Labrune syndrome is a rare neurological disorder, with less than 100 reported cases since its identification. This disorder causes progressive cerebral degeneration. This case report describes a 21-year-old male patient who presented with tonic-clonic seizures. Upon examination, he was found to have symmetrical dense calcifications in the bilateral basal ganglia, thalami, and dentate nuclei, as well as in the white matter of both hemispheres, accompanied by cysts. MRI brain revealed confluent areas of T2/FLAIR hyperintensities involving the deep periventricular white matter in both cerebral hemispheres with sparing of subcortical U-fibres and two cysts in the left frontal and right posterior temporal region. No serologic evidence of a parasitic infection was found. Treatment was directed at addressing symptoms, and surgery was not required as the cysts were not causing a mass effect. The condition is the result of an autosomal mutation in the SNORD118 gene, a non-protein encoding gene that mediates rRNA synthesis. First described by Labrune in 1996 in three pediatric patients, the disease had imaging features such as white matter degeneration with cysts along with calcification ,3. RecenA 21-year-old male with a normal developmental history presented with one episode of tonic-clonic movements of all four limbs lasting for a few minutes associated with the involuntary passage of urine and stools and post-ictal confusion. There was no history of antecedent trauma, and he had no focal neurological deficits. Visual field acuity and fundus examinations were unremarkable.Complete blood count, erythrocyte sedimentation rate (ESR), calcium, liver and renal function tests, alkaline phosphatase, lactate, phosphate, serum thyroid, and parathyroid hormones were within reference ranges. Cytomegalovirus, hydatid cyst, Toxoplasma gondi, and HIV 1 and 2 serological tests were found to be negative.CT scan of the brain revealed symmetric dense calcifications in bilateral basal ganglia, thalami, dentate nuclei, and the white matter of both hemispheres. Calcifications were noted in ventral pons and basal ganglia with diffuse hypodensities in the periventricular white matter. Two cysts were seen in the left frontal and right parietal regions without any surrounding edema and minimal mass effect Figure .Brain MRI revealed confluent areas of T2/Fluid-attenuated inversion recovery (FLAIR) hyperintensities involving the deep periventricular white matter in both cerebral hemispheres with sparing of subcortical U-fibres and two cysts in the left frontal and right posterior temporal region with minimal mass effect and no surrounding edema , hydatid disease, and cryptococcosis . CerebraIn conclusion, LCC represents a specific recognizable clinical and radiologic entity, with degenerative cerebral microangiomatous changes being the most prominent histopathologic feature. LCC has a strong genetic predisposition, as highlighted by the clustering of LCC in families. LCC is a genetic disorder caused by mutations in the SNORD118 gene, which produces a type of RNA that is involved in ribosome synthesis but does not encode proteins. It is unclear how this ribosomal dysfunction leads to the specific manifestation of cerebral microangiopathy. To confirm the diagnosis and rule out other potential causes of intracranial cysts with calcifications and leukoencephalopathy, extensive diagnostic testing must be performed before genetic counseling can be provided. Currently, there is no standard protocol for diagnosing or treating LCC, but the disease displays a characteristic imaging pattern, and genetic testing can confirm the SNORD118 gene mutation. Diagnosis can be achieved by excluding similar pathologies, and definitive diagnosis can be achieved through genetic analysis of SNORD118. Treatment is primarily symptomatic, involving surgery to remove mass effects and medical management to control seizures and mental status changes.


