It is now well established, at least in animal models, that pathological changes in the gutmicrobiota (dysbiosis) can influence inflammation in the central nervous system (CNS). Theidea of a disease-modifying therapy for MS that acts through the microbiota, safely andrelatively non-invasively, is certainly attractive; and progress is ongoing towardsimmunomodulatory treatments of this nature. However, the proposal that the same approach canpromote remyelination in people with MS is not supported by current evidence.I will address this proposal in three parts:Can correcting gut dysbiosis ameliorate inflammation?Can this promote remyelination?Does this apply to people with MS? Meanwhile, gnotobiotic animal models have yielded convincing evidence for a causalrole of dysbiosis in MS pathogenesis. For example, Berer et al. demonstrated how faecal microbial transplantation (FMT) from an identical twin withMS can trigger CNS autoimmunity in mice much more reliably than colonisation from theirunaffected twin. In turn, a variety of interventions that target the microbiota have beenshown to ameliorate inflammation and disease severity in animal models of MS – includingantibiotics, probiotics, prebiotics and FMT (reviewed).In short: yes. Over the past decade, -omics approaches have revealed reproducibletaxa-level differences between the gut microbiota of people with MS and healthy controls. While these three interventions all produced changes in the inflammatory response totoxin-induced demyelination, they had no convincing impact on remyelination itself.Broad-spectrum antibiotics caused a delay in oligodendrocyte progenitor cell (OPC)differentiation; however, this finding was not reversed by FMT and, alongside the negativedata from other models, it likely represented off-target effects of the antibiotic regime.Notably, in the complete absence of a microbiota, GF mice regenerated myelin to the sameextent and with the same ultrastructural appearance as control mice.A coordinated inflammatory response removes myelin debris and provides growth factors toencourage remyelination, so there is a theoretical basis for changes in the microbiota toinfluence remyelination via neuroinflammation. We tested this hypothesis in germ-free (GF),antibiotics-treated and probiotic-treated mice. Prophylactic antibiotic treatment before disease onset protected the mice fromdeveloping EAE but giving antibiotics in established disease had no clinical effect. Thisfinding is further evidence that, while the microbiota is key to the induction of CNSautoimmunity, it then becomes a relatively minor player during ongoing damage andrepair.Other work interrogating the timing of microbial depletion in a different model,spontaneous experimental autoimmune encephalomyelitis (EAE), gives a consistent picture. but there are other hypothetical means for the microbiota to influence remyelinationbesides neuroinflammation. Gut microbial metabolites such as butyrate and p-cresol can signal directly to oligodendrocyte progenitor cells in vitro and are respectivelypositive and negative regulators of their differentiation to oligodendrocytes. However, atpresent there is no evidence to show that such metabolites, when produced by the microbiotain vivo, have a physiological effect on remyelination.We observed an uncoupling of remyelination from changes in the innate immune response, administered a probiotic to 9 relapsing-remitting MS patients and 13 healthycontrols, demonstrating anti-inflammatory changes in blood monocytes and dendritic cells.However, the question as to whether these interventions lead to amelioration of CNSinflammation can only be answered through MRI outcomes or clinical relapses. A singlerandomised control trial (N = 60) showed an improvement in expandeddisability status scale (EDSS) among patients receiving a probiotic. Results from further studies using imaging and clinical outcome measures are awaited,to build upon this encouraging outcome.Several clinical trials are ongoing to test microbiota-based interventions in MS, but thereis little published literature at the time of writing. Most studies focus on changes in theperipheral immune response, which is in more direct contact with the microbiota and easilyassessed through blood tests. For example, Tankou et al.against the microbiota being an importantfactor in remyelination. It therefore seems unlikely that correcting dysbiosis would give ameaningful signal in patients, among additional experimental noise not seen in laboratoryanimals – such as genetic diversity, lifestyle and concomitant medications. With the fieldof remyelination-promoting clinical therapies in its infancy, it would be prudent to focuson interventions that have the strongest experimental basis.No study has directly addressed whether similar interventions could promote remyelinationin people. However, such a trial would be low priority given the negative preclinical data,combined with the added challenges of measuring remyelination in human subjects. Whereas themicrobiota’s effects on neuroinflammation have a strong basis in rodent models, thepreclinical evidence argues In summary, the preclinical evidence shows that remedying a dysfunctional microbiota canimprove inflammation – but not promote remyelination – in animal models of demyelination.For people with MS, current trials mainly focus on the peripheral immune response andstudies with imaging outcomes are awaited. The question of whether correcting dysbiosiscould promote remyelination in MS has not been studied directly, but this seems far-fetchedin the context of the evidence to date.As the literature linking the microbiota to host physiology has expanded in recent years,‘correcting gut dysbiosis’ is sometimes touted as a panacea among academics and the publicalike. However, as with any biological system, there will be limits to what the microbiotacan achieve. While the idea is enticing, the promotion of remyelination for patients with MSmost likely lies beyond these limits.


Falls are the leading causes of accidental injury in older adults and directly contribute to more than 600,000 deaths each year worldwide. Although the issue of falls is complex, balance dysfunction is one the principal contributors to the heightened incidence of falls in older adults. A nationally representative survey of older adults in the United States showed that an inability to stand on a foam pad with the eyes closed was associated with more than a six-fold increase in the odds of reporting “difficulty with falls.” As stability in the “eyes closed, on foam” condition is reliant upon intact vestibular cues, these data implicate age-related vestibular loss as a potential contributor to falls, yet, the specific causal mechanism explaining the link between age-related vestibular loss and imbalance/falls was not known. Here we review recent data showing that, vestibular perceptual thresholds, an assay of vestibular sensory noise, were found to, (1) account for nearly half of subclinical balance impairment in healthy older adults and (2) correlate with postural sway in healthy young adults. Based upon the identified links between balance dysfunction and vestibular noise in healthy adults, we posit the following causal chain: (a) increased “noise” in vestibular feedback - yielding a reduced signal-to-noise ratio in vestibular feedback-increases sway, (b) excessive sway leads to imbalance, and (c) imbalance contributes to falls. Identifying the “cause” of age-related balance dysfunction will inform the development of interventions tailored to prevent falls, and fall-related injuries, in the growing population of older adults. A common consequence of aging is a progressive decline in balance –3 leadinUsing a large nationally representative National Health and Nutrition Examination Survey (NHANES) sampling of older adults , Agrawal, et al.  found thBalance represents one’s ability to maintain their center of mass within their base of support ,13, alloThe vestibular system senses both linear acceleration and gravity using two otolith organs and rotations using three orthogonally oriented semicircular canals. This complexity allows humans to sense rotations and translations of the head in six degrees of freedom and provides a suitable mechanism by which to sense, and subsequently respond to, balance perturbations. To identify the specific contributions of the vestibular system to age-related imbalance, the integrity of each of the five vestibular sensor pairs  must be determined. Thus, while the ability to stand on foam with vision removed is suggestive of vestibular impairment, the relative effects of the specific vestibular end organs  and associated sensory modalities  on balance performance cannot be determined from balance testing in isolation. We posit that comparing specific, sensitive, quantitative measures of vestibular function to valid measures of balance performance can provide unique insights into the role of vestibular cues in postural sway.Bermúdez-Rey and colleagues measured a battery of vestibular perceptual thresholds, alongside the “eyes closed, on foam” balance task  in a sample of 99 adults aged 18 to 89 . Roll tiThe categorical test limitation was addressed in a recent publication by Karmali et al. in the Journal of Neurophysiology . KarmaliHere, we have described studies where vestibular thresholds have been compared to postural sway measured only under quiet stance conditions. Given the breadth of our definition of balance-which additionally includes dynamic anticipatory, and dynamic compensatory responses-quiet stance represents but one of several sub functions that comprise the human balance system. Nevertheless, we posit that the significant correlations observed between quiet stance postural sway and falls support the ability of quiet stance sway metrics to quantify the integrity of the human balance system. Thus, quiet stance sway metrics may provide a relatively simple screening test for fall risk.Several investigators over the past 40 years have attempted to relate static, anticipatory, and compensatory balance measures to falls, with the static balance measures resulting in the most accurate predictions of falls. In the early 1990’s, Maki, et al. used quantitative measures of quiet stance postural sway to prospectively predict the incidence of falls over a 1-year follow-up period in a sample of 100 healthy adults [In this study, Maki also tested dynamic compensatory and anticipatory postural sway as well as clinical measures; a stepwise analysis selected mediolateral sway during eyes closed quiet stance “as the single measure that best differentiated between fallers and nonfallers” . SubsequFurthermore, Maki included both quiet stance and dynamic postural control measures and described potential methodological problems with dynamic tasks that yielded wide inter-participant variability in the performance of anticipatory tasks and a lack of real-world transient responses . These lThe identified link between vestibular noise, assayed using vestibular thresholds, and quiet stance balance performance provides insight into one potential factor contributing to fall risk among otherwise healthy older adults. While correlation alone cannot prove causation, the identified robust correlation between roll tilt thresholds  and balaWe emphasize three additional points for consideration:Once balance screening has identified those at risk of falling, effective fall prevention will likely benefit from the inclusion of a detailed and biofidelic set of tests that quantify the integrity of multiple elements relevant to balance control .As additional data accumulate, dynamic balance tests that overcome previous methodological limitations may eventually replace the quiet stance balance screening if substantially stronger links to falls are measured in side-by-side comparisons.Use of such balance and vestibular screening tests could provide data to guide the use of therapeutic interventions designed specifically to prevent the onset of falls by improving the use of vestibular cues for postural control. Such methods may include rehabilitation focused on improving tilt and/or lateral translation sensation or the use of prosthetic devices to restore the perception of tilt and/or lateral translation cues.


Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder with extensive genetic and aetiological heterogeneity. While the underlying molecular mechanisms involved remain unclear, significant progress has been facilitated by recent advances in high-throughput transcriptomic, epigenomic and proteomic technologies. Here, we review recently published ASD proteomic data and compare proteomic functional enrichment signatures with those of transcriptomic and epigenomic data. We identify canonical pathways that are consistently implicated in ASD molecular data and find an enrichment of pathways involved in mitochondrial metabolism and neurogenesis. We identify a subset of differentially expressed proteins that are supported by ASD transcriptomic and DNA methylation data. Furthermore, these differentially expressed proteins are enriched for disease phenotype pathways associated with ASD aetiology. These proteins converge on protein–protein interaction networks that regulate cell proliferation and differentiation, metabolism, and inflammation, which demonstrates a link between canonical pathways, biological processes and the ASD phenotype. This review highlights how proteomics can uncover potential molecular mechanisms to explain a link between mitochondrial dysfunction and neurodevelopmental pathology. Autism Spectrum Disorder (ASD) is a lifelong neurodevelopmental condition that is characterized by heterogeneous genetic origins and a poorly understood aetiology . AlthougWe propose that the integration of ASD proteomic data with large scale ASD transcriptomic and DNA methylation (DNAm) data may yield insight into the molecular mechanisms of ASD. Despite the aetiological and genetic complexity of ASD, this underlying heterogeneity is thought to converge on a limited number of biochemical pathways . IntegraThis review integrated data from large-scale quantitative meta-analyses from both transcriptomic and DNAm data, as well as from ASD proteomic datasets published over the past five years. Overall, data were collated from 19 studies and meta-analyses from ASD cohorts published between 2017 and 2021 . The pubhttps://david.ncifcrf.gov/conversion.jsp. Accessed on 8 March 2021)  against the Molecular Signatures Database (MSigDB) , using til 2021) ,36. Eachil 2021) . These ehttps://maayanlab.cloud/Enrichr/. Accessed on 12 April 2021) [https://www.networkanalyst.ca/NetworkAnalyst/home.xhtml. Accessed on 12 April 2021) [The proteomic datasets were examined to identify a subset of differentially expressed proteins that were also implicated in transcriptomic and DNAm data in ASD. After conversion to NCBI Entrez gene IDs, this subset of proteins was annotated with respect to significantly enriched Hallmark canonical pathways, ClinVar disease pathways and transcription factor protein–protein interactions (TF-PPIs) using the Enrichr gene list analysis tool suite (il 2021) ,39. TF-Pil 2021) , using til 2021) . This neAfter collating the data from 19 different studies , we deteThe four additional canonical pathways that were consistently implicated across molecular datasets were the xenobiotic metabolism, p53, adipogenesis and coagulation pathways. Both the xenobiotic metabolism and adipogenesis pathways were implicated in enrichment signatures from brain tissue using all three molecular approaches and were also implicated in studies of younger children using proteomic ,15, tranIt is important to note that four of six proteomic datasets included in this review are blood-based datasets, which means that they provide limited insight into which proteins might be differentially expressed in the brain. Therefore, this review compared the canonical pathways implicated in blood-based proteomic profiles with those enriched in proteomic, transcriptomic and DNAm data from brain tissue in order to highlight canonical pathways that could have functional implications in ASD. The coagulation pathway was the canonical pathway that was most consistently enriched in the ASD proteomic data. This pathway was implicated in five out of six proteomic datasets, including three datasets derived from blood samples in children between 18 months and 15 years ,15,16 asWe also used a second approach to explore how the proteomic data articulated with the transcriptomic and DNAm data associated with ASD. We identified a subset of 121 proteins that were implicated in ASD using all three molecular approaches . Of thesThe subset of 121 proteins that were implicated using all three molecular approaches was also enriched for five ClinVar disease pathways associated with neurological, immunological, and metabolic diseases . NotablyMolecular research of ASD requires a “multi-omics” approach to comprehensively characterise the convergent biological processes associated with its complex genetic architecture. Proteomic, transcriptomic, and epigenomic approaches are well-established as ways to investigate changes in gene regulation, expression, and function in ASD. DNA methylation is widely recognized as an epigenetic regulator of gene expression that contributes to ASD aetiology . TranscrDespite these limitations, proteomics can be an essential component of a multi-omic molecular approach to ASD aetiology. Protein expression studies can be used to investigate biologically relevant protein interaction networks and signalling pathways  and can We found that the canonical pathways involved in metabolism, redox homeostasis, inflammation and proliferation are consistently supported by proteomic, transcriptomic and DNAm data in ASD . This reThe common canonical pathways highlighted above are each established as molecular mechanisms contributing to ASD aetiology. In addition, in vitro and in vivo model systems have demonstrated that these pathways play an essential role in the regulation of neurodevelopment, and converge on a link between mitochondrial dysfunction, neurogenesis, and inflammation. Notably, the functional enrichment signatures of most of the ASD omics datasets included in this review are not representative of early embryogenesis, due to the challenges associated with accessing relevant tissue samples or databanks. Therefore, the datasets included in this review provide limited insight into the mechanisms that might be dysregulated during neurodevelopment. However, this review highlights canonical pathways that are dysregulated in functional enrichment signatures obtained using three different molecular approaches from a wide range of tissue types and individuals of different ages. Therefore, these common pathways may point to common underlying mechanisms in ASD, which has potential relevance in the context of neurodevelopment. While this discussion does not aim to demonstrate a direct link between these molecular mechanisms and disease aetiology, it is useful to consider how the canonical pathways implicated in this review are established as aspects of ASD aetiology, and to review the implications of the dysregulation of these pathways during neurodevelopment.Firstly, a role for mTORC1 signalling is well described in ASD ,58. MutaWe also observed a consistent enrichment of the adipogenesis pathway in ASD molecular data, which implicates the same networks that regulate stem cell metabolism and differentiation. Adipogenesis is regulated by the “opposite interplay” between WNT/B-catenin signalling and peroxisome proliferator-activated receptor gamma (PPARGy), each of which negatively regulates the other . WNT sigOn the other hand, PPARGy acts as a master regulator of lipid metabolism and regulates target genes necessary for differentiation, fatty acid transport, carbohydrate metabolism, and energy homeostasis . MitochoA dysregulation of the signalling between mitochondrial metabolism and neurogenesis has significant implications for neuronal development and function. Firstly, mitochondrial oxidative phosphorylation is one of the primary producers of intracellular reactive oxygen species (ROS) and disruptions to mitochondrial metabolism can lead to oxidative stress . IncreasMany of the canonical pathways highlighted in this review are implicated as mechanisms involved in the response to oxidative stress and gliosis during neurogenesis. Clinical data has reported mTOR signalling as a mechanism that connects mitochondrial disease to gliosis , with boGliosis is characterized by highly reactive microglia and astrocytes, leading to an overproduction of glial-specific fibrillary acidic protein (GFAP) and inflammatory cytokines . This reOur analysis of recent ASD proteomic profiles further supports a role for neuroinflammation in ASD. The complement and coagulation cascades were implicated in three and five out of six ASD proteomic studies respectively, which is supported in independent reviews of ASD proteomic data ,92,93. BCollectively, the canonical pathways highlighted in this review are consistent with known pathways that to contribute to ASD aetiology, as well as pathways that have been implicated in independent reviews of ASD molecular data. Importantly, our review also considers the interactions between these canonical pathways, particularly in the context of neurodevelopment. The latter is often overlooked when the relevance of each canonical pathway is evaluated in isolation. Previous reviews have comprehensively described the role of mTORC1 signalling in protein synthesis, neuronal differentiation, migration, and patterning , but theThe genetic and phenotypic complexity of ASD makes it challenging to identify the molecular mechanisms that contribute to its aetiology. Proteomic approaches can yield novel insight into the dysregulation of biological processes and signalling networks in ASD. Despite the power of proteomics, there are currently limitations to this approach, both in terms of sample acquisition, processing, and analysis, and in accurately capturing variation between different tissue types and developmental stages. In light of these caveats, we integrated recently published ASD proteomic profiles with large-scale meta-analyses of whole-genome transcriptomic and DNAm data to compare the functional enrichment signatures of disparate molecular datasets. Our analysis demonstrates that ASD proteomic, transcriptomic and DNAm data consistently support the dysregulation of mTORC1 signalling, oxidative phosphorylation, adipogenesis and the response to inflammation and oxidative stress. The mTORC1-, WNT- and PPARGy-signalling pathways are each well-established regulators of neurodevelopment that are also implicated in ASD and neurodevelopmental pathology. The mTORC1 signalling pathway regulates oxidative phosphorylation via PPARGC1A, which operates in concert with PPARGy to regulate mitochondrial respiration and fatty acid oxidation. These pathways play an essential role in the tight coupling between stem cell proliferation, differentiation, and mitochondrial metabolism during neurogenesis. If this coupling is disrupted, this can induce metabolic and oxidative stress in NSCs. Both metabolic and oxidative stress are known to disrupt neurogenesis, promote gliosis and induce microglial activation. This proposes a link between mitochondrial dysfunction, oxidative stress, and gliosis, each of which are well-established features of ASD aetiology. Given the central role played by glial networks in neuronal migration and synaptogenesis, gliosis is implicated as a mechanism involved in neuroinflammation and the neuropathophysiology associated with ASD. In summary, this review demonstrates that ASD molecular data converges on canonical pathways involved in mitochondrial function, neurogenesis and neuroinflammation, highlighting how these three key aspects of ASD aetiology interact, and the relevance of these interactions in the context of neurodevelopment.


Although initial findings proved inconclusive, it is now increasingly recognized that ALS-CSF may exert toxicity both in vitro and in vivo. Nevertheless, the mechanism underlying CSF-induced neurodegeneration remains unclear. This review aims to summarize the 40-year long history of CSF toxicity studies in ALS, while discussing the various mechanisms that have been proposed, including glutamate excitotoxicity, proteotoxicity and oxidative stress. Furthermore, we consider the potential implications of a toxic CSF circulatory system in the pathophysiology of ALS, and also assess its significance in the context of current ALS research.Based on early evidence of  Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a neurodegenerative condition that is pathologically characterized by the accumulation of ubiquitinated intracellular inclusions containing TAR DNA-binding protein 43 (TDP-43) . Clinicain vitro experiments were conducted, in which anterior horn cells were exposed to diluted serum from ALS patients , which is often considered as an ultrafiltrate of plasma, is a clear colorless liquid that surrounds most of the central nervous system (CNS). In addition to providing buoyant support and protection to the brain, it also serves a regulatory role, made possible by substantial exchange of material between CSF and interstitial fluid (ISF). In view of the close proximity of CSF to neuronal cells, it was hypothesized that the toxin could also be present in the CSF circulation. The first study to assess the toxicity of ALS-CSF thus emerged in 1981 . Measuriin vitro evidence, several in vivo studies have also been performed, demonstrating a range of pathological changes upon CSF injection. In the following sections, we elaborate on the various in vitro and in vivo observations, and discuss the potential underlying mechanisms  receptors , an antagonist of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainite receptor, could protect against CSF-induced neurodegeneration . Althougeceptors , resultseceptors . It was eceptors . Thus, gvia ionotropic glutamate receptors, increased glutamate concentrations did not correlate with the degree of induced neurotoxicity , which is expressed by astrocytes and is involved in glutamate uptake, following exposure to ALS-CSF . Variousvia a glutamate-dependent pathway could still be observed  and tumor necrosis factor alpha (TNF-α), while increasing production of nitric oxide (NO) and reactive oxygen species (ROS) . ExpressAlthough many potentially toxic factors have emerged from studying the effects of ALS-CSF on glial cells, chitotriosidase-1 (CHIT-1), an inflammatory product specific to microglia, has been proposed to play a particularly important role in CSF-mediated neurodegeneration . ProteomThere are also intriguing observations derived from co-culture studies that suggest that the glial influence may be more complex than a direct contribution to neuronal loss. Although exposure of motor neuron mono-cultures to both ALS-CSF and control-CSF resulted in neuronal death, motor neurons co-cultured with glia experienced no significant decrease in survival following ALS-CSF exposure, with administration of control-CSF even leading to an increase in cell count . As wellWhile ALS is now recognized as a proteinopathy, proteotoxicity initially received comparatively little attention as a possible underlying mechanism in both ALS pathophysiology and CSF-mediated neurodegeneration. In fact, it was found that CSF toxicity could neither be suppressed by prior heating nor by using a 5 kDa filter, thus appearing to exclude the possibility of the toxic agent being a protein . Much moin vitro findings of TDP-43 mislocalization were again observed following ALS-CSF exposure, a feature which has previously been shown to be partially reversed by vascular endothelial growth factor (VEGF) supplementation , a marker of lipid peroxidation, when raised to that of ALS-CSF, have been found to induce neuronal loss in vitro . Potentiin vitro . While t ALS-CSF . In addi ALS-CSF , immunog ALS-CSF . Finallyin vitro and in vivo models in response to ALS-CSF administration. During the 1990s, increased neurofilament phosphorylation was reported when chick spinal cord neurons were exposed to ALS-CSF (in vivo, with the change being considerably more pronounced in ventral horn motor neurons (Several pathological changes have been observed across both  ALS-CSF , a findi neurons . Despite neurons . Ultrast neurons . Mitocho neurons . While a neurons , it is av1.6 and Kv1.6 channels (In addition to cellular changes, intrathecal and intraventricular infusion of ALS-CSF in rat models were also found to result in motor impairment and other musculoskeletal features . These cchannels , althougchannels . A more channels . The celchannels . OverallIntriguingly, several neuroprotective factors have also emerged from CSF toxicity studies. VEGF, which has previously been implicated in ALS pathophysiology , has alsDespite the increasing recognition that ALS-CSF may promote neurodegeneration, with various studies having attempted to characterize its toxicity, synthesizing the current body of literature remains challenging . Most pr•What is the nature of the circulating toxin responsible for CSF-induced neurodegeneration?•What is the cellular origin of this circulating toxin?•What is/are the mechanism/s by which it triggers neurodegeneration?•Do astrocytes and microglia play a role in mediating CSF toxicity?•To what extent does CSF composition reflect that of ISF?•What is the contribution of CSF toxicity toward ALS pathophysiology?•in vivo conditions?How accurately do the models employed to study CSF toxicity recapitulate human •Could similar mechanisms explain CSF toxicity in sporadic and familial forms of ALS?It is still unclear why conflicting findings have been obtained in early toxicity studies, both in those involving serum and CSF. Studies concomitantly investigating the toxicity of serum and CSF in ALS patients have, to our knowledge, not been conducted, and could potentially reveal additional insights into their association. Furthermore, no significant correlation has to date been observed by studies assessing the possible relationship between CSF toxicity and demographic and clinical variables, suggesting that CSF toxicity may not represent a possible biomarker for disease stratification . AlthougIn spite of this, there are a number of advantages to considering the neurotoxicity of CSF in an ALS model. First, CSF toxicity, which has been observed across both sporadic and familial forms of ALS, could potentially form part of a common pathogenic pathway in ALS, thus helping to reconcile the two forms of ALS. Although its contribution in ALS pathophysiology has not yet been established, ALS-CSF toxicity appears to possess many common features, including an apparent predilection for motor neurons and an important cell non-autonomous component. As previously mentioned, the presence of a circulating toxin in CSF could also offer possible explanations for the spread of pathology in ALS . Future via a process mediated by both astrocytes and microglia (While drawing definite conclusions at this stage may not be possible, we believe, based on the numerous observations derived from past studies, that ALS-CSF contains both toxic and protective factors, and is able to promote neurodegeneration either directly or indirectly icroglia . The neuAdditional studies are nevertheless required to improve our understanding of CSF toxicity based on both its constitution and dynamics. Although proteomic and lipidomic studies have revealed altered levels of inflammatory markers as well as a different lipid profile in ALS-CSF , the litin vivo and in vitro evidence of CSF toxicity, striking similarities have been observed between CSF-mediated neurodegeneration and ALS pathophysiology. Although it would be difficult at this stage to argue for the role CSF toxicity as a driver of the disease process, we believe that the potential promise of CSF toxicity in capturing the broader pathophysiological picture of ALS may warrant its additional attention as an area of active research.From initial findings of serum toxicity to current KN and AM conceptualized the work. KN wrote the first draft of the manuscript, supervised by AM. All authors provided critical input and revised subsequent drafts, before approving the final manuscriptThe 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.


Reproductive aged women are at risk of pregnancy and sexually transmitted infections (STI). Understanding drivers of STI acquisition, including any association with widely used contraceptives, could help us to reduce STI prevalence and comorbidities. We compared the risk of STI among women randomised to three contraceptive methods.We conducted a secondary analysis to assess the risk of chlamydia and gonorrhoea in a clinical trial evaluating HIV risk among 7829 women aged 16–35 randomised to intramuscular depot medroxyprogesterone acetate (DMPA-IM), a copper intrauterine device (IUD) or a levonorgestrel (LNG) implant. We estimated chlamydia and gonorrhoea prevalences by contraceptive group and prevalence ratios (PR) using log-binomial regression.At baseline, chlamydia and gonorrhoea prevalences were 18% and 5%, respectively. Final visit chlamydia prevalence did not differ significantly between DMPA-IM and copper IUD groups or between copper IUD and LNG implant groups. The DMPA-IM group had significantly lower risk of chlamydia compared with the LNG implant group . Final visit gonorrhoea prevalence differed significantly only between the DMPA-IM and the copper IUD groups .The findings suggest that chlamydia and gonorrhoea risk may vary with contraceptive method use. Further investigation is warranted to better understand the mechanisms of chlamydia and gonorrhoea susceptibility in the context of contraceptive use. Reproductive aged women are at risk of both pregnancy and sexually transmitted infections (STI). The modern contraceptive prevalence among married and unmarried women in South Africa is 54% and 64%, respectively, with injectable progestins being most widely used.While STIs are a significant global health burden, data on STI prevalence by gender and drivers of infection are limited, hindering an effective public health response.The ECHO Trial  was a multicentre, open-label randomised trial of 7829 HIV-seronegative women seeking effective contraception in Eswatini, Kenya, South Africa and Zambia; detailed trial methods and results have been published.Women were enrolled in the ECHO trial from December 2015 through September 2017. Institutional review boards at each site approved the study protocol and women provided written informed consent before any study procedures. In brief, women who were not pregnant, HIV-seronegative, aged 16–35 years, seeking effective contraception, without medical contraindications, willing to use the assigned method for 18 months, reported not using injectable, intrauterine or implantable contraception for the previous 6 months and reported being sexually active, were enrolled. At every visit, participants received HIV risk reduction counselling, HIV testing and STI management, condoms and, as it became a part of national standard of care, HIV pre-exposure prophylaxis. Counselling messages related to HIV risk were implemented consistently across the three groups throughout the trial.The trial was implemented in accordance with the Declaration of Helsinki and Good Clinical Practice. Informed consent was obtained from participants or their parents/guardians and human experimentation guidelines of the United States Department of Health and Human Services and those of the authors' institution(s) were followed.At enrolment, women were randomly assigned (1:1:1) to DMPA-IM, copper IUD or LNG implant.Chlamydia trachomatis and Neisseria gonorrhoeae was conducted at screening and final visits, at the visit of HIV detection for participants who became HIV infected and at clinical discretion. Any untreated participants with positive NAAT results were contacted to return to the study clinic for treatment.The primary outcomes of this secondary analysis were prevalent chlamydia and gonorrhoea infection at the final visit. Syndromic STI management was provided at screening and all follow-up visits. Nucleic acid amplification testing (NAAT) for At baseline (inclusive of screening and enrolment visits), we collected demographic, sexual and reproductive risk behaviour and reproductive and contraceptive history data. Baseline risk factors evaluated as covariates included age, whether the participant earned her own income, chlamydia and gonorrhoea status, herpes simplex virus type 2 (HSV-2) sero-status and suspected PID. Final visit factors evaluated as covariates included number of sex partners in the past 3 months, number of new sex partners in the past 3 months, HIV serostatus, HSV-2 serostatus, condom use in the past 3 months, sex exchanged for money/gifts, sex during vaginal bleeding, follow-up time and number of pelvic examinations during follow-up. Age and HSV-2 serostatus were evaluated for effect measure modification.We conducted analyses using R V.3.5.3 , and log-binomial regression to estimate chlamydia and gonorrhoea prevalences within each contraceptive group and pairwise prevalence ratios (PR) between each arm in as-randomised and consistent use analyses.In the as-randomised analysis, we analysed participants by the contraceptive method assigned at randomisation independent of method adherence. We estimated crude point prevalences by arm and study site and pairwise adjusted PRs.In the consistent use analysis, we only included women who initiated use of their randomised contraceptive method and maintained randomised method adherence throughout follow-up. We estimated crude point prevalences by arm and pairwise adjusted PRs, with evaluation of age and HSV-2 status first as potential effect measure modifiers, and all covariates above as potential confounders. Study site and age were retained in the final model; other covariates were retained if their inclusion in the base model led to a 10% change in the effect estimate through backwards selection.Additional supporting analyses to assess postrandomisation potential sources of bias were conducted to inform interpretation of results. These include evaluation of recent sexual behaviour at enrolment, month 9 and the final visit; cohort participation  and health outcomes  and frequency and results of pelvic examinations by STI status, site and visit month by randomised arm.A total of 7829 women were randomly assigned as follows: 2609 to the DMPA-IM group, 2607 to the copper IUD group and 2613 to the LNG implant group . ParticiBaseline characteristics were similar across groups . Nearly The duration of participation averaged 16 months with no differences between randomised groups . A totalIn total, 18% of women had chlamydia at baseline  and 15% Among all women, 5% had gonorrhoea at baseline and the final visit . Women aFourteen per cent of women randomised to DMPA-IM, 15% to copper IUD and 17% to LNG implant had chlamydia at the final visit .The prevalence of chlamydia did not significantly differ between DMPA-IM and copper IUD groups ) or between copper IUD and LNG implant groups ). Women in the DMPA-IM group, however, had a significantly lower risk of chlamydia compared with the LNG implant group ). Findings from the consistent use analysis were similar, and neither age nor HSV-2 status modified the observed associations.Four per cent of women randomised to DMPA-IM, 6% to copper IUD and 5% to LNG implant had gonorrhoea at the final visit . GonorrhTo assess the potential for outcome ascertainment bias, we evaluated the frequency of pelvic examinations and abdominal/pelvic pain and discharge by study arm. Women in the copper IUD group were generally more likely to receive a pelvic examination during follow-up as compared with women in the DMPA-IM and LNG implant groups . Similar10.1136/sextrans-2020-054590.supp1Supplementary dataAmong women who had chlamydia at baseline, 23% were also positive at the final visit . Nine peWe observed differences in final prevalences of chlamydia and gonorrhoea by contraceptive group in both as-randomised and consistent-use analyses. The DMPA-IM group had lower final visit chlamydia and gonorrhoea prevalences as compared with copper IUD and LNG implant groups, though only the DMPA-IM versus the copper IUD comparison of gonorrhoea and DMPA-IM versus LNG implant comparison of chlamydia reached statistical significance. These are novel findings that have not previously been reported to our knowledge and were determined in a randomised trial setting with high participant retention, robust biomarker testing and high randomised method adherence. Interestingly, the copper IUD group had higher gonorrhoea and lower chlamydia prevalence compared with the LNG implant group, though neither finding was statistically significant.Two recent systematic reviews of the association between contraceptives and STIs found inconsistent and insufficient evidence on the association between the contraceptive methods under study in ECHO and chlamydia and gonorrhoea.Lactobacillus crispatus, which is less abundant in BV, has been shown to inhibit HeLa cell infection by Chlamydia trachomatis and inhibits growth of Neisseria gonorrhoeae in animal models.Lactobacillus crispatus and/or dominated by dysbiotic species are associated with inflammation, which is a driver of both STI and HIV susceptibility. Thus, while the exact mechanisms of chlamydia and gonorrhoea infection in the presence of exogenous hormones and varying host microbiomes are unknown, it is biologically plausible that these complex factors may result in differential susceptibility to chlamydia and gonorrhoea among DMPA-IM, copper IUD and LNG implant users.The emerging science on the biological mechanisms underlying HIV susceptibility demonstrates the complex relationship between the infectious pathogen, the host innate and adaptive immune response and the interaction of both with the vaginal microbiome and other -omes. Data on these factors in relationship to chlamydia and gonorrhoea acquisition are much more limited but can be assumed to be equally complex. Vaginal microbiome composition, including microbial metabolic by-products, have been shown to significantly modify risk of HIV acquisition and to vary with exogenous hormone exposure, menstrual cycle phase, ethnicity and geography.An alternative explanation for these findings may be postrandomisation differences in clinical care and/or sexual behaviour. Participants in the copper IUD arm were more likely to have pelvic examinations and more likely to have discharge compared with women in the DMPA-IM and LNG implant groups. While interim STI testing and/or treatment were not documented, women in the copper IUD arm may have been more likely to receive syndromic STI treatment during follow-up due to more examination and observed discharge. More frequent STI treatment in the copper IUD group would theoretically lower the final visit point prevalence relative to women in the DMPA-IM and LNG implant arms, suggesting that the observed lower risk of STI in the DMPA-IM arm is not due to differential examination, testing and treatment. Differential sexual risk behaviour may also have influenced the results. As reported previously, women in the DMPA-IM group less frequently reported condomless sex and multiple partners than women in the other groups, and both DMPA-IM and LNG implant users less frequently reported new partners and sex during menses than copper IUD users.A second alternative explanation may be differences in randomised method non-adherence, which was greater in the DMPA-IM group, compared with copper IUD and LNG implant groups. Yet, the consistency of findings in the as-randomised and continuous use analyses suggests that method non-adherence had minimal effect on study outcomes. Taken as a whole, these findings indicate that there may be real differences in chlamydia and gonorrhoea risk associated with use of DMPA-IM, the copper IUD and LNG implant. However, any true differential risk by method must be evaluated in light of the holistic benefits and risks of each method.The high observed chlamydia and gonorrhoea prevalences, despite intensive counselling and condom provision, warrants attention, particularly among women ages 24 years and younger and among women in South Africa and Eswatini. While the ECHO study was conducted in settings of high HIV/STI incidence, enrolment criteria did not purposefully target women at highest risk of HIV/STI in the trial communities, suggesting that the observed prevalences may be broadly applicable to women seeking effective contraception in those settings. Improved approaches are needed to prevent STIs, including options for expedited partner treatment, to prevent reinfection.As expected, few women testing positive for chlamydia or gonorrhoea presented with symptoms , and a substantial proportion of women who were positive and treated at baseline were infected at the final visit despite syndromic management during the follow-up. Given that syndromic management is the standard of care within primary health facilities in most trial settings, these data suggest that a large proportion of infection among reproductive aged women is missed, exacerbating the burden of curable STIs and associated morbidities. Routine access to more reliable diagnostics, like NAAT and novel point-of-care diagnostic tests, will be key to managing asymptomatic STIs and reducing STI prevalence and related morbidities in these settings.This secondary analysis of the ECHO trial has strengths and limitations. Strengths include the randomised design with comparator groups of equal STI baseline risk. Participants had high adherence to their randomised contraceptive method.In conclusion, our analyses suggest that DMPA-IM users may have lower risk of chlamydia and gonorrhoea compared with LNG implant and copper IUD users, respectively. Further investigation is warranted to better understand the mechanisms of chlamydia and gonorrhoea susceptibility in the context of contraceptive use. Moreover, the high chlamydia and gonorrhoea prevalences in this population, independent of contraceptive method, warrants urgent attention.The prevalence of chlamydia and gonorrhoea varied by contraceptive method in this randomised trial.High chlamydia and gonorrhoea prevalences, despite intensive counselling and condom provision, warrants attention, particularly among young women in South Africa and Eswatini.Most chlamydia and gonorrhoea infections were asymptomatic; therefore, routine access to reliable diagnostics are needed to effectively manage and prevent STIs in African women.


Despite substantial progress in the prevention and treatment of cardiovascular diseases, mortality and morbidity remain unacceptably high; stroke and myocardial infarction are still one of the biggest killers worldwide.Primary preventions and treatments have focused on lipid-lowering drugs and, more recently, anti-inflammatory drugs.Nanomedicine, a rapidly developing field with some remarkable preclinical achievements so far, holds a lot of promise in the delivery of more potent and specific therapies for atherosclerosis.In a recent issue of EBioMedicine, Luo and colleagues present a novel engineered HDL-like phospholipid-based nanoparticle, termed ‘Michigan Nanoparticle’ (miNano).There are a few limitations associated with the study. The team used Polyethylene Glycol (PEG) to ensure the engineered particles are sufficiently low fouling and are not recognised by the immune system. Although FDA approved, PEG is non-biodegradable and can accumulate in tissue with unknown long-term consequences. In addition, PEG antibodies are highly prevalent in the general population.Cholesterol accumulation and the formation of CC is not only seen in atherosclerotic plaques but also several other conditions including non-alcoholic steatohepatitis (NASH), another epidemic health burden.Overall, the study highlights the importance of developing novel therapies for cardiovascular disease that could potentially further reduce this large health burden. As with all preclinical studies, further work is required moving from additional preclinical efficacy testing in large animals to long term safety studies. The 6-week safety testing results presented are encouraging, but for something that needs to be administered lifelong, more studies are likely required.The author declares no conflict of interest.


After pediatric kidney transplantation, immunosuppressive therapy is given to avoid acute and chronic rejections. However, the immunosuppression causes an increased risk of severe viral complications and bacterial infections and is associated with serious side effects. It is therefore crucial to achieve the optimal individual balance between over- and under-immunosuppression and thereby avoid unnecessary exposure to immunosuppressive drugs. In routine use, steering of immunosuppressants is performed primarily by monitoring of trough levels that mirror pharmacokinetics . Other diagnostic and prognostic markers to assess the individual intensity of immunosuppression are missing. Potential methods to determine immune function and grade of immunosuppression, such as analysis of the torque teno virus (TTV) load, QuantiFERON Monitor®, and ImmuKnow® as well as virus-specific T cells (Tvis), are currently being evaluated. In some studies TTV load, QuantiFERON Monitor® and ImmuKnow® were associated with the risk for post-transplant rejections and infections, but randomized controlled trials after pediatric kidney transplantation are not available. Post-transplant monitoring of Tvis levels seem to be promising because Tvis control virus replication and have been shown to correlate with virus-specific as well as general cellular immune defense, which represents the individual’s susceptibility to infections. Additional Tvis-monitoring provides an innovative opportunity to personalize the antiviral management and the dosing of the immunosuppressive therapy after pediatric kidney transplantation to avoid unnecessary therapeutic interventions and identify over-immunosuppression. For many years, kidney transplantation has been the preferred treatment for pediatric patients with end-stage renal disease. To avoid acute and chronic graft rejections, lifelong immunosuppressive therapy is necessary, but this is associated with the risk of serious bacterial and viral complications. Moreover, immunosuppressive medication has side effects which include nephrotoxicity, arterial hypertension, anemia, leucopenia, new-onset diabetes mellitus, dyslipidemia, hypertrichosis, bone mineral disorders, growth impairment, malignancies, and delayed sexual maturation –6. It isThe immunosuppressive treatment impairs the individual cellular immune response resulting in an elevated incidence of severe viral complications, notably after pediatric transplantation. Post-transplant primary infections or reactivations, especially by cytomegalovirus (CMV), BK polyomavirus (BKPyV), or Epstein-Barr virus (EBV) are associated with increased morbidity, mortality, and graft failure, for example from CMV disease , 8, BKPyIn routine use, diagnostic and prognostic markers to assess the individual intensity of immunosuppression are missing. Monitoring of immunosuppressive treatment is most often performed using pharmacokinetic (PK) monitoring by measuring trough levels of immunosuppressants. Unfortunately, the lack of validated PK exposure targets and the difficulty in extrapolating the pharmacodynamics (PD) from current exposure levels are a major limitation in the routine application of PK monitoring. Actually, no direct assays that measure the pharmacodynamic effect of immunosuppressants are available for routine use.Accordingly, the search for appropriate markers of the individual strength of the immune response is crucial to achieve the aim of a personalized immunosuppressive therapy. Currently, ImmuKnow®, QuantiFERON Monitor®, and monitoring of the torque teno virus (TTV) load or virus-specific T cells (Tvis) are evaluated to characterize the individual immune function and the intensity of immunosuppression. Representing virus-specific as well as general cellular immune response, the analysis of Tvis level seems to be one of the most promising methods to steer antiviral and immunosuppressive therapy after pediatric kidney transplantation Table .Table 1In the last few years, multiple methods to measure the grade of immunosuppression and thus to enable effect-related immune monitoring have been assessed. Cytokines and chemokines, especially IL-6 that can be routinely measured in most hospitals, showed some correlation with clinical events after pediatric kidney transplantation, but they seemed to be insufficient for immune monitoring and failed to predict future infectious events . DiffereFunctional assays to determine immune function seem to be a promising tool to optimize the dosing of immunosuppressants after solid organ transplantation. ImmuKnow®  is a commercially available assay measuring the amount of intracellular adenosine triphosphate (ATP) produced by CD4 T cells from whole blood after stimulation with phytohemagglutinin. Some observational trials observed low ATP levels in association with infections and high ATP levels in case of rejections after kidney transplantation  whereas The torque teno virus (TTV) load was thought to serve as a possible endogenous marker of the immune function. TTV is a non-pathogenic, ubiquitous, circular single-strand DNA virus which mirrors the net state of immunosuppression . TTV loaVirus-specific T cells (Tvis) have been shown to play a key role in the control of virus replication . Virus-sAlso in children, it has been shown that the number of Tvis is associated with the risk of virus diseases –33. RegaA number of different assays are currently available for the detection of the cellular response to viral antigens , the mai2) of everolimus  and numerically lower doses of cyclosporin A  resulting in significantly lower trough levels (μg/L) of everolimus  and of cyclosporin A . In addition, fewer patients in the intervention group received glucocorticoids 2 years after transplantation . Caused by CD4 Tvis <2 cells/μl a total of 125 dose reductions of immunosuppressants (mainly based on ADV-Tvis) was performed in 28/31 children of the intervention group with a median of 4 Tvis-based dose reductions (range 0–10) per patient. Nearly half of the Tvis-based dose reductions were carried out in the first 6 months after transplantation. Only three Tvis-based dose increases were implemented in two children. Despite reduced immunosuppressive therapy, the number of biopsy-proven acute rejections did not increase in the intervention group but was even numerically lower than in the control group (p=0.11). Furthermore, the intervention group showed a numerically lower risk for EBV DNAemia (p=0.09). The numbers of DSAs and (serious) adverse events were comparable in both groups [Post-transplant monitoring has shown that the Tvis-levels fluctuated depending on the intensity of immunosuppression in pediatric kidney recipients. During the initial post-transplant period—at the time of intensified immunosuppressive therapy—the number of Tvis was decreased and showed an increase after reduction of the immunosuppressive drugs . Interestingly, the risk of viremia, such as EBV, correlated with the number of CD4 Tvis, not only against EBV but also against other virus types as CMV and adenovirus (ADV) . Accordingly, it is hypothesized that Tvis represent not only the virus-specific but also the general cellular immune defense and thereby correlates with the individual susceptibility to infections. It is also speculated that a high number of Tvis could also represent underimmunosuppression and might therefore be associated with a higher risk for immunological events such as acute and chronic cellular and humoral infections. Serving as a marker of over- or under-immunosuppression, additional post-transplant monitoring of Tvis levels might therefore optimize dosing of immunosuppressive drugs compared to blood level monitoring alone. On this basis, we conducted the investigator-initiated, multicenter IVIST trial, which is the first randomized, controlled trial to consider the benefit of additional steering of immunosuppressive drugs by Tvis levels using intracellular cytokine staining followed by FACS analysis , 38. Sixh groups . ConsequIn pediatric kidney transplantation, new diagnostic strategies, which mirror the individual cellular immune response such as Tvis, seem to be promising to decide on the necessity of antiviral medication and/or reduction of immunosuppressive therapy and thereby detect over-immunosuppression. The measurement of Tvis at the time of onset of viremia, challenging whether a therapeutic intervention should be performed, could become a part of routine practice. Prospective, interventional trials comparing standard of care with T cell-based steering of antiviral and immunosuppressive therapy in case of post-transplant viral infections are needed in order to confirm the usability of this antiviral management after pediatric transplantation. In addition to virus-specific immune response, the levels of Tvis represent the general cellular immune defense and thereby the intensity of immunosuppression after pediatric kidney transplantation serving as a marker to detect over-immunosuppression, avoid unnecessary exposure to immunosuppressive drugs, and reduce their undesirable side effects. Within a randomized controlled trial, the additional Tvis-based immune monitoring has proven to be safe and reduce immunosuppressive therapy after pediatric kidney transplantation, likely resulting in lower drug costs and thereby even in an economical benefit. Analysis of Tvis may become an important step towards the introduction of precision medicine in pediatric kidney transplantation to detect the individual intensity of immunosuppression, realize an effect-related drug monitoring, and target a tailor-made immunosuppressive therapy. With regard to existing data, Tvis seem to be a reliable indicator of over-immunosuppression but lesser effective to identify under-immunosuppression. Larger validation trials in separate patient cohorts are needed before this method can become standard of care. Cut-off values might have to be adopted in different patient populations as compared to the published levels.Other immune markers, such as the TTV load, ImmuKnow®, QuantiFERON Monitor®, miRNA, or further cytokines and chemokines, may offer additional benefits for immune monitoring, but in contrast to Tvis-based management, none of these biomarkers has been evaluated within a randomized controlled trial after pediatric kidney transplantation. Further interventional trials are needed to investigate their potential for steering immunosuppression after solid organ transplantation. In the future, a panel using different parameters of cellular and humoral immune response in the urine and blood, including immunosuppressant trough levels but also Tvis, cytokines, miRNA, and others, could more accurately characterize the individual strength of the immune system of each kidney recipient to detect over- as well as under-immunosuppression. Artificial intelligence, that can use this panel to suggest an adjustment of immunosuppressive medication but which can also take into account all individual risk factors such as HLA-antigen mismatches, ischemia time, underlying disease, donor and recipient age, viral risk constellations, DSAs, prior rejection episodes, and virus DNAemia as well as the choice of immunosuppressive drugs and their specific side effects, might then become the next step in precision medicine for pediatric kidney recipients. This will herald a new era of personalized immunosuppressive therapy leading to better graft and patient survival in the future.


Bipolar disorder (BD) is a complex psychiatric disorder characterized by dysfunctions in three domains including emotional processing, cognitive processing, and psychomotor dimensions. However, the neural underpinnings underlying these clinical profiles are not well understood. Based on the reported data, we hypothesized that (i) the core neuropathology in BD is damage in fronto-limbic network, which is associated with emotional dysfunction; (ii) changes in intrinsic brain network, such as sensorimotor network, salience network, default-mode network, central executive network are associated with impaired cognition function; and (iii) beyond the dopaminergic-driven basal ganglia-thalamo-cortical motor circuit modulated by other neurotransmitter systems, such as serotonin , the sensorimotor network and related motor function modulated by other non-motor networks such as the default-mode network are involved in psychomotor function. In this review, we propose a neurocircuit-based clinical characteristics and taxonomy to guide the treatment of BD. We draw on findings from neuropsychological and neuroimaging studies in BD and link variations in these clinical profiles to underlying neurocircuit dysfunctions. We consider pharmacological, psychotherapy, and neuromodulatory treatments that could target those specific neurocircuit dysfunctions in BD. Finally, it is suggested that the methods of testing the neurocircuit-based taxonomy and important limitations to this approach should be considered in future. Bipolar disorder (BD) is a complex psychiatric disorder characterized by severe mood fluctuations associated with dysfunctional cognition that often persist throughout the entire life of patients and abnormal psychomotor activity , 2. The BD has traditionally been associated with dysfunction in the fronto-limbic neural circuits underlying emotional regulation, as well as hypersensitivity in the fronto-striatal neural circuits responsible for rewarding processing, although it is now recognized that alterations in distinct large-scale networks seems to play a fundamental role in the phenomenological dimensions, including affective, cognition, and motor functions –10. MostFunctional neuroimaging research has revealed intrinsic brain activities, the functional architecture as organized in distinct brain networks in accordance to connectivity patterns, and related setting of input/output processing involve in the psychopathology of affectivity, psychomotricity, and thought in BD . Within The expression of psychomotor dimensions of BD is traceable to modulation of motor cortex and motor network by non-motor cortical networks, i.e., default-mode network and sensory networks. Additionally, the dopamine-driven basal ganglia-thalamo-cortical motor circuit modulated by other monoaminergic neurotransmitter systems such as serotonin  is also involved in psychomotor mechanisms . Based oIn this review, we enlarge on previous models of the neurocircuitry of BD to propose a heuristic neurocircuit-based taxonomy, which could be used to guide the diagnosis and treatment of the disorder in future. We present hypothetical links between underlying neurocircuit dysfunctions and the three domains of clinical presentation in BD and discuss how treatments that more specifically target these circuits may benefit patients and improve therapeutic response. We suggest ways in which this neurocircuit-based taxonomy could be tested in future research to support or refute our proposed links between aspects of clinical phenomenology across different mood states, specific neurocircuit alterations, and treatment methods. Likewise, the neurocircuits are not as segregated as they may appear in the following sections and highly interactive, and the neurocircuits are certainly more complex and not limited to the neurocognitive and behavioral alterations we describe here.Emotional hyper-reactivity and mood instability have a detrimental impact on functioning, relapses, and suicide attempts in BD patients. Excessive reactivity to negative events might be a core dimension of BD and could represent an endophenotype during both manic and mixed states in comparison to patients in remitted phases , 20. ResWe will first provide an overview of the prefrontal cortical regions including the anatomy and the fronto-limbic functional connectivity that have been implicated in emotional processing. The functional localization and division of the human prefrontal cortex are orbitofrontal cortex (OFC), dorsomedial prefrontal cortex (dmPFC), dorsolateral prefrontal cortex (dlPFC), ventrolateral prefrontal cortex (vlPFC), and ACC . The venThe fronto-limbic circuit includes subcortical and cortical brain regions involved in generating emotional responses  and evaluating whether those responses are appropriate or require regulation (vmPFC) . The vmPIt is hypothesized that the abnormal emotional ventral system and hypoactive dorsal system result in a loss of homeostasis in emotional processing, which may contribute to mood liability in BD disorder. This ventral network is involved in identifying salient emotional stimuli and in mediating autonomic responses; while the dorsal system is usually involved in selective attention, planning and explicit regulation of emotional states, with its hypoactivation being underpinning of the unstable cognitive control of emotions and affect in BD . The defMoreover, dysregulation of the amygdala by PFC seems to be crucial to better understand the pathophysiology of the disease. The amygdala is an evolutionarily ancient critical area within the fronto-limbic system that is responsible for flight/fight responses to threats, and is hyperactive in mania, whereas contrasting results have been found during depression . SystemaMost of the treatment regimens of BD owe their discovery to combination of fortune, intellectual rigor, and the careful observation of human and animal phenotypes . The undCurrent pharmacotherapy for BD is based on administration of mood stabilizers  and increasingly, on the administration of second-generation antipsychotics. It is worth mentioning that lithium appeared to induce a rapid suppression of amygdala over-activation and to show substantial treatment response in BD. Results from neuroimaging studies in patients with BD treated with lithium support the hypothesis that enhancement of neuroplasticity is a potential mechanism underlying the therapeutic effects of lithium. Such studies have also revealed brain changes in both gray and white matter, especially in hippocampal volume , 38.Currently, an increasing number of meta-analyses have evaluated the efficacy of cognitive-behavioral therapy (CBT) for BD –41. CBT Neuromodulation holds promise for a vast number of medically refractory neurological and psychiatric disorders and has been guided by advances in neuroimaging and neurophysiology, which had led to new strategies for better targeting, identification of optimal stimulation sites, and understanding of its therapeutic mechanisms. Repetitive transcranial magnetic stimulation (TMS) is a dominant noninvasive stimulation treatment that delivers short magnetic pulses via an electromagnetic coil and is operated to transiently stimulate or inhibit specific brain regions. TMS has had a growing impact on the treatment of unipolar depression and has already been approved by the FDA for use in treatment-resistant depression . AlthougA recent review on TMS for BD suggests the potential of repetitive TMS for reducing depressive symptoms . It has Mounting evidence suggests BD is associated with common cognitive deficits, including executive function, memory, social cognition, and response timing –53. A laAlthough the neurophysiological basis of cognition and emotion are typically studied independently, recent work in this field increasingly highlight evidence showing substantial overlap in brain regions and networks involved in both emotion and cognitive processes. Cognition‐emotion integration requires the dynamic coordination and flexible switching between four functional networks that are linked to key adaptive processed, including emotion regulation, goal-directed attentional control, decision making, and self-monitoring .The DMN, also known as the “task-negative network”, was initially identified as brain regions showing consistently synchronized deactivation during tasks and prominent activation during rest  Fig. 3)3). The CRecently, evidence from fMRI studies point to aberrant activity of networks in BD as common neuronal correlates of cognitive impairment –67. It hIn addition to decreased frontoparietal CEN recruitment, cognitive dysregulation in BD is also associated with disrupted SN recruitment . A recenIn BD, graph analysis studies indicate distinctive abnormalities of node-level and inter-hemispheric connectivity patterns, altered DMN dysconnectivity and decreased white matter organization of anterior limbic system tracts supported by reductions in efficiency and clustering connecting cingulate and subcortical limbic structures . MagioncIn the past several years, studies have explored the application of rTMS in BD utilizing resting state electroencephalography (EEG) data. Changes in resting state networks (RSNs) between pre and post rTMS were explored utilizing EEG functional network analysis, evaluated by exact low-resolution electromagnetic tomography. Bilateral stimulation of dlPFC produced changes in the activity of the SMN and resulted in significant changes in the executive functions, verbal memory, and depression symptoms . One stuThe studies on the neural correlates of TMS-induced cognitive function have shown that fMRI-based neurofeedback targeted at dlPFC and superior frontal gyrus and suppression of activity in DMN regions like the hippocampus in which activity was correlated with working memory performance resulted in cognitive improvement , 91. MisTo date, nonpharmacological approach has been implemented to remediate cognitive impairments among people with BD using computerized cognitive training . The cogAlthough historically neglected, one of the most important findings in research of core behavioral features of BD is hyperactivity, reckless actions, impulsivity, and agitation during the manic phase, as well as physical and mental sluggishness, akinesia, volitional inhibition, and decreased activity levels during the depressive phase of illness. Manic and depressive episodes of BD show opposite psychomotor symptoms and the exact neurophysiological mechanism of psychomotor excitation and inhibition in mania and depression remain unclear. There are only a few MRI studies on the neural correlates of psychomotor phenomena. These psychomotor symptoms may depend on distinct patterns of alterations in the SMN, DMN, and CEN , 96, 97.The alterations in large-scale brain intrinsic activity, subcortical-cortical coupling, and neurotransmitters signaling, such as dopamine (DA) and serotonin 5-HT) have been independently detected in BD , 106. Ba-HT have The psychomotor abnormalities are characterized by specific symptom pattern and constellation of motor, emotional, and cognitive symptoms , 108. ThThe neurobiological models that draw links between internal cognitive deficits, emotional processing, psychomotor activity dysfunction and neurocircuitry are beneficial because this approach meaningfully increases our understanding of BD with respect to clinical management. We propose a heuristic model of how to integrate information generated by recent neuroimaging studies into guiding principles toward treatments of BD. We hypothesized that (1) the core pathological alteration in BD is damage of fronto-limbic network that mainly results in emotional dysfunction; (2) that changes in intrinsic brain network, such as SMN, SN, DMN, CEN are associated with alterations of cognitive function; and (3) beyond the dopamine-driven basal ganglia-thalamo-cortical motor circuit modulated by other neurotransmitter systems such as 5-HT , the SMN and related motor function modulated by other non-motor networks such as the DMN are involved in psychomotor function. Although cognitive, emotional, and psychomotor domains are typically studied independently, basic research and emergent findings in BD suggest that there are important ties between cognitive deficits, the emotional and psychomotor disturbances observed in BD. Understanding these relationships is critical for elucidating relevant aspects related to functionality and vulnerability within BD and is essential for the development of novel treatment interventions. The following strategies based on neurocircuitry include: (1) enhancing PFC function to downregulate overactivated fronto-limbic activity via the engagement of top-down dorsal prefrontal regions, to alleviate impairments in emotion regulation; (2) modulating neurotransmitter transmission to balance the activities of excitatory and inhibitory neural networks involved in psychomotricity, affectivity and cognition; and (3) non-invasive neurostimulation in different cortical systems that modulate subcortical–cortical motor circuits to alleviate psychomotor symptoms. If the therapies of BD targeting specific circuit and corresponding clinical profiles, the treatment efficacy will be improved and guide clinical practice.


Chronic low-grade inflammation is involved in coronary atherosclerosis, presenting multiple clinical manifestations ranging from asymptomatic to stable angina, acute coronary syndrome, heart failure and sudden cardiac death. Coronary microvasculature consists of vessels with a diameter less than 500 μm, whose potential structural and functional abnormalities can lead to inappropriate dilatation and an inability to meet the required myocardium oxygen demands. This review focuses on the pathogenesis of coronary microvascular dysfunction and the capability of non-invasive screening methods to detect the phenomenon. Anti-inflammatory agents, such as statins and immunomodulators, including anakinra, tocilizumab, and tumor necrosis factor-alpha inhibitors, have been assessed recently and may constitute additional or alternative treatment approaches to reduce cardiovascular events in atherosclerotic heart disease characterized by coronary microvascular dysfunction. Ischemic cardiac pain in the context of non-obstructed epicardial coronary arteries, a phenomenon frequently encountered in clinical cardiology practice, has been recognized as a clinical entity of increased cardiovascular risk when compared to control subjects ,2, contrCoronary microvasculature consists of vessels with a diameter less than 500 μm, whose remodeling due to various stimuli could lead to structural and functional abnormalities and, consequently, result in inappropriate dilatation and the inability to meet the required oxygen demands. Known cardiovascular risk factors, such as diabetes mellitus and arterial hypertension, are implicated in this process due to their deleterious vascular effects. Ultimately, patients with CMVD could progress to a phenotype of heart failure with preserved ejection fraction, with variable prognosis due to a lack of disease-specific treatment .Chronic low-grade inflammation is undoubtedly involved in coronary atherosclerosis. Importantly, favorable cardiovascular outcomes have been reported in recent trials of patients with documented coronary artery disease (CAD) receiving either broad based or target anti-inflammatory treatment ,6,7. ConEvaluation of coronary blood flow velocity and coronary blood flow after the administration of vasodilating substances during cardiac catheterization are important determinants of coronary flow reserve (CFR), a measure of epicardial and microcirculatory blood flow. In the absence of epicardial artery obstruction, a reduced CFR value is indicative of CMVD. Corrections for age and systolic blood pressure in individuals should always be implemented. However, scientific research is currently focused on noninvasive methods of CMVD assessment.To begin with, echocardiography has been involved in CMVD assessment since 1998, when Wei et al. infused air-filled albumin microbubbles intravenously in an effort to quantify myocardial blood flow (MBF) in an epicardial coronary artery. Next generation microbubbles, destructible by ultrasound, allowed the more accurate calculation of MBF by assessing their mean velocity (rate of reappearance after destruction in the setting of a constant intravenous infusion) and the microvascular cross-sectional area (microbubble concentration in the myocardium) ,11. MoreCardiac CT angiography (CCTA) appears to be another appealing approach in the assessment of CMVD, since information about coronary anatomy and myocardial perfusion can be acquired from one study . By obtaInterestingly, recent advancements in the detection of coronary inflammation via perivascular fat imaging in CT has garnered scientific attention and could be also applied in the context of CMVD . The fatFAI may also be of use in the setting of an acute myocardial infarction, with higher FAI values around the culprit lesions compared to FAI around non-culprit lesions. At the follow-up evaluation, the FAI around the culprit lesion was lower than baseline, with values comparable to those detected around stable atherosclerotic regions ,21,22. AThe incremental prognostic value of perivascular adipose tissue attenuation could become an important imaging option towards further characterization of the residual cardiovascular risk, which may not be adequately estimated by traditional scoring methods or inflammatory biomarkers. It is believed that the presence of residual inflammation in the coronary arterial bed and its detection might aid towards a more precise risk stratification and, consequently, the institution of an appropriate treatment approach, which might include anti-inflammatory agents. The use of statin and aspirin might modify this residual risk and, in such cases, FAI is no longer predictive