Despite all the scientific data gathered in the cancer research domain, this disease remains one of the major death causes worldwide and a heavy societal burden by its associated comorbidities. In this light, drug discovery technologies, their optimization along with the rapid bioinformatics programs development are essential for enlarging cancer therapy approaches ,2.Current methodologies for drug development are remotely optimal; as such, we are experiencing an abundance of stage III clinical trial failures. The lack of solid understanding of cancer biology, knowledge that can support the design of confirmatory trials is one of the causes of this failure .Cancer research and drug development have recently entered a new era, along with the concomitant emergence of new technologies, such as whole-genome, proteome profiling or exome sequencing; all these new approaches have led to innovative information. There are several reasons for the discrepancies between the large number of possible future drugs and those approved. US FDA and EMA grant around 20 new molecular drugs entities per year, but in spite of this number there is still a large uncovered area in cancer therapy .The initial research on drug discovery is developed on an academic level, generating all the premises for a certain therapeutic effect obtained upon the inhibition/activation of a protein/pathway/cellular network. Before progression into the lead discovery phase, further validation of the selected target is required .During the last decade, important steps were taken toward the understanding of overall cancer biology and hence specific therapy. Thus, molecular research has revealed major mutations for many cancer types, pinpointing specific targets and, therefore, drug development. Another important step was the comprehension of intratumor cellular pheno/genotype variation that could explain drug's efficacy differences in terms of aiming primary tumors versus metastatic ones in the same patient. An additional significant step was the identification of several processes developed during tumor cells interaction with their microenvironment, process that governs metastasis. Molecular mechanisms of therapy resistance gained knowledge in the drug discovery field .All this recently gathered information converged to the necessity to tailor individualized cancer treatment. The biotechnology landscape confirms that, for each patient, developing gene sequencing, individual protein profiling, intracellular signaling pattern or miRNA signature are paving the road to personalized medicine concept and toward patient-dedicated therapy.Technology optimization for drug discovery along with sophisticated bioinformatics programs are essentials for optimal cancer therapy. In this view, overlapping biomarkers group and therapy targets clusters seems to be the best approach to design a pool of candidate biomarkers that will serve as major source for potential therapy targets discovery. The most advanced technologies that meet the ‘overlapping criteria’ are next-generation sequencing (NGS), protein/gene array technologies and microRNAs identification as anticancer drugs.The key preclinical stages in the process of drug discovery were reviewed by Hughes in 2011 , and, whin vitro and in vivo biological response.Target identification and validation appear as key problems, since appropriate targets have to match several characteristics: to be safe, to be clinically efficacious when targeted, to solve a prior unmet clinical need and, above all, to be easily accessible for the drug's action. After matching these features, upon interaction with the specific drug, the process has to produce a measurable The Era that is following the complex project ENCODE (Encyclopedia Of DNA Elements) launched in 2003 has developed high-throughput sequencing technologies and computational strategies. The aim was to evaluate transcriptional process and gene expression in highly complex dynamic molecular and signaling networks. Due to the well-established tumor genomic heterogeneity, NGS technologies empowered clinical new drugs application, tailoring the best target drugs for the each patient .In 2014, a multianalytic panel (MUT-MAP) was developed using next-generation mutation technology. MUT-MAP detected 120 somatic mutations in 11 therapeutic genes ,9.NGS-generated data need specific interpretation, hence recently an Integrated Pathway Analysis Database was designed in order to analyze new and existing drug treatment options in particular stratified patients. Therefore, systematically integrating pathway – disease – drug – organ is crucial for understanding the interrelationships between signaling regulatory pathways and drug action. This integration is based on high-throughput omics data  ,11. ReceOutlining the NGS technology involvement in the biotechnology landscape of cancer drug discovery will lead to unveiling new anticancer drugs.At the borderline of genomics and proteomics, powerful regulators of cellular activities through post-translational control of protein expression, miRNAs emerged in the last few years, as both disease markers and future drugs. As disease markers, deregulation of miRNAs was found associated to tumorigenesis, initiation and progression in many human cancer types, having versatile functions as oncogenes or tumor suppressors . Individin vitro that restoring their normal expression level reduces tumor cells invasiveness or switches them to a ‘normal’ cell phenotype.miRNA expression profiles performed by specific molecular techniques, which include miRNA microarray technology, could improve cancer diagnostic and therapy based on miRNA signature . CirculaNew achievements regarding miRNAs involvement in cancer biology define these molecules as excellent candidates for anticancer therapies targets, predicting the outcome or the monitoring therapy efficacy – theranosis .The main step in drug discovery research is to identify new molecules (or new exploitation of known molecules) as anticancer drugs. The ‘core’ of hits to leads discovery is represented by the intensive use of high-throughput screening (HTS).HTS identifies therapeutically effective compounds within molecular libraries (hits), followed by structural optimization and consecutive testing for increased efficacy drug assemblies (leads) to address the molecular/therapeutic target. One important stage consists in the continuous optimization of screening technology (up to the level of ultrahigh throughput technologies) and the intensive use of robotics. In the optimization of this process, bioinformatics and other computational methods are used, aiming to sort-out new hits and leads from different compounds classes . InteracA considerable advantage is conferred by the possible existence of hits and leads that binds to known domains in a molecule. Molecular modeling, such as docking studies, represents another strategy to define potential agents targeting known targets. This generates the possibility to model the interaction of related (existing or designed) structures. Besides modeling the actual interaction, simulation of efficacy, safety or pharmacokinetics properties simulation and cost-efficacy evaluation can be done.HTS methods can be cost effective for new drug-molecules discovery; therefore, they can be extended with computational methods, such as virtual screening, which are increasingly important in integrating structural data with more traditional lead optimization techniques .in vitro screening; this high-throughput approach uses libraries of potential therapeutic agents assayed on multiple cell lines. A literature-based approach – discovery by analogy – can refine the potential drug list and provide a smaller number of active agents aiding the previously mentioned labor intensive method [Repurposing of existing drugs also involves the use of e method .Reassessment of the correct balance between basic and clinical cancer research aiming toward drug development would have a clear positive outcome in terms of resources and skills dedicated to fundamental cancer research in the era of personalized medicine.The optimization of drug discovery technologies in cancer achieved by novel methods appears to hold particular promise for strengthening the preclinical valuation of drug candidates.The application of these technologies should help decision-making regarding drug properties: efficacy, selectivity, mode of action and off-target interactions. This optimal critical path choice would lead to advancement and development of drugs, reducing the inherently high risk associated with drug innovation.Systematic and consistent integration of biomarker development is necessary for optimized drug delivery based on predicted activity, but also based on patterns of resistance. This emphasizes the need for biological research and biomarker integration to select patients for appropriate therapy, switching from a ‘which patient for this drug’ approach to a ‘which drug for this patient’ approach .Technology optimization for novel cancer drug discovery encompasses high expectation in the benefit of cancer patients. The main guiding principles that aim to accelerate the optimization of technologies include various programs fostering research in drug discovery and accelerating ‘discovery enabling technologies’ progress. Moreover, new multidisciplinary partnerships are mandatory in order to provide patients with an enlarged access to tailored treatments, since the main goal of technology optimization for novel cancer drug discovery is the improvement of cancer patients’ clinical management.


Converging behavioral findings support recent models of motor control suggesting that estimates of the future positions of a limb as well as the expected sensory consequences of a planned movement may be derived, in part, from efference copies of motor commands. These estimates are referred to as forward models. However, relatively little behavioral evidence has been obtained for proposed forward models that provide on-line estimates of current position. We report data from a patient (JD) who reached accurately to visualized targets with and without vision of her hand despite substantial proprioceptive loss. Additionally, we administered a double-start reaching test to examine the possibility that efference copy information could be used to estimate current limb position. JD reached accurately, without vision, to a final target after actively reaching to a landmark, but exhibited severely impaired reaching after passive movements to the landmark. This finding suggests that forward modeling of efference copy signals may provide relatively accurate estimates of current limb position for the purpose of motor planning. The possibility that such estimates may also contribute to the awareness of body position and to self-recognition is discussed.