In many cases, additional coactivators or regulators, including mediator complexes, connect the gene-specific transcription factors and transcription machinery , thereby transducing signals from the cis-acting regulatory sequences to the core promoter to modulate target gene expression.Plants have their roots fixed in the soil, so they are unable to escape from adverse environments. Thus, they must deal with various biotic and abiotic stresses by regulating gene expression to induce cellular tolerance responses. To initiate gene transcription correctly, RNA polymerase II must come together with several general transcription factors on a core promoter to form a large multiprotein–DNA preinitiation complex. In contrast, gene-specific transcription factors recognize specific upstream In eukaryotic cells, genomic DNA is packed into the nucleus by wrapping it around histones to form nucleosomes, the basic unit of chromatin structure. To initiate the transcription of a gene, the DNA–histone interaction in the surrounding chromatin must be relaxed to enable access by transcriptional activators and RNA polymerase. Gene expression is accompanied by chromatin remodeling . In addition, small and long non-coding RNAs modulate gene expression at the transcriptional and posttranscriptional levels. The epigenetic changes can be transmitted to newly developed cells during vegetative growth and even inherited by the progeny. Thus, plants pre-exposed to stressful conditions often grow better under subsequent stressful conditions in the same generation and in the next generation of the plants.International Journal of Molecular Sciences includes a total of five contributions. Three original articles describe the discovery and characterization of gene-specific transcription factors from cotton, strawberry, and iris [This Special Issue entitled ‘Transcription control mechanisms for plant stress responses’ in the and iris ,2,3. In and iris  providesand iris  reviewedVerticillium dahliae. In that study, a cis-acting element-FC-rich motif was found to be responsible for the defense response to V. dahliae. Upon inoculation with the fungus, the GhHSFB2a gene transcripts accumulated in the roots, stems, and leaves. Ectopic expression of GhHSFB2a in Arabidopsis enhanced resistance to V. dahlia, while virus-induced gene silencing of the gene significantly impaired cotton resistance. Transcriptome analyses revealed that GhHSFB2a participates in cotton disease resistance by regulating abscisic acid (ABA) and ethylene signaling, linoleic acid metabolism, and the phenylpropanoid pathway.Liu et al.  identifiLi et al.  identifiIris japonica Thunb and the deciduous Iris tectorum Maxim, by evaluating their morphological and physiological characteristics to ensure their developmental status. Under artificial dormancy-inducing conditions, the deciduous iris entered into dormancy earlier than the evergreen iris. The expression patterns of the dormancy marker genes involved in key pathways of winter dormancy suggested important roles for phytohormones and carbohydrates in coordinating growth and stress responses during dormancy induction in both iris species. In particular, it appears that dormancy-related MADS-box genes and Snf1-related protein kinases (SnRKs) represent a bridge between carbohydrate and phytohormone interactions during dormancy. These findings allude to a mechanistic model for investigating the key factors contributing to later dormancy in the evergreen iris relative to the deciduous iris. This study provides a basis for future research into the molecular mechanisms in perennials that exclusively exhibit eco-dormancy in the transition zone between temperate and subtropical climates, together with a reference for postharvest storage, shipping, and breeding.Xu et al.  investigMediator complexes transmit signals delivered by gene-specific transcription factors to the transcription machinery assembled at promoters to control transcription initiation. Chen et al.  present Drosophila and Caenorhabditis elegans) and the process of flowering in plants, the authors propose a hypothetical model for the mechanism of mitotic transmission in transcriptional memory. In this model, epigenetic marks, including modified histones  and chromatin regulators  protein complexes and trithorax group (TrxG) complexes) remain bound to chromatin loops formed in response to stress and are transmitted through mitosis. Certain transcription factors and chromatin remodeling complexes remain in close proximity to the chromatin of a memory locus, establishing a subsequent transcriptional status . However, there is little evidence to support the notion that chromatin architecture formation contributes to the memory of drought-stress tolerance in plants. Therefore, this speculative model should be verified in future studies of the mechanisms of drought-stress memory.Nguyen et al.  reviewedFor transgenerational inheritance, possible roles for DNA methylation are discussed , with reThe identification of specific transcription factors in a wide range of agronomically important crops, and elucidation of the molecular mechanisms underlying environmental stress tolerance, will facilitate the breeding of crops that are able to withstand global climate change more effectively. In particular, the principles and mechanisms underlying cellular memory should be further exploited to improve agronomic technology and crop breeding because epimutations can be artificially induced more rapidly than through traditional genetic manipulation.


Neutrophils, as the first defenders against external microbes and stimuli, are highly active and finely regulated innate immune cells. Emerging evidence has challenged the conventional dogma that neutrophils are a homogeneous population with a short lifespan that promotes tissue damage. Recent findings on neutrophil diversity and plasticity in homeostatic and disease states have centered on neutrophils in the circulation. In contrast, a comprehensive understanding of tissue-specialized neutrophils in health and disease is still lacking. This article will first discuss how multiomics advances have contributed to our understanding of neutrophil heterogeneity and diversification in resting and pathological settings. This discussion will be followed by a focus on the heterogeneity and role of neutrophils in solid organ transplantation and how neutrophils may contribute to transplant-related complications. The goal of this article is to provide an overview of the research on the involvement of neutrophils in transplantation, with the aim that this may draw attention to an underappreciated area of neutrophil research. In 24 hours . Aged ne24 hours . Recent 24 hours . