fail to meet the 2030 Sustainable Development targets .2 Biannual mass drug administration (MDA) of azithromycin has been shown to reduce child mortality in several large trials.6 Delivery via MDA offers the opportunity to impact the most marginalized and disadvantaged communities, as MDA programs appear to be among the most equitable intervention platforms in low-resource settings.8 However, in the largest of these trials (Macrolide Oraux pour Réduire Les Décès avec un Oeil sur la Résistance [MORDOR]), conducted in three African countries, the site-specific effect size was only significant in Niger, where the baseline mortality rate was highest. Although mortality reductions were observed in the other sites, the statistically nonsignificant effects and fact that the study was not powered to evaluate effect modification by site complicate their interpretation, especially when considering the balance of risk (including toxicity and emergence of antibiotic resistance) versus benefit. This has led to uncertainty surrounding whether such an intervention should be recommended in lower mortality settings.Dramatic global reductions in child mortality over the past several decades have not been equitably realized across populations.AJTMH, both Oron et al. and Porco et al. provide secondary analyses of available studies of azithromycin delivered by MDA to understand whether the effect size of the observed mortality benefit differs by the baseline mortality rate.10 Importantly, neither analysis concluded that there was a strong relationship between baseline mortality and effect size, although neither could exclude a modest interaction  may not be representative of the population that participated in the trial. For example, the baseline mortality rates observed at the Niger site of the MORDOR study differ substantially from estimates provided by DHS/MICS. By contrast, Porco et al. estimated mortality using baseline census data from the individual studies, modeling effects using cluster-level geographical units. The use of estimates derived from the original study may raise concerns of endogeneity bias, where an included covariate  is correlated with the error term of the outcome , although the linear mixed effect model used by Porco et al. may address this concern.Although estimates from the two studies were similar, there were some discrepancies, which may be due to differences in methodology. Oron et al.12 However, it is not clear how azithromycin reduces mortality, limiting our ability to base decisions regarding implementation of azithromycin MDA on the underlying potential mechanisms of benefit. Although mortality is lower in most other settings, many countries have significant capacity to benefit from reductions in child mortality. For example, Tanzania, the lowest mortality country included in these analyses, has an under-five mortality rate of 54 deaths per 1,000 live births. This is more than double the target for the Sustainable Development Goals and 10-fold higher than the average child mortality observed in high-income countries.13 Policy-makers are now confronted with interpreting these findings and making recommendations regarding which populations should be targeted with azithromycin to reduce child mortality.If differences in baseline mortality are largely attributable to the prevention or treatment of infectious diseases, the effect of azithromycin will be dependent on the proportion of mortality attributable to pathogens that are preventable or treatable with macrolide antibiotics. This may partially explain why the MORDOR trial suggests an association with the baseline mortality. Two-thirds of the deaths in MORDOR occurred in Niger, in a setting highly endemic for malaria, for which azithromycin has demonstrated preventative efficacy.The articles from Oron et al. and Porco et al. focus on whether differences in baseline mortality between settings can be considered to determine where such an intervention might be most effective. Although these analyses reinforce that azithromycin mass administration in high-mortality settings appears highly beneficial, they cannot exclude benefit in lower mortality settings. As the authors of both articles note, there does not need to be evidence of a relationship between baseline mortality and effect size to justify limiting mass administration of azithromycin to high-mortality settings. Targeting azithromycin delivered by MDA to high-mortality settings and populations is likely to increase the cost-effectiveness of the intervention and to minimize the risks of drug toxicity and emergence of drug resistance. Such risk stratification already forms the basis of a number of important public health interventions, including seasonal malaria chemoprevention, empiric deworming, and community management of malnutrition.14 As a result, interventions needed to accelerate progress toward the 2030 Sustainable Development targets likely need to already be supported by strong clinical trial evidence if they are to have a reasonable chance of being scaled up in time to impact these goals. Multiple trials have demonstrated that azithromycin can reduce child mortality in low-resource settings. The secondary analyses presented here do not conclusively exclude a lack of mortality benefit in lower mortality areas. As a result, decisions regarding which populations should be targeted for MDA with azithromycin should not be based on the observed statistical fluctuations in effect size from these studies. Instead, such decisions should be based on the absolute number of deaths likely to be averted by such an intervention, weighed against potential individual and population-level risks.On average, it takes 17 years for novel interventions to be supported by guidelines and widely available at scale.


JNCI Cancer Spectrum, Klek and colleagues (In this issue of lleagues  describeTumor-only profiling by next-generation sequencing has been widely implemented in oncology practices to help guide therapeutic decisions, clarify diagnosis, and aid in prognostication. This approach has been adopted by both academic centers and commercial companies alike . AlthougKlek et al. demonstrate that involvement of clinical genetics in a tumor-only sequencing data review process can improve the identification of patients and families with germline pathogenic variants in hereditary cancer predisposition genes. After implementing a formal tumor-only sequencing data review and genetic counseling referral process, the percentage of patients undergoing tumor-only sequencing with a detected pathogenic germline variant increased from 1.4% to 7.5%. Their findings are in agreement with recent studies demonstrating that the inclusion of germline genetics expertise in tumor-sequencing analysis improves the identification of germline cancer risk in various cancer-patient populations ,9. NotabNF1 or TSC1 are believed to have high penetrance, many patients may have milder presentations and may not be diagnosed until examined specifically for associated features. Several studies have shown that this is even more complex for diseases caused by lower penetrance genes, such as hereditary breast and ovarian cancer and Lynch syndrome. Guideline-directed genetic testing misses a substantial proportion of patients with pathogenic germline variants for these disorders (Estimating the possibility of a variant having germline vs somatic origin can be complex and requires an expert review of multiple factors, including variant attributes in sequencing data and the prior probability for the individual to have a germline pathogenic variant in a given gene. A few automated approaches to tumor-sequence analysis have been developed to predict which variants are likely to be germline in origin, and guidelines have been proposed for implementing such variant filters in laboratory practices . Howeverisorders . Having Klek et al. show that the review of tumor-sequencing data by a molecular tumor board increases the yield for detecting pathogenic germline variants and that this methodology can contribute to detecting hereditary cancer susceptibilities in individuals who otherwise may not have had genetic testing. However, as the authors suggest, most tumor-only sequencing panels do not provide complete coverage of all target genes and are limited in their ability to detect certain variant types such as exon-level copy number variants and variants in high homology regions. Therefore, it should be recognized that tumor sequencing is not a substitute for clinical genetic testing where the gene panels are designed and validated specifically for germline variant detection, and all variants are scrutinized and interpreted according to American College of Medical Genetics and Genomics criteria . MoreoveIn this study, Klek et al.  clearly The authors declare no conflicts of interest.


This paper describes the evolving role of robotics in healthcare and allied areas with special concerns relating to the management and control of the spread of the novel coronavirus disease 2019 (COVID-19). The prime utilization of such robots is to minimize person-to-person contact and to ensure cleaning, sterilization and support in hospitals and similar facilities such as quarantine. This will result in minimizing the life threat to medical staff and doctors taking an active role in the management of theCOVID-19 pandemic. The intention of the present research is to highlight the importance of medical robotics in general and then to connect its utilization with the perspective of COVID-19 management so that the hospital management can direct themselves to maximize the use of medical robots for various medical procedures. This is despite the popularity of telemedicine, which is also effective in similar situations. In essence, the recent achievement of the Korean and Chinese health sectors in obtaining active control of the COVID-19 pandemic was not possible without the use of state of the art medical technology.  The World Health Organization (WHO) on January 30, 2020 publicly declared the COVID-19 pandemic as a “global emergency” because of the rapidity at which it had spread worldwide [Despite the scarcity of publicly available data, scientists around the world have made progress in estimating the scale of the pandemic, the progression rate, and various transmission patterns of the disease . RecentlAccording to the WHO’s situational report 127 published on May 26, 2020, so far, 5,404,512 confirmed cases have been reported worldwide with 343,514 casualties [Patients with pre-existing cardiovascular diseases/hypertension, diabetes, cancer, and chronic respiratory disease have greater probability to pass away due to covid-19 complications compared to patients without comorbid conditions . United Considering the current disastrous situation, robots are well suited for caring for the well-being of COVID-19 patients thus replacing or at least sharing the workload of the medical staff in hospitals under oversaturated conditions. A number of robotic systems are used for medical support in hospitals today . In ChinThe purpose of this study is to explore strategic healthcare digitization innovation through robotics utilization in terms of global COVID-19 management perspectives. This study will provide decision-makers and policy-makers with strategic insights in improving the healthcare quality in local and global disasters together with pandemic settings and other similar situations. This paper is organized as follows: The applications of robotics and automation in healthcare and allied areas is increasing day by day ,9. The IThe requirement of kinematics and dynamics of a medical robot are application dependent. Serial as well as parallel robots are used in various tasks ranging from surgical and rehabilitation to service robots ,13. One In order to carryout diverse tasks with high precision, reliability, and repeatability while minimizing the effects of external disturbances, the control of medical robotics is a challenging issue . MoreoveRobots designed for use in healthcare and medicine have stringent cleaning requirements as they must be free of germs and microbes which can spread communicable and contagious diseases to other patients . Most ofThis is one of the prime requirement in medical robotics as the operator’s safety is very important while handling a robot in the hospital premises . It shouRobots in hospitals are designed to be operated by medical technicians, medical doctors, and staff without engineering knowledge and troubleshooting skills. Therefore, the designers always need to ensure simple architecture, easy handling and quick maintenance for long-term usage of such machines . MedicalIn order to operate medical robots, AC/DC power must be available without interruption so that these critical systems can work continuously. Since, medical facilities vary from large scale centrally located city hospitals to purpose-built field hospitals, various renewable energy sources are also utilized for reliable power solutions . WirelesSince, healthcare robotic solutions are needed at a large scale, they must be cost effective for easy installation and wide spread availability throughout the world, including developing nations . High coRobots are mainly classified with various applications in healthcare and related fields. These classifications are broadly designated such as receptionist robot area, nurse robots in hospital area, ambulance robot area, telemedicine robot area, hospital serving robot area, cleaning robot area, spraying/disinfestation robot area, surgical robot area, radiologist robot area, rehabilitation robot area, food robot area, and outdoor delivery robot area. These types of robots are preferably used at a hospital’s reception to disseminate information about various units/sections of the hospital and guide patients and visitors as shown in These robots are meant to assist doctors in the hospital in the same manner as that of human nurses. Nurse robots are commonly used in Japanese hospitals as Japan has the highest percentage of elderly (above 75 years) individuals among OCED countries. This poses a growing challenge for the medical facilities in the country. Without sufficient recruitment for elderly care, more Japanese citizens are socially bound in taking care of aging family members at home instead of doing a job . In addiHumanoid nursing robots (HNRs) are likely to replace future nurses in Japanese healthcare facilities. Robots in nursing are becoming popular in offering services 24/24 and 7/7 with minimal costs . In JapaAs per statistics, around 800,000 people per year suffer from cardiac arrest in the European Union (EU), out of which only 8% survive this emergency . The maiThe immediate medical aid after an accident is critical in order to prevent intensification of trauma. Thus, by speeding up emergency response, more lives can be saved as a result of fast recovery . This isSuch robots are helpful in telemedicine applications where a remote doctor takes all the physiological parameters and diagnoses a disease using audiovisual aids . Such syThere are many tasks in hospitals where pushing and pulling of material is required. These heavy-duty tasks can be easily carried out by using serving robots . Robots Robots are used in hospital cleaning using dry vacuum and/or mopping . CleaninMany such systems are depicted in Such robots are widely used in spraying antiseptic mixtures over large outdoor areas e.g., residential centers of the city. These robots are remotely controlled to avoid hazardous contact with the disinfectant spray. Autonomously guided hand sanitizer dispensing robots are designed to alleviate infections on human hands and faces. Such alcohol-based sanitizers remove bacteria, viruses, and other microbes to prevent the spread of contagious diseases among large populations as shown in Surgical robots offer minimally invasive surgery (MIS) with precision and accuracy compared to human surgeons. Many tele-operators have been designed for remote surgeries . The Da Nowadays, fourth-generation Da Vinci surgical systems  with complex machines but simple movements continue to advance MIS across a wide spectrum of surgical techniques. This offers upgradable design with flexible configurations and a dependable interface for surgeons using Da Vinci systems as shown in Many other types of specialized surgical robots are in use for general endoscopic, cranial and spine surgery as well as for biopsy as shown in The LBR Med is a sensitive seven-axis lightweight robot; it is very flexible and easy to integrate into medical products for numerous surgical interventions. It is perfectly suited to applications in medical technology due to its responsive sensors, inclusive safety provisions, hygiene-optimized surfaces, and a controller intended for direct collaboration with the human operator .Radiology is one of the key technologies where robots are installed on special demand due to high level of radiations and safety issues for human operators. Twin Robotic X-ray  by Siemens is an innovation in radiology which offers fluoroscopy, angiography, and 3D imaging as shown in Cyberknife precise robotic  treatment is used for radiotherapy of cancer patients as shown in These robots are helpful in rehabilitation of patients after an accident or stroke . They arThese robots are an integral part of a hospital’s kitchen and pantry in order to deliver high quality food as per hygienic standards . From coSuch robots are useful in transporting/delivering drugs and blood samples to/from the hospital. These fully autonomous robots can operate on the ground or in the air autonomously or with man-in-the-loop operation whereas an operator at a distance can remotely control them. Example systems include drone delivery robots by “Flirtey ” which aim to save lives and improve lifestyles by making delivery instant for everyone as shown in Starship robots  are another example of ground based delivery robots that can carry less than 100 pound items within a 4-mile (6 km) radius as shown in (a)Healthcare facilities should prioritize only urgent and emergency visits to fight against COVID-19. All elective and non-urgent admissions must be rescheduled.(b)Preserving staff personal protective equipment (PPE) and patient care supplies for the safety of both is very important.(c)Routine dental and eye-care visit must be postponed.(d)All inpatient and outpatient elective surgical and procedural cases must be delayed to give priority to COVID-19 patients.(e)Old age patients with underlying conditions are more vulnerable compared to young patients.(f)Patients with underlying chronic medical conditions and pregnancy are at high risk due to this disease.(g)Patients with mild clinical presentation may not initially require hospitalization.(h)However, all patients with worsening signs and symptoms should be monitored closely with respect to the infection progress to the lower respiratory tract during the second week of illness.(i)The decision to monitor a patient in the inpatient or outpatient setting is dependent on the clinical presentation.(j)The estimated incubation period for COVID-19 is four days (interquartile range: 2–7 days) while some studies recommend a wider incubation of 2–14 days based on data from other coronaviruses .As shown in recent reports regarding COVID-19, most fatalities occur in old aged people especially with comorbidities as shown in COVID-19 patients admitted to hospital have indicated symptoms e.g., fever, cough, shortness of breath, and fatigue as shown in Specimens collected from the nose of patients are analyzed in labs for possible detection of COVID-19. Nasopharyngeal (NP) specimen is preferred for the detection of upper respiratory tract infection. Specimen from the lower respiratory tract including lung biopsy can also be helpful for patients presented with more severe disease. Serum analysis is helpful in monitoring antigens/antibodies count in COVID-19 patients. CT images of the chest have shown bilateral involvement in most patients .Since, there is no currently available treatment for COVID-19, recommended infection prevention and control measures and supportive management of complications is the only possible clinical management. In some cases advanced organ support may be recommended as per need . Few antThe Chinese health ministry actively pursued the management of COVID-19 to avoid the blowout of the disease. In this pursuit, various robotic technologies were used to control and administer this epidemic as shown in From service robots to disinfectant robots, hospitals frequently utilized technology to deal with a wide number of infected patients. Based on the technology-based solutions, very few cases were reported where infection was transmitted to the healthcare professionals. In China, such robots are effective in receiving the patients at the reception desk and monitoring their initial symptoms (such as flu and fever) and to disinfect them right at the entry point during the COVID-19 epidemic period. CloudMinds (USA) donated 5G Cloud Robots to various hospitals in Wuhan and Shanghai to help the Chinese healthcare community to fight against the coronavirus as shown in It has been observed from expert reviews that the Chinese and Korean governments’ prompt reply in addressing the epidemic of COVID-19 was a successful attempt by using advanced measures and technology to manage the situation. These guidelines have been open for the world to take the same measures in order to stop COVID-19 fatalities. As seen from the data presented in This study presents a comprehensive overview of the robotics potential in medicine and allied areas with special relation to the control of the COVID-19 pandemic. Effective management of COVID-19 can significantly reduce the number of infected patients and casualties as witnessed in the case of the Chinese outbreak. Since, it has currently turned out to be a global challenge, technologically advanced countries can aid others by donating support equipment and robotic infrastructure to enable a good outcome in controlling this disease. This review substantiates that the introduction of medical robotics has significantly augmented the safety and quality of health management systems compared to manual systems due to healthcare digitization. Classification of medical robots is only done using application based categories to fit every aspect of hospital services ranging from cleaning robots to highly sophisticated surgical robots. Many opportunities are available in the design and operation of medical robots such as a cyber-physical system (CPS), power management using optimized algorithms and renewable sources, as well as fault tolerant control and dependable architectures for reliable and safe operation within the healthcare facilities.