Rewards are fundamental to everyday life. They confer pleasure, support learning, and mediate decisions. Dopamine-releasing neurons in the midbrain are critical for reward processing. These neurons receive input from more than 30 brain areas and send widespread projections to the basal ganglia and frontal cortex. Their phasic responses are tuned to rewards. Specifically, dopamine signals code reward prediction error, the difference between received and predicted rewards. Decades of research in awake, behaving non-human primates (NHP), have shown the importance of these neural signals for learning and decision making. In this review, we will provide an overview of the bedrock findings that support the reward prediction error hypothesis and examine evidence that this signal plays a role in learning and decision making. In addition, we will highlight some of the conceptual challenges in dopamine neurophysiology and identify future areas of research to address these challenges. Keeping with the theme of this special issue, we will focus on the role of NHP studies in understanding dopamine neurophysiology and make the argument that primate models are essential to this line of research. Rewards are a central feature of everyday life that promote learning, incentivize value-based decisions, and provide a currency for social exchanges. Dopamine neurons respond to rewarding events. Specifically, phasic dopamine activity reflects the difference between received and predicted rewards, i.e., reward prediction errors. Systems neuroscience studies in non-human primates (NHP) have been critical to understanding this coding scheme, as well as investigating the behavioral implications of reward prediction error coding.Right now, we stand at the threshold of a new neuroscientific age. This age will be defined by big data and molecular control of neural information processing. From this vantage point, this review endeavors to provide a brief introduction to dopamine neurons, examine the critical findings revealed by NHP studies that have shaped our understanding of dopamine function, and evaluate what role this valuable species should have in future investigations. We will attempt to identify outstanding challenges to our current understanding of this critical brain system, propose areas for future research, and reinforce the need to preserve and technologically advance behavioral neurophysiology studies in NHP. Keeping with the theme of this special issue on NHP studies of basal ganglia function, this review does not attempt to be comprehensive and passes over many of the recent advances observed in rodent models. In addition, we do not discuss the role of dopamine cell loss in Parkinson’s disease, nor the valuable contribution of the monkey MPTP Parkinson’s disease model , and ventral tegmental area (VTA), respectively. . l-DOPA is converted to dopamine via aromatic l-amino acid decarboxylase (AAAD) and packaged into vesicles by the vesicular monoamine transporter (VMAT)  tonic activity and phasic (burst firing) activity when the impulse rate can briefly reach 20–30 imp/s , whereas rewards that are worse than predicted inhibit dopamine activity (negative prediction error responses). Modeling studies demonstrated that the prediction error term in popular reinforcement learning (RL) algorithms closely resembles the phasic dopamine signal  as a function of physical value Debreu . Risk-avAn outstanding question related to economic value coding is whether economic costs reduce the magnitude of dopamine responses. In one study, increasing the effort required to get a reward resulted in reduced responses of some dopamine neurons, but not others  determining whether dopamine neurons are functionally homogenous, (2) elucidating the relationship between behavioral measures and striatal dopamine release, and (3) defining the functional role of dopamine signals in the cortex.Several studies have reported that a fraction of dopamine neurons are excited by novel or aversive stimuli and outcomes (Brischoux et al. Multiple aspects of dopamine signaling may contribute to the observed complexity of dopamine responses, including context dependency and complex temporal dynamics. Dopamine neurons are exquisitely sensitive to the experimental context. For instance, when visual stimuli predict both appetitive and aversive stimuli, approximately 40% of dopamine neurons respond to the stimulus predicting the aversive outcome (Matsumoto and Hikosaka The temporal dynamics of the dopamine response can further complicate the interpretation of these responses. Short latency activations can occur 50–90 ms following behavioral events that reflect physical impact, novelty, and stimulus generalization Fiorillo . These sClassic studies have repeatedly shown that, even during operant paradigms, dopamine responses are time-locked to external reward predictors, rather than to the onset of well controlled, single joint movements or associated EMG activity Fig. a Ljungb. In contIt is widely believed that phasic dopamine signals update action values in the striatum (Shen et al. Electrophysiological recordings from dopamine cell bodies in the midbrain have demonstrated that phasic dopamine responses code reward prediction error, the difference between received and predicted reward. Studies in awake, behaving NHP have been critical to this endeavor, because they are highly trainable and can provide a wealth of data through in-depth exploration of single unit dopamine activity. NHP possess a rich and complex behavioral repertoire which has led to advanced understanding of the role of dopamine in learning, movement, and decision making. Not discussed here but worth mentioning, the MPTP monkey model has been critical to the study of neuronal and behavioral deficits associated with Parkinson’s disease. In short, the unique properties of NHP models have made them essential to understanding midbrain dopamine function and dysfunction.The findings reviewed here demonstrate that, even for studying a relatively simple and evolutionarily old neural structure like dopamine neurons, there are significant advantages to using NHP models. Non-human primates possess behavioral and anatomical characteristics that are more similar to humans than any other experimental animal model. From a behavioral standpoint, the cognitive capability and choice flexibility reviewed here and demonstrated elsewhere (Eiselt and Nieder A new generation of molecular tools—including optogenetics and in vivo single cell imaging—has revolutionized how we ask questions and even what questions we can ask. These technologies, however, have not been widely incorporated into monkey neurophysiology studies. Although progress is being made, as reviewed elsewhere in this issue (Galvan et al.


Cytomegalovirus (CMV) retinitis is a common opportunistic infection in immunocompromised patients, which may lead to blindness. CMV retinitis is not an uncommon infectious disease in patients with immune regulatory abnormalities, for example, human immunodeficiency virus (HIV) patients. However, CMV retinitis in a patient with acute lymphosarcoma leukemia (ALL) undergoing allogeneic hematopoietic stem-cell transplantation (HSCT) phase is very rare.A case of CMV retinitis in a patient receiving immunosuppressive therapy as a part of ALL allogeneic HSCT is described including the pathogenesis, clinical signs, and therapy.CMV retinitis.Ganciclovir intravitreal injection at weekly intervals for 4 weeks.Patient's vision had improved and the load of CMV deoxyribonucleic acid (DNA) in the aqueous humor declined. The CMV retinitis and perivascular of retina infiltration regressed.We propose that the concentration of CMV DNA load in the aqueous humor could be useful in making the diagnosis and in selecting the optimal treatment in this kind of CMV retinitis. Generally speaking, CMV infection is diagnosed by the isolation of CMV or by the detection of viral protein/nucleic acid in body fluids or specimen tissue. However, CMV retinitis is usually diagnosed by a competent ophthalmologist who detects the presence of lesions during fundoscopy in immunocompromised individuals such as HIV patients. CMV retinitis is very rare in patients undergoing allogeneic hematopoietic stem-cell transplantation (HSCT) during the immunosuppressive phase of this treatment. We performed a literature search for more information about this secondary disease, but currently there are only a few case reports of CMV retinitis occurring in patients receiving allogeneic HSCT.–6 Little is known about the pathogenesis or which laboratory tests are useful in the diagnosis of CMV retinitis in patients receiving immunosuppressive therapy as a part of allogeneic HSCT. We present a rare case of this kind of CMV retinitis and describe the laboratory tests applied in its diagnosis.Opportunistic infections suffered by immunocompromised patients are usually caused by cytomegalovirus (CMV) that is a deoxyribonucleic acid (DNA) virus.2A 44-year-old male patient, who had been diagnosed with acute lymphosarcoma leukemia (ALL) and was receiving immunosuppressive therapy as a part of allogeneic HSCT, complained of an abrupt blurring of vision in his left eye (light perception) with normal eyeball movements and normal bulbar and palpebral conjunctiva. HIV testing was conducted twice in this patient, in both cases with negative results. His right eye was normal. However, his left eye showed the characteristics of CMV retinitis when viewed with a fundus camera Fig. . Fluores3 In our immunosuppressed ALL patient, the characteristic lesions of fundus and laboratory assay of aqueous humor confirmed that he had developed CMV retinitis and in his case; this was not secondary to HIV.CMV retinitis is a common opportunistic infection in immunocompromised patients, usually in HIV patients who have low CD4+ T cells counts. One previous report claimed that about 20% to 35% of allogeneic HSCT recipients may develop CMV infection if they do not receive any antiviral prophylaxis. It is rather common that the retina is affected in acute leukemia, with about 70% of patients experiencing retinal symptoms, but it is very rare for an ALL patient undergoing allogeneic HSCT to suffer CMV disease. Since there were clear signs of lesions in the retina in the fundoscopic and fluorescein angiographic evaluation, the pathology of this case of CMV retinitis seemed to involve vascular occlusion, hemorrhage, and exudates. We speculate that the endothelial cells of the retina capillary wall are the crucial tissue being invaded by viral particles. In the clinic, the common treatment for CMV retinitis is laser photocoagulation combined with either oral or IV administration of antiviral drugs such as ganciclovir.,12 However, the treatment outcomes for CMV retinitis tend to be poor and prone to relapse. In this case, we assayed the aqueous humor for CMV, which increased the reliability of the diagnosis. In addition, the concentration of CMV DNA load in the aqueous humor declined to 5.12E + 03 copy/mL, and the patient's vision improved. We propose that the concentration of CMV DNA load in the aqueous humor can be used to confirm the diagnosis and will subsequently be advantageous in selecting the appropriate treatment for secondary CMV retinitis in ALL patients receiving immunosuppressive therapy as a component of their allogeneic HSCT. It is noteworthy that the CMV DNA load in aqueous humor is normal value in the patients with CMV infection undergoing HSCT but having not retinitis, rather something like hepatitis and encephalitis, or in the most commonly seen cases such as pneumonia or gastrointestinal tract infection. In addition, there were some risk factors for secondary CMV retinitis such as transplantation, the use of high-dose corticosteroids, and graft-versus-host disease.–16Bone marrow transplantation usually requires high-dose immunosuppressant therapy, which may impair immunity and make the patient susceptible to CMV infection including ocular, even in patients not infected with HIV.Furthermore, ophthalmologists should be aware that all patients who are being treated with immunosuppressive drugs may potentially have an elevated risk of suffering a CMV infection.


Legionella pathogenesis as this organism employs over 300 secreted virulence proteins and loss of individual proteins rarely impacts intracellular growth. We also discuss selective pressures that drive the maintenance of redundant mechanisms, the current methods used to resolve redundancy and features that distinguish between redundant and non-redundant virulence mechanisms.Redundancy has been referred to as a state of no longer being needed or useful. Microbiologists often theorize that the only case of true redundancy in a haploid organism would be a recent gene duplication event, prior to divergence through selective pressure. However, a growing number of examples exist where an organism encodes two genes that appear to perform the same function. For example, many pathogens translocate multiple effector proteins into hosts. While disruption of individual effector genes does not result in a discernable phenotype, deleting genes in combination impairs pathogenesis: this has been described as redundancy. In many cases, this apparent redundancy could be due to limitations of laboratory models of pathogenesis that do not fully recapitulate the disease process. Alternatively, it is possible that the selective advantage achieved by this perceived redundancy is too subtle to be measured in the laboratory. Moreover, there are numerous possibilities for different types of redundancy. The most common and recognized form of redundancy is functional redundancy whereby two proteins have similar biochemical activities and substrate specificities allowing each one to compensate in the absence of the other. However, redundancy can also exist between seemingly unrelated proteins that manipulate the same or complementary host cell pathways. In this article, we outline 5 types of redundancy in pathogenesis: molecular, target, pathway, cellular process, and system redundancy that incorporate the biochemical activities, the host target specificities and the impact of effector function on the pathways and cellular process they modulate. For each type of redundancy, we provide examples from  In this case, the proteins and their functions are completely unrelated but they serve a common goal. Thus, redundancy can occur at multiple levels within a system and is largely defined by what a bacterium is trying to accomplish.Bacteria are one of nature's ultimate survivalists, able to adapt to extreme and dynamic environmental conditions. One of the reasons for their robustness is redundancy, contingency plans for a given process that enhances their fitness. Genetic redundancy describes two copies of the same gene whereby the protein encoded by one can function in place of the other. A classic example of genetic redundancy occurs in metabolism, where two genes encode proteins that catalyze the same reaction  to avoid digestion in the lysosome  using similar genetic screening strategies was relatively unsuccessful, identifying only a small handful of IDTS-encoding genes that were important for L. pneumophila pathogenesis P3 preventing PI(3)P accumulation at the LCV P from the LCV P accumulation at the surface  Specific defects in host cell biology resulting from loss of bacterial proteins could be predicted for genes based on the characterization of other members of its group: this identified three sets of proteins that independently contribute to the maintenance of replication vacuole membrane integrity; (4) Different combinations of bacterial genes were required for optimal growth in different hosts defining sources of adaptation to host variation. By grouping individual effectors that commonly manipulate a single host pathway and redundant pathways that contribute to a single process, iMAD defines functional relationships between effectors at the target, pathway, cellular process, and system levels. With more efficient methods for generating arrayed bacterial mutant libraries, commercially available RNAi libraries and the development of CRISPR technology to facilitate host cell protein depletion, and the replacement of DNA microarrays with massively parallel sequencing techniques to monitor bacterial mutant populations, more comprehensive, high-throughput iMAD screens are now possible.iMAD is a genetic screening strategy developed to resolve redundancy amongst effectors by defining sets of bacterial proteins that target common host pathways and parallel pathways exploited by a pathogen to accomplish a single task  (Mirrashidi et al., C. trachomatis and thus, potential sources of redundancy. Moreover, the C. trachomatis Inc-human interactome had significant overlap with that of other pathogens. Comparisons with three viral-human interactomes (Jager et al., C. trachomatis and at least one of the three viruses. Similarly, a number of the Inc host protein targets are also common targets of L. pneumophila IDTS including Rtn4 (Kotewicz et al., C. trachomatis Inc proteins and L. pneumophila IDTS and differences in the host protein complex subunits targeted demonstrates that each bacterial pathogen has acquired or evolved different mechanisms to modulate the same host proteins, pathways and/or cellular processes. Comparing effector functions between pathogens not only allows additional redundant virulence mechanisms to be defined but establishes a critical set of events central to microbial pathogenesis.Proteome-based analyses that use high throughput mass spectrometry allow the interactomes of entire effector subfamilies to be mapped. Affinity purified-mass spectrometry has been used to define the host interacting partners of 58 secreted virulence factors in P. syringae pan-genome effector repertoire consists of 57 effectors but different subsets of effectors are sufficient for growth in the same plant host. Computational analyses that correlate specific combinations of effectors and host tropism (Baltrus et al., L. pneumophila SdhA is a critical virulence determinant in macrophages (Laguna et al., sdhA mutant is due to loss of vacuole integrity that leads to a robust host innate immune response and consequently either bacterial or host cell death (Laguna et al., L. pneumophila encodes two paralogs of SdhA, SidH, and SdhB, but their deletion only moderately enhances the already severe intracellular growth defect of the ΔsdhA mutant (Laguna et al., Legionella feeleii lacks a sdhA paralog but grows almost as well as the wild type strain of L. pneumophila in macrophages (Figure sidH in L. feeleii may compensate for the absence of sdhA, deletion of sidH does not impair L. feeleii growth in macrophages (Figure L. feeleii is not due to the lack of plaA and/or traI, which suppresses the ΔsdhA mutant phenotype in L. pneumophila (Creasey and Isberg, L. pneumophila pathogenesis, the entire family of SidH paralogs is dispensable in L. feeleii. While there are a number of explanations for this discrepancy, L. feeleii encodes 27 additional putative IDTS that are not conserved in L. pneumophila (Burstein et al., Comparative genomics combined with phenotypic analyses provide a means to define correlates between effector conservation and redundant virulence mechanisms (Baltrus et al., s Figure . While ts Figure . The disMuch of the research in microbial pathogenesis employs a reductionist's approach, where the individual components are investigated in isolation. While this strategy has proven extremely useful in identifying key players and their functions, it does not offer tremendous insight into the complex interactions that exist at the systems level. Pathogens invest an incredible amount of resources to build a robust virulence strategy. Redundancy allows pathogens to rapidly adapt to frequently changing environments and the elaborate, multi-tiered antimicrobial strategies employed by their hosts. As more and more effectors are characterized, a striking pattern of redundancy is beginning to emerge. In this review, we establish a structured nomenclature for the different forms of redundancy observed across multiple levels of biological organization. The types of redundancy defined here are not mutually exclusive nor are they expected to be exhaustive as more virulence factors are characterized. Instead, we offer a framework to generate a broader, more dynamic view of the mechanisms governing microbial pathogenesis.SG generated data presented in the manuscript. SG and TO wrote the manuscript.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.


Focal hand dystonia in musicians is a neurological motor disorder in which aberrant plasticity is caused by excessive repetitive use. This work's purposes were to induce plasticity changes in a dystonic musician through five daily thirty-minute sessions of 1 Hz repetitive transcranial magnetic stimulation (rTMS) applied to the left M1 by using neuronavigated stimulation and to reliably measure the effect of these changes. To this aim, the relationship between neuroplasticity changes and motor recovery was investigated using fine-grained kinematic analysis. Our results suggest a statistically significant improvement in motor coordination both in a task resembling the dystonic-inducing symptoms and in a reach-to-grasp task. This single case study supports the safe and effective use of noninvasive brain stimulation in neurologic patients and highlights the importance of evaluating outcomes in measurable ways. This issue is a key aspect to focus on to classify the clinical expression of dystonia. These preliminary results promote the adoption of kinematic analysis as a valuable diagnostic tool. Dystonias are a group of disorders characterized by intermittent or sustained muscle contractions causing twisting and repetitive movements . TheDystonia may be task-specific producing abnormal motor performance for only a specific task, such as in musician's dystonia (MD). MD affects isolated fingers that perform complex and repetitive motor tasks during actions associated with musical play, but can also lead to impaired adjacent finger flexion . This ovAlthough its underlying pathophysiology remains unclear, several studies in patients with MD have shown that repeated and prolonged hand use might result in abnormal activity in the cortical representation of the hand , 8. In fAlthough prompt initiation of treatment could rescue some patients, dystonia is often misdiagnosed or neglected since the lack of objective diagnostic criteria and reliable biomarkers prohibits early diagnostic recognition . So far,Given the sparse literature on this topic, there are no clinical practice guidelines on how to recover voluntary motor control. To date, the preferred treatment for dystonia is botulinum toxin injection, but it only transiently works in a minor fraction of patients and its application is limited by the spread of weakness to adjacent muscles, which causes further motor performance impairment .Recently, motor training has been combined with neurostimulation methods in an attempt to normalize brain excitability and recover motor performance , 24. NotNeedless to say, the principle of the measurement must be based on the phenomenology of each patient. Motor assessment must be specifically related to the compromised movement , rather than to a more general skill e.g., , 31). As. As31]).neural plasticity. Moreover, we considered two behavioral measures of performance plasticity: (i) a repetitive sequence of fingers' movement (task 1) and (ii) a reach-to-grasp action (task 2). Since guitar arpeggios involve a rapid succession of fine and isolated finger movements, the finger flexion task was conceived as a realistic attempt to execute the affected flexion pattern. As concerns the grip task, it was specifically chosen to investigate the distinct contribution of the two separate reaching and grasping components ).An intriguing hypothesis points to a malfunctioning in the parietal-premotor pathway of dystonic patients . ParietaNotably, an initial positive outcome was observed during the post-TMS session of day 1, when all the parameters jointly showed a significant improvement. This effect, however, was neutralized and reversed during the post-TMS session of day 2, which was then followed by a stabilization phase for the remaining three days. The convergent oscillation of all these parameters seems to indicate that rTMS inhibitory stimulation might be beneficial in the very short term, but it provides a stable advantage only in the course of a 5-day training. This result might suggest that it takes many days of intervention to rebalance motor activity.Overall, these results suggest that kinematic assessments of abduction independence, abduction degree, and reaching and grasping components are useful parameters for objective quantification of MD before and after training. Moreover, the reach-to-grasp task might allow studying situations similar to those participants facing in their daily life motor activities. This points to the effectiveness of assessing kinematics in conjunction with individual clinical scores such as the Arm Dystonia Disability Scale (ADDS). Although they probe different aspects of motor impairment and might not correlate with each other , they shIn neural terms, no trend was observed when considering rMT. This is a counterintuitive—though not rare—output. Veugen and colleagues  recentlyIn this respect, the study described here highlights the importance of evaluating brain stimulation outcomes in a more systematic way, beyond classical measures of neural plasticity such as MEP size. The cause of MD is obscure, but a loss of inhibition in the central nervous system and a loss of the normal regulation of plasticity are classically reported –51. PlasThis line of intervention holds several advantages over pharmacologic therapy : It is safe and effective, as demonstrated by kinematic analysis, and there is no risk of impairing movement in adjacent fingers. Moreover, it can be applied to patients unresponsive to a variety of commonly used medical treatments. Noninvasive brain stimulation can transiently normalize corticospinal excitability to the affected muscles and can improve the degree of motor coordination over time. Objective quantifications of this treatment can be experimentally obtained with EMG and 3D movement analysis, paving the way for developing novel evaluation tools to optimize therapeutic strategies for motor disorders.As the rehabilitation research in limb dystonia develops, it will be relevant to investigate comparative effectiveness of interventions to understand which approach holds the most promise.To develop an effective diagnostic tool based on neurophysiologic and behavioral measures for early identification of patients and for quantifying changes in symptomsTo investigate how dystonia affects the parietal-premotor pathway (reaching and grasping components)To determine the best frequency and duration for interventions and after effects following rehabilitation.The present results could support three future research aims:n methodology such as single subject experimental design studies with repeated measures that allows for detailed analysis of within subject variability. Needless to say that definitive statements cannot yet be made regarding efficacy of this paradigm. Randomized controlled measurements are essential for future studies to compare different outcomes with similar frequency and duration.A limit of the present study is the small sample adopted. However, according to Kimberley and colleagues , 53, stuIdentifying the motor dynamics underlying this disorder will be helpful for moving forward both in diagnosis and in treatment, to optimize therapeutic outcomes. Since the available medical approaches are only moderately effective, preventing dystonia is just as much important.We argue that an enhanced understanding of how neural plasticity can be assessed in FDH affected patients will provide helpful insights for designing more effective patient-tailored therapies based on noninvasive brain stimulation and for evaluating different treatment approaches.


To reconcile the apparent contradiction of clinical susceptibility to disease and the host immune response findings when contrasting newborn to adult, it will be essential to capture the entirety of available host-defense strategies at the newborn’s disposal. Adults focus heavily on the disease resistance approach: pathogen reduction and elimination. Newborn hyperactive innate immunity, sensitivity to immunopathology, and the energetic requirements of growth and development (immune and energy costs), however, preclude them from having an adult-like resistance response. Instead, newborns also may avail themselves of disease tolerance (minimizing immunopathology without reducing pathogen load), as a disease tolerance approach provides a counterbalance to the dangers of a heightened innate immunity and has lower-associated immune costs. Further, disease tolerance allows for the establishment of a commensal bacterial community without mounting an unnecessarily dangerous immune resistance response. Since disease tolerance has its own associated costs (immune suppression leading to unchecked pathogen proliferation), it is the maintenance of homeostasis between disease tolerance and disease resistance that is critical to safe and effective defense against infections in early life. This paradigm is consistent with nearly all of the existing evidence.Newborns suffer high rates of mortality due to infectious disease—this has been generally regarded to be the result of an “immature” immune system with a diminished disease-fighting capacity. However, the immaturity dogma fails to explain (i) greater pro-inflammatory responses than adults  The world has seen under-five mortality greatly reduced over the last two decades but this progress has least benefited those in the first 28 days of life—the neonatal period—which now accounts for nearly half of all under-five deaths . InfectiScience paper titled “Disease Tolerance as a Defense Strategy”  An avoidance strategy reduces the risk of infection by preventing exposure to infectious agents. Human avoidance of rotten meat consumption through an olfactory response to the metabolites produced by bacteria breaking down tissue is an example of avoidance . Limitatmodus operandi of the immune system (and thus the focus of most prophylactic or therapeutic interventions). However, unleashing antimicrobial immune responses can also cause collateral damage  disease resistance approach aims to reduce pathogen burden and has traditionally been considered the primary l damage . In factl damage . For exal damage . Given tl damage  implicatl damage , 23. Impl damage , 24. It l damage . This lel damage ], while l damage , 24, 26.Newborns thus likely also rely on employing the third strategy of host defense, disease tolerance. (iii) Disease tolerance reduces potential harm to the host without reducing pathogen burden, generally by minimizing the level of immunopathology that results from a resistance response . This stA disease tolerant vs. intolerant phenotype would be expected to display a lower morbidity/mortality relative to a same pathogen load, and/or a higher pathogen load at a similar mortality level . While mPerhaps, a higher bacterial load in infected newborns does not seem surprising at first glance—after all, neonates are more susceptible to suffer from infection, and higher bacterial loads would seem to be entirely in line with this observation. However, this simple concept begins to unravel when age-specific mortality statistics are taken into consideration. While bacterial load correlates with outcome across all ages, there are log-fold differences in the scale of circulating bacteria which neonates are able to survive in comparison to adults. Studies have shown 100% mortality in adult patients with greater than 100 CFU/ml blood  and 84% Staphylococcus aureus infection in neonatal and adult mice attributed a delayed clearance in neonates to inefficient phagocytosis and a limited neutrophil recruitment to the site of infection. Specifically, in neonates, neutrophil production dropped off despite the continued presence of bacteria, whereas in adult animals, a diminishing neutrophil production corresponded with bacterial clearance. Other studies have implicated impaired neutrophil recruitment as a potential explanation for the increased susceptibility to infection in early life  also found that the exposure of neonatal PMNs to adult plasma resulted in adult levels of bactericidal activity and hydrogen peroxide production (against S. aureus)  , 46. Sime groups . This brin vitro comparisons of neonatal and adult phagocytic cells have contributed to the theory that neonatal susceptibility to infection is a result of “immaturity,” so has the evidence accrued which describes diminished in vitro pro-inflammatory responses when comparing neonatal and adult cells , newborns would benefit from mechanisms that would reduce the risk to unleash a harmful antimicrobial immune response. The molecular mechanisms related to this have recently begun to be deciphered and highlight a direct connection to disease tolerance. An g adults . Neonatanfection , 56. Thein utero without rejection of maternal cells by the fetus  and disease resistance  must maintain a state of homeostasis for optimal host defense. Without active suppression of inflammatory innate signaling, the initial influx of microbes from the birth process could prompt an enormous, potentially lethal inflammatory response; even if this inflammatory response did not result in mortality, there would be serious short- and long-term health ramifications as a result of inadequate bacterial diversity in the gut  to an invasive agent must be weighed in terms of the potential for self-inflicted damage, or immunopathology. The resultant immunopathological impact of any given response can range from negligible  to fatal , and thus the immunopathology associated with an immune response has been described as the “immune cost” of a response . The thrIn the last decade, a vast body of research has emerged, implicating the microbiome as a critical mediator of neonatal immune development , 60–62. Bacteroides and Clostridia acquired from their mothers, the composition of their microbiota is still different from their mothers with Escherichia/Shigella, Bifidobacterium, Streptococcus, and Enterococcus occupying roughly half the space of the entire intestinal microbiome in newborns but only about 10% in their mothers [the exception is Bacteroides, which feature prominently in both  via a mechanism involving the recruitment of Tregs to the colon  was shown to promote type 1 IFN signaling in lung dendritic cells, resulting in a less damaging response to influenza challenge and an increased animal survival, while the viral burden in DAT-treated mice remained unchanged . Newbornhe colon . A secon disease .Taken together, host-commensal bacteria crosstalk in newborns is highly dependent on maternal care for both original inoculation and continued support through breastfeeding and controlled environmental exposure. This complete dependence is unique to the newborn period, highlighted by both the devastating consequences of suboptimal breastfeeding practices and the reworking of intestinal and microbial architecture once solid foods are introduced. During this time, commensals selected to thrive in newborns promote disease tolerance by boosting anti-inflammatory immune responses and disease avoidance by excluding potentially pathogenic organisms from coming into contact with the epithelium, thus preventing infection of the mucosal and systemic sites.Listeria monocytogenes challenge and found TLR agonists to be protective as well. Cord blood monocytes stimulated with endotoxin showed an enhanced activity both 7 and 14 days later. Moreover, a retrospective analysis revealed correlation between histological chorioamnionitis (a condition prompting an inflammatory response) exposure and a reduction in late-onset neonatal sepsis  less energetically intensive , (b) less likely to incur serious damage associated with bacterial clearance (neonates are more sensitive to immunopathology than adults and seem to have a heightened innate immune response), and (c) less likely to interfere with the development of the gut microbiome (overactive resistance pathways could result in a dangerous inflammatory response and interfere with colonization). Maintaining homeostasis between disease resistance and disease tolerance is a critical outcome of fighting and preventing infection. Fortunately, interventions, which work within these constraints, have been identified and promise to finally usher in the desperately needed reduction of global newborn mortality rates.DH, NA, and TK conceived of the presented ideas. DH wrote the manuscript with assistance from RB-O, NH, and TK. All authors provided critical feedback and editing through the writing process.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.


Chorioamnionitis is a major cause of preterm birth and brain injury. Bacterial invasion of the chorion and amnion, and/or the placenta, can lead to a fetal inflammatory response, which in turn has significant adverse consequences for the developing fetal brain. Accordingly, there is a strong causal link between chorioamnionitis, preterm brain injury and the pathogenesis of severe postnatal neurological deficits and cerebral palsy. Currently there are no treatments to protect or repair against brain injury in preterm infants born after pregnancy compromised by intrauterine infection. This review describes the injurious cascade of events in the preterm brain in response to a severe fetal inflammatory event. We will highlight specific periods of increased vulnerability, and the potential effects of therapeutic intervention with cell-based therapies. Many clinical trials are underway to investigate the efficacy of stem cells to treat patients with cerebral palsy. Stem cells, obtained from umbilical cord tissue and cord blood, normally discarded after birth, are emerging as a safe and potentially effective therapy. It is not yet known, however, which stem cell type(s) are the most efficacious for administration to preterm infants to treat brain injury-mediated inflammation. Individual stem cell populations found in cord blood and tissue, such as mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs), have a number of potential benefits that may specifically target preterm inflammatory-induced brain injury. MSCs have strong immunomodulatory potential, protecting against global and local neuroinflammatory cascades triggered during infection to the fetus. EPCs have angiogenic and vascular reparative qualities that make them ideal for neurovascular repair. A combined therapy using both MSCs and EPCs to target inflammation and promote angiogenesis for re-establishment of vital vessel networks is a treatment concept that warrants further investigation. Most cases are termed subclinical chorioamnionitis, with no obvious symptoms during pregnancy, but placental histopathology after preterm birth revealing significant levels of activated neutrophils and macrophages, indicative of infection  is a critical contributor to poor neurodevelopmental outcome in preterm infants who were exposed to chorioamnionitis Preterm birth and chorioamnionitis is characterized by periods of brain hypoxia, either from inflammation of the placenta disrupting blood flow to the fetus or as a result of inflammation  is one of the most common experimental compounds used to mimic infection. LPS is a component of gram-negative bacterial wall and acts via toll-like receptors  to illicit a strong inflammatory response , TLRs , TNF, and excitatory amino acid agonists including glutamate, that act together to initiate neural cell apoptosis  pathway  collection volumes of UCB are proportional to gestational age and preterm birth is therefore implicated in low collection volumes , brain derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), glial derived neurotrophic factor (GDNF), and IL-10 , ARC Future Fellowship to SM and the Kahli Sargent Research Studentship to MP.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.


Cytomegalovirus (CMV) infection is increasingly recognized in critically ill immunocompetent patients. Some studies have demonstrated an association between CMV disease and increased mortality rates, prolonged intensive care unit and hospital length of stay, prolonged mechanical ventilation, and nosocomial infections. However, there is a considerable controversy whether such association represents a causal relationship between CMV disease and unfavorable outcomes or just a marker of the severity of the critical illness. Detection of CMV using polymerase chain reaction and CMV antigenemia is the standard diagnostic approach. CMV may have variety of clinical manifestations reflecting the involvement of different organ systems. Treatment of CMV in critical care is challenging due to diagnostic challenge and drug toxicity, and building predictive model for CMV disease in critical care setting would be promising to identify patients at risk and starting prophylactic therapy. Our objective was to broadly review the current literature on the prevalence and incidence, clinical manifestations, potential limitations of different diagnostic modalities, prognosis, and therapeutic options of CMV disease in critically ill patients. CMV disease is usually a disease acquired by adolescence and follows a benign course, while it might reactivate in patients with immune suppression and associated with high mortality and morbidity.There is growing evidence that critically ill immunocompetent patients can develop CMV disease. Studies have described CMV infection in immunocompetent surgical, septic, burn, or trauma critically ill patients , 2. SomeThe objective of this review is to examine the up-to-date literature regarding CMV disease in critically ill patients. We will review the studies that assessed prevalence and incidence of CMV disease refuting the differences among them leading to different results, clinical manifestations, pathogenesis, potential limitations of different diagnostic modalities, association with outcomes, and treatment options of CMV disease in critically ill patients.Primary CMV infection usually occurs during childhood and early adolescence and is usually asymptomatic or mild and self-limiting disease in immunocompetent patients. After the resolution of acute infection, CMV establishes latent phase mainly within leukocytes, namely mononuclear cells, and this stage is diagnosed with a positive anti-CMV IgG serology (seropositivity) and is characterized by maintenance of the viral genome in the absence of production of lytic infectious virions but with the ability of the viral genome to reactivate under certain conditions .CMV literature focused on immunocompromized population like transplant and AIDS populations; therefore, CMV disease statuses and definitions were based on that literature which defined CMV infection as detection of CMV genetic or molecular material in the patients’ serum or body fluids, indicating active replication of the virus. CMV infection according to that literature can occur as a result of reactivation of latent CMV or reinfection with an exogenous strain. Recurrent infection in immunocompromized patients is the detection of CMV genetic or molecular material in a patient who had previous documented infection and who has not had virus detected for an interval of at least 4 weeks during active surveillance –7, or neCMV disease in critically ill adults will probably fall under one of these three mechanisms. Meta-analysis done by Osawa and Singh  has showCMV end-organ disease has been defined as evidence of virus replication associated with clinical manifestations due to viremia or the invasion of organs such as the lungs, bone marrow, and colon .The scope of this article is to examine CMV disease literature in critically ill overtly immunocompetent patients.In summary, CMV is usually acquired in childhood, and the most common mechanism of the disease in adulthood is reactivation of latent virus whether in immunocompromized or critically ill population, followed by rare incidence of recurrent new or de novo new infection.CMV is the most common member of the herpes viruses to infect humans. Its double-stranded linear DNA duplex contains 165 genes that encode viral proteins that mimic and interact with human cellular proteins and are related to its virulence and latency.CMV is maintained in a latent or low production state within monocytes mainly and dendritic cells (DC). They do not usually express viral genes in significant number due to the robust CD8+ cytotoxic T lymphocyte response and T memory cells. In immunocompetent individuals, asymptomatic viral shedding may be detectable in the saliva or urine; however, cell-mediated host immune responses prevent the development of overt CMV disease .CMV genome is detected within early progenitor myeloid CD34+ cells, and monocytes and (DC) differentiation will be the only lineage that will pass the CMV genome. Viral expression is closely related to expression of immediate early (IE) genes within monocytes and (DC), but expression of infectious (lytic) virions only happens within (DC), a process regulated by major IE enhancer promoter (MIEP) which is normally under repressors closely related to other factors and cytokines within the cells [CMV disease occurs as a result of immunosuppression associated with critical illness. A landmark study by Clari showed that CMV infection in critically ill patients was consistently associated with undetectable IFN-γ T cell responses within the first 2 days of admission to the ICU, and that viral load was inversely related to IFN-γ T cell responses . A studyUnder such critical conditions observed during sepsis, burns, trauma, or major surgery, the CMV genes are expressed and viral replication is initiated , 15, invIn addition, when CMV starts to replicate within leukocytes, it has inherent escape mechanisms from the host immune system, and the CMV unique short  proteins down-regulate the surface expression levels of HLA-1 and HLA-2 on leukocytes that mark these cells to be attacked by CD8+ T lymphocytes .Other CMV genes encode structural proteins, such as the matrix protein pp65, that is involved in down-regulation of HLA-1 leukocytes surface markers and used as a target of antigen detection immune assays .In addition, virulence is also related to boosting immune response causing more tissue damage, and this is due to homology of some of CMV proteins to inflammatory cytokines as human tumor necrosis factor alpha receptor and CXC chemokine such as interleukin-8 .Animal model studies suggested that the outcome after reactivation might be determined by the viral load of the original infection, which correlates with the number of CMV-specific T memory cells, i.e., immunological responses (higher IgG levels), CD-8 cytotoxic cells, and hence inflated immune response during reactivation, and this might be a promising marker to predict the outcome in patients with reactivation , 19.In addition, the virus has an immunosuppressive effect via its modulatory effect on cytokine production, which may enhance the susceptibility to secondary bacterial and fungal infections. CMV also has a direct suppressive effect on the bone marrow.Some CMV proteins are also related to antiviral mechanisms, including the viral DNA polymerase UL54 and UL97, which encodes a protein phosphotransferase enzyme that phosphorylates the antiviral drug ganciclovir, an essential activation step required for its inhibitory effect on CMV DNA replication –22.In summary, CMV has a complicated genome that allows the virus to go into latent state and facilitate its evasion from immune response and homology to human chemokines, all of which is involved in its pathogenesis.Several factors have been identified to be associated with CMV disease in critically ill patients Table , includiBlood transfusion, especially in the first 24 h of critical illness, has been shown to be an important risk factor for CMV disease , which hIn summary, mechanical ventilation and blood transfusion in the ICU have been associated with the development of CMV disease, but no association with severity scores was found.Several epidemiologic studies assessed the incidence of CMV disease in critically ill patients Table , and theVariation in diagnostic methods used including selecting different specimens, some used serum, while others used urine, saliva, or bronchoalveolar lavage samples, tests were performed at different points in the ICU stay and testing time and frequency was not standardized in all studies as some left it up to the judgment of the treating team. Recent studies showed that CMV disease typically occurs within the first 2 weeks of critical illness. A study performed by Kalil and Florescu  showed tIn summary, the incidence and demographics of CMV disease in the ICU were highly variable across studies, as a result of variation in study design and definition of the disease.Identification of CMV disease in immunocompetent patients is complicated by its non-specific symptoms, multiorgan involvement, and the fact that its clinical manifestations converge with those of the critical illness. Heininger et al.  reportedVascular manifestations have been reported such as portal or femoropopliteal vascular thrombosis and pulmonary embolism that is thought to be related to vascular endothelial cells damage .The immunomodulatory effects of CMV may be responsible for increased risk of secondary bacterial and fungal infections in critical care setting , 4.CMV pneumonia is a well-known clinical manifestation of CMV disease in immunocompromized patients. However, lung involvement may be less recognizable in immunocompetent critically ill patients especially if they were intubated for other reasons, but few studies demonstrated that the prevalence of this disease in immunocompetent critically ill patients may be as high as 50% in patients with ventilator-associated pneumonia or ICU-acquired acute respiratory distress syndrome . HoweverIn general, CMV affects multiple organs at varying rates and severity. ICU-acquired pneumonia, especially VAP, appears to be a common CMV-associated disease that draw attention of ICU physicians and researchers.Critically ill patients have dynamic immune system that affects the CMV detection window. The fact that immune suppression is not expected usually on presentation to intensive care, coupled with the ability of infected individuals to control the disease and eventually clear the virus at some point, affects the accuracy of diagnostic methods for CMV, all of that in addition to the differential sensitivities and clinical utilities of the techniques used to detect CMV Table . In one Testing for CMV for the diagnosis of CMV disease should be based on predictors of CMV disease in addition to signs and other laboratory investigations directing toward viral origin of the current clinical status as indicators of liver and gastrointestinal involvement .The most commonly used tests to measure CMV-specific IgM or IgG levels are the enzyme-linked immune assays and anticomplement immunofluorescence assays. The presence of IgM antibodies indicates an acute CMV infection and can last for 4–6 months . BecauseDue to its high sensitivity and rapid turnaround time, PCR is considered the gold standard method of diagnosing CMV infection . Both quAntigen assays using immunofluorescent antibodies are quick and easy to perform and can be used to detect the CMV pp65 antigen in leukocytes . In one Culture-based assays are not clinically used due to their low sensitivity and delay in receiving the results . In a meHistopathology is the most specific method for diagnosing CMV, especially by detecting organ-specific manifestations related to CMV. However, this method is invasive and has a limited sensitivity that depends on the sampling site and pathologist’s skills.We suggest using CMV PCR or CMV antigen detection assays to diagnose CMV disease not earlier than 3 days and up to 2 weeks after the onset of critical illness, especially when the pretest probability of the disease is high , 8.Studies addressing association of CMV disease and outcome in critically ill patients revealed inconsistent results.A systematic review by Osawa and Singh  concludeIn a landmark prospective cohort study by Limaye et al.  of 120 CRegarding specific ICU population, a recent observational prospective study that included 86 CMV-seropositive septic patients found an association between CMV disease and longer ICU stay, prolonged mechanical ventilation, and impaired pulmonary gas exchange . Coisel On the other hand, a prospective observational study of 80 mechanically ventilated patients that were seropositive for CMV found no association between CMV disease and 28-day mortality, ICU mortality, ICU length of stay, or duration of mechanical ventilation, although the SOFA score was significantly higher in CMV-infected group . SimilarThese inconsistent findings are probably related to differences of studied populations, retrospective nature of several studies, differences in diagnostic tests, the unmeasured confounders; therefore, it is difficult to establish proved causality based on the existing studies, necessitating future studies with strict methodology in relation to blinding, studied population, testing timing, and method of testing preferably with tissue studies to clarify the causal relation between CMV disease and ICU mortality and morbidity.In conclusion, although the current literature is inconsistent, there is strong evidence suggesting an association between CMV disease and higher morbidity and mortality in the ICU.The central controversy of CMV disease in critically ill patients is whether to treat or not and whether treatment makes a difference to the patient’s outcomes or not.Treatment of CMV disease as any other disease should be based on a benefit/risk ratio, taking into consideration all other factors associated with the diagnostic process and treatment such as invasiveness of the diagnostic method, side effects of anti-CMV medications which might be serious especially in critical ill patients, and risk of emergence of CMV resistance to the medications . There iSimilarly, the curative treatment of clinically confirmed CMV disease  in immunocompetent critically ill patients has been recommended, and support for such approach comes from studies like the one by Eddleston et al.  that exaHowever, the benefit of preemptive treatment of subclinical detected viral replication with no proven direct organ pathology attributed to CMV, and the prophylactic treatment in immunocompetent patients deemed to be at risk of developing CMV disease is much less clear . It is pChallenges for CMV preemptive and prophylactic treatment includes discouraging safety profiles of anti-CMV medications on the kidney and bone marrow especially in critically ill patients who already have organ dysfunction that puts them at extra risk of further dysfunctions and secondary infections Table .Table 4The other challenge is the detection of CMV, the current used methods, namely CMV PCR and CMV antigenemia, are highly accurate regarding sensitivity and specificity, but the challenge is that detection of CMV is highly sensitive to the timing and frequency of testing which is related to the window of emergence of CMV infection within the first 2 weeks of critical illness but not earlier than 3 days , 44; secPapazian recommended in his recent review that treatment for evident CMV replication  is not indicated unless it is associated with lung infiltrates and at least two factors  which if found points for CMV being a pathogen invading multiple organs and not only a bystander or innocent viral shedding .So far no definite criterion is available to guide which critically ill patients should be screened for CMV disease. According to available literature certain populations as septic, burns, trauma, ICU-acquired pneumonia especially mechanically ventilated patients have been found at high risk of developing CMV disease across multiple studies , 41, 47.Regarding preemptive treatment, immunological assessment of IFN-γ produced by CMV-specific CD8+ T cells and NK cell function as mentioned in virulence section might be a strong trigger to start preemptive treatment for detected CMV, because there is evidence that impaired CMV-specific CD8+ T cells IFN-γ production prior to CMV reactivation predicts poor outcome, which favors treatment. This has not been applied clinically so far but might be promising in the future for challenging cases .CMV might acquire resistance to the limited number of medications that are currently available; hence, their prophylactic use should be confined to confirmed cases or preemptive treatment until clear risk assessment tools for prophylactic therapy are developed in high-risk groups in the ICU .There are many uncertainties about CMV disease in the critically ill patients. First, while identification of the virus is common in critically ill patients, the actual rate of CMV as a disease in critically ill patients is unclear. Second, the importance of CMV detection in critically ill patients remains questionable, especially in the absence of histologic evidence of infection. On the other hand, the existing evidence is strong regarding the association between CMV detection and increased mortality and morbidity rates in ICU settings.Still there are no high-quality data to guide the decision regarding when to treat detected CMV in ICU patients if there is no definite clinical confirmation of CMV disease (preemptive treatment), and there is no risk assessment tool to guide prophylactic therapy in ICU setting.There is a need for well-conducted studies to develop risk assessment tool of CMV disease in critically ill patients, to estimate the real burden of CMV disease, and to examine the effect of prophylactic and preemptive treatment on morbidity and mortality. Potential answers to these questions will hopefully be answered by currently ongoing trials related to CMV in critical care. “Cytomegalovirus Control in Critical Care trial” (NCT01503918) is addressing the safety and success rate regarding preventing reactivation of latent cytomegalovirus infection in critically ill patients when treated with one of two different antiviral regimens: “Valaciclovir/Aciclovir or not.” “Study of Ganciclovir/Valganciclovir for Prevention of Cytomegalovirus Reactivation in Acute Injury of the Lung and Respiratory Failure” (NCT01335932) is addressing whether administration of ganciclovir in CMV-seropositive patients reduces serum IL-6 levels in immunocompetent adults with severe sepsis or trauma-associated respiratory failure based on the hypothesis that pulmonary and systemic CMV reactivation amplifies both lung and systemic inflammation mediated through specific cytokines. “Preemptive Treatment of Herpesviridae trial” (NCT02152358) is addressing whether preemptive treatment by ganciclovir (for positive CMV viremia) or aciclovir  is able to increase the number of ventilator-free days at day 60 in ICU patients with prolonged mechanical ventilation having evident viral replication.


Adult patients having schizophrenia, bipolar disorder or major depression display indicators of brain dysfunctions that may be detectable in healthy children-adolescents at genetic risk, such as those born to an affected parent . For instance, cognitive deficits are displayed by both adult patients and children at risk . We had reported that schizophrenia patients present diminished amplitudes and delayed latencies of rod and cone photoreceptor responses  and we recently found that bipolar patients have similar ERG anomalies. We had also reported preliminary data in a small sample of 29 children born to an affected parent showing that young offspring had rod diminished amplitudes .The present objectives were i) under the hypothesis that offspring would display many of the ERG anomalies that schizophrenia or mood disorder patients carry , to look for cone and rod response anomalies in a large sample of young high-risk offspring; ii) to describe the relationship between ERG anomalies and other risk endophenotypes in the offspring; and iii) look at the relationship between ERG anomalies and the risk clusters already shown to predict later transition to illness.The sample consisted of 84 young offspring (aged 6 to 27) of a parent affected by schizophrenia or bipolar disorder, compared to 224 healthy controls balanced for age and sex. Full-field cone and rod ERG was measured in non-dilated eyes for all subjects. In the young offspring, we also collected measures of different cognitive domains, attenuated symptoms of psychosis, non-psychotic DSM diagnosis and/or an episode of poor GAF functioning in childhood-adolescence, childhood trauma, and cannabis use .In comparison to controls the offspring displayed three ERG anomalies that were observed in adult patients: prolonged cone b-wave latency (p=0.04), diminished rod b-wave amplitude (p=0.04) and prolonged rod b-wave latency (p=0.006). These ERG anomalies were shared by offspring of a parent with schizophrenia or bipolar disorder, an observation of ERG commonality that we had made in adult patients. The three ERG amplitude and latency anomalies tended to aggregate in a child at risk, a trend we also observed in another endophenotype modality such as deficits in different cognitive domains. However, in these high-risk children and adolescents, the patterns of aggregation suggest that ERG anomalies would depict another risk pathway than that marked by cognitive deficits.First, ERG anomalies in high-risk children have neurobiological implications for future research on the illness neurodevelopment. Second, as found for other modalities of risk endophenotypes in children at genetic risk , multiple rod and cone ERG anomalies tended to cluster together in a child. Such an aggregation may be compatible with the multifactorial polygenic theory with a threshold. Remarkably, a clustering of risk indicators is also observed in children at risk of metabolic cardiovascular disorders and is presently considered in practice guidelines for these children. The clustering of risk indicators may provide an empirical basis for the staging of the risk status of children at genetic risk and has immediate implications for their longitudinal surveillance in the clinic.