of incident cardiovascular risk . HoweverFAI, other than being an attractive alternative imaging option regarding the detection of vascular inflammation, may also be less expensive, with lower radiation exposure for the patient. However, its association with the existence of CMVD has not been explored and further research is required in this direction to better define FAI’s role in the evaluation of CMVD.The most extensively studied noninvasive method of MBF estimation has undoubtedly been cardiac Positron Emission Tomography (PET) . Even thLast but not least, improvements in cardiac MRI protocols have made the imaging of microcirculation feasible by utilizing the diffusion of contrast medium from the microvasculature into the interstitium during the first pass. Integrated approaches, such as the Fermi model , have beWith regards to biomarkers, there have been several studies evaluating their role in CMVD . SchrodeEvidence from studies in autoimmune rheumatic diseases have stressed the decreased nitric oxide (NO) bioavailability together with the high assembly of reactive oxygen species (ROS) as the link between the pro-inflammatory state and endothelial dysfunction observed in CMVD . CMVD caThe normal coronary physiology is disrupted to varied degrees as a result of CMVD. Patients with hypertrophic cardiomyopathy and those with arterial hypertension have structural abnormalities that are responsible for the development of CMVD . In patiChronic low-grade systemic inflammation seen in the cluster of comorbidities  that are considered risk factors for CMVD merits specific attention ,61 Figu. ArteriaIn individuals with diabetes mellitus (DM), CMVD is often the prodrome of overt CAD and is a strong predictor of complications and mortality ,71,72. IWeight status constitutes a significant role in the progression of atherosclerotic disease . ObesityThis term describes the various commensal microbial species in the gastrointestinal tract . During Several anti-inflammatory drugs have been assessed over the years in either small or large randomized controlled trials . Their aThe effects of statins are well known for their pleiotropic actions and they have been the cornerstone of treatment for cardiovascular risk reduction and prevention . StatinsLuo et al. showed that statin treatment was associated with low morbidity and mortality in patients with coronary microvascular dysfunction, during a follow up of 5 years. That was strengthened when the results were adjusted for various factors of the disease, such as smoking, sex, hyperhomocysteinemia, abnormal glucose tolerance, diabetes, hypertension and hyperlipidemia . SeveralIn this aspect, aspirin increases cell apoptotic rate by decreasing the cell proliferation rate of vascular smooth muscle cells. It suppresses atherosclerosis progression by down-regulating the expression of NFκB1 and its targets, which might well provide us with more therapeutic strategies for treatment of the disease . There i(NOD)-like receptor protein 3 (NLRP3) inflammasome is a protein complex with an important role in inflammatory progression . CholestThere is only one study referring to CMVD which revealed that inhibition of inflammatory cytokines by colchicine or a receptor antagonist seems to improve CFR, myocardial contractility and relaxation in patients with rheumatoid arthritis .Anakinra is an IL-1 receptor antagonist, which was first used for rheumatoid arthritis treatment. It binds to the IL-1 receptor to exert powerful IL-1α and IL-1β blocking activity . It has The CANTOS trial enrolled approximately 10,000 patients with a history of myocardial infarction and elevated hsCRP levels. Patients were stratified in canakinumab group and placebo, for a median follow up of 3.7 years. The CANTOS study showed that Canakinumab, a monoclonal antibody inhibitor of IL-1β, decreased the risk of cardiovascular events by lowering systemic inflammation in high cardiovascular risk patients ,126. MorTocilizumab is a monoclonal antibody that competitively inhibits IL-6 receptor and has been shown to be useful in the treatment of rheumatoid arthritis, a chronic inflammatory disease . TocilizHolte et al. showed that administration of Tocilizumab after MI did not affect CFR during hospitalization or after 6 months. Vascular cell adhesion molecule 1 (VCAM-1) levels were increased, but this was not associated with reduced CFR in these patients . On the 2, while a reduction in resistance artery myogenic responsiveness was observed in mice [Another target is TNF, whose inhibitors are available and well-evaluated drugs without severe adverse events. Agents from this drug category have been evaluated solely in patients with rheumatological conditions, additionally examining the incidence of MACE. In that subgroup a significant decrease in MACE was observed ,133. The in mice ,137.With regards to CMVD, the treatment of psoriasis patients with etanercept for 4 months led to an 11% improvement in coronary flow reserve as reported in a randomized trial by Ikonomidis et al. , confirmCoronary microvascular dysfunction, a frequently encountered phenomenon in cardiology practice, is the result of endothelial dysfunction while systemic inflammation appears to be a significant contributing factor stemming from the cluster of comorbidities which are present. Recent pharmacological advances in the field of anti-inflammatory therapy may become essential for attenuating the residual cardiovascular risk in CAD with microvascular dysfunction.


Change in body size can be driven by social (density) and non-social  factors. In expanding metapopulations, spatial sorting by means of dispersal on the expansion front can further drive the evolution of body size. However, human intervention can dramatically affect these founder effects. Using long-term monitoring of the colonization of the remote Kerguelen islands by brown trout, a facultative anadromous salmonid, we analyse body size variation in 32 naturally founded and 10 human-introduced populations over 57 years. In naturally founded populations, we find that spatial sorting promotes slow positive changes in body size on the expansion front, then that body size decreases as populations get older and local density increases. This pattern is, however, completely different in human-introduced populations, where body size remains constant or even increases as populations get older. The present findings confirm that changes in body size can be affected by metapopulation expansion, but that human influence, even in very remote environments, can fully alter this process. The dirBoth processes within and between populations driving body size evolution are likely to be strongly impacted by the current pace and magnitude of global change ,11. ManyAt the core of the metapopulation, as populations get older, the body size is generally expected to decrease as local density increases, triggering competition over resources , except Other mechanisms, however, may tamper with these general expectations: local environment may trigger phenotypic plasticity in growth, producing different body sizes and affecting dispersal propensity ,22. Yet Salmo trutta L.), where part of individuals are resident (entire life cycle in fresh waters) and part of individuals migrate at sea (anadromy) out of the reproductive window [n = 10) while some populations have been naturally founded (n = 32) via dispersal [To investigate and disentangle the above hypotheses, we considered a facultative anadromous species, the brown trout , with a stepwise approach to fit the full model and all nested models of interest. In order to assess the statistical importance of each fixed factor in the model, the Bayesian information criterion (BIC) [To investigate a change in body size, we used a linear mixed-effects model. We tested the effect of two fixed continuous factors  and one categorical factor  and their interactions on the relationship between the logarithm of body size and the day of capture. Population age was taken as a proxy of density increase , reflecton (BIC)  was used. 3The comparison of models using the BIC approach indicates that the most complex model provides the best predictive model for the data . This implies that the ages of metapopulation and populations, respectively, as well as the status of river colonization  all significantly and interactively influence variation in body size , whereas. 4Looking at changes in juvenile body size over a half-century (10–15 generations), our analysis aimed at revealing large scale patterns driven by metapopulation expansion. Although we found evidence that change in body size was correlated to local increase in density and spatial sorting , we also showed a clear contrast between naturally founded populations and human stocked populations.We found that juvenile body size is influenced by phenotypic sorting during natural expansion (founder effect), with slow-paced changes towards bigger body sizes. The increase in body size through spatial sorting is consistent with the available literature, where migrants are generally fast-growing individuals ,26. It aIn stocked rivers, juvenile body size also increases in the most recently introduced rivers, but this pattern here cannot be related to spatial sorting. Interestingly, body size measured soon after the introduction was always lower than in newly naturally colonized rivers, possibly indicating strong non-adaptive founder effects related to introduction conditions or already strong competition induced by propagule pressure. The various genetic origins, numbers and life stages of propagules used to stock these rivers  may alsoJuvenile body size in naturally founded populations decreases as the population grows  as expected under a competition for resource hypothesis . The speMore strikingly, we found no evidence of a decrease in body size as stocked populations aged, whereas density steadily increased . We assuTo disentangle relative parts of phenotypic plasticity and genetic evolution in the observed patterns of body size evolution, large scale investigation of population genetics in relation to ecosystem-level processes seems a mandatory avenue . This isIn conclusion, while our analysis generally concurs to support the idea that density gradients, and to a lesser extent spatial sorting, are two important drivers of rapid changes in juvenile body size in expanding metapopulations , the imp