Research has suggested that processing the spatial interrelationship of facial features is crucial to face perception . However, recent research that has examined the effect of stretched and sheared images has suggested that early visual processes do not discriminate between an undistorted image and a severe geometric distortion of the same image . In two experiments, we show that both familiar and unfamiliar face recognition may be robust to geometric distortions. Using a familiar/unfamiliar judgment task, Experiment 1 compared correct reaction times and accuracy for undistorted face images to vertically and horizontally stretched front-view images. In Experiment 2, we compared undistorted face images to stretched, sheared, and twisted face images seen in front- and three-quarter-viewpoints. Observers saw all familiar and unfamiliar faces randomly in all distorted conditions. In both experiments, we found robust accuracy in all conditions despite effects on correct reaction times and substantial within-image deformation in distorted conditions. The findings suggest that processing the spatial interrelationship of features may not be crucial for correctly recognising a familiar face and correctly rejecting an unfamiliar face. This raises questions about the role of configural information in face processing for identity.


Although clinical nutrition is a frequently used intervention in inpatient care, high quality trials proving its effectiveness and safety when used in the acutely-ill polymorbid medical inpatient population are largely lacking. From an evolutionary perspective, illness-related low appetite is protective and part of the host response to improve recovery from disease. Large and well performed trials in the intensive care setting have shown deleterious effects of  feeding strategies aiming at higher caloric intakes compared to lower intakes, raising the question of whether feeding per se may be simply maladaptive in acute severe illness. Outside critical care, similar large-scale studies are lacking with basic clinical questions regarding the optimal amount/composition of nutrition and best patient selection remaining largely unanswered. Also, the interplay of nutritional interventions and its influence on the microbiome remains largely unclear. Given the magnitude of morbidity caused by malnutrition and the high number of affected patients, it is surprising how little the medical community has invested in better understanding ways to improve this condition. It is now time to perform high-quality trials to better understand how to best deal with this condition in the acute care setting. Such trials will allow change from a one-size-fits-all approach, to more evidence-based, personalized nutritional interventions, ultimately improving patient outcomes. While there is ongoing discussion about definition of malnutrition, we should rather focus on the identification of patients who do or do not benefit from nutritional interventions. Let food be thy medicine and medicine be thy food”). Today, however, there are few rigorously conducted trials of nutritional interventions that assess their impact on mortality, morbidity, or other patient-centered outcomes. This is particularly true for the acute, non-critical medical care inpatient setting, where there is an important lack of studies to guide clinicians in the optimal use of nutrition in an “evidence-based” manner and help us understand the potential of nutrition to cure disease, or at least to improve patient outcomes [Nutritional research experienced a very promising start in 1747 with James Lind conducting the first ever randomized controlled trial comparing six different treatments for 12 sailors with scurvy [Regarding the question of nutrition for primary prevention of disease, several large randomized trials have demonstrated impact on mortality and morbidity. For example, the PREDIMED trial showed the positive effects of a Mediterranean diet on cardiovascular and metabolic disease . AdditioEvidence from critical care studies showing harmful effects when clinical nutrition is used , 6 highlRemarkably, therefore, basic questions such as, “What is the optimal amount of calories and protein for medical inpatients?”; “Which medical inpatients have the most benefit from nutritional interventions?”; and “What type of nutrition (if any) is beneficial for the medical inpatient?” remain largely unanswered . FurtherIn the acute care medical setting – outside critical care – malnutrition remains an increasing problem, affecting as much as 30–50% of patients . UndoubtDespite strong associations between malnutrition and adverse outcomes, causal inferences remain largely unproven. Additionally, whether provision of nutritional therapy in the acute phase of a medical illness has the potential to reverse the adverse effects associated with malnutrition in the non-critical care inpatient setting remains unclear. Given the magnitude of morbidity caused by malnutrition and the high number of patients affected by this condition, it is surprising how little the medical community has invested in recent years to better understand ways to improve this condition in an “evidence-based” manner. Although the use of nutritional therapy is a common intervention in medical inpatients, there is no strong current scientific evidence of its efficacy or standard algorithms for its use in medical inpatients. This may be explained by difficulties in standardization, blinding, and patient compliance in nutritional trials, and insufficient industry-funding due to low product margins, among other issues . Still,


The 2014–2015 outbreak of Ebola in West Africa claimed over 11,000 lives and laid bare the challenges of responding to a large-scale, swiftly evolving public health emergency. Prominent among these difficulties was disagreement about the ethics of conducting clinical research during epidemics and whether clinical trials of vaccines and therapeutics should employ randomization and concurrent controls. To facilitate rapid, well-coordinated responses to future public health emergencies, the United States National Academies of Sciences, Engineering, and Medicine established a committee to assess the clinical trials conducted in Guinea, Sierra Leone, and Liberia during the outbreak. The key findings and conclusions regarding ethical issues raised about conducting research during public health crises are briefly described here and are fully evaluated in the Committee’s report  rare circumstances… every effort should be made to implement them during epidemics” .Third, the committee rejected the claim made by some stakeholders that due to Ebola’s high mortality rate, equipoise would not exist for studies of therapeutic interventions that included the possibility of randomization to a standard-of-care control arm . In partIn addition, the claim that randomized designs of interventions during the 2014 Ebola outbreak would have entailed the unethical withholding of potentially beneficial interventions from people in desperate need also rested on the unwarranted assumption that interventions in the early stages of development were more likely to be highly efficacious than to worsen participants’ already fragile condition. Available preclinical data did not support such enthusiasm. Even if it had, 90% of novel interventions fail to prove effective for any indication , a statiFourth, effectively communicating reliable scientific information to local communities—including uncertainty about the efficacy and safety of investigational interventions, a cornerstone of respectful community engagement—is an essential component of ethically responsible research. Public health emergencies are contexts of heightened uncertainty and mistrust. Public resistance to randomized trials in some Ebola-affected regions was fueled by a misconception that the interventions were highly efficacious “secret serums” . This arThis engagement, however, cannot be initiated late in the game. The Committee’s report includes several recommendations for increasing planning and preparedness during interepidemic periods so that reliable, ethically acceptable research can be organized, reviewed, and launched expeditiously when the next outbreak strikes.Finally, to frontline caregivers facing overwhelming clinical need and acute shortages of supplies and manpower in the early stages of the outbreak, research felt like an unjustifiable diversion of scarce resources. The question of whether rigorous clinical trials of novel therapeutics and vaccines should or can be implemented during epidemic emerging infectious diseases has been affirmatively answered during the West Africa Ebola outbreak. The National Academies of Sciences, Engineering, and Medicine report emphasizes that sustained, coordinated international support for health systems in low- and middle-income countries is now of paramount importance. This includes investing in their medical infrastructure, enhancing their capacity to conduct public health surveillance and research, and ensuring that collaborations provide lasting benefits to affected communities.S1 File(PDF)Click here for additional data file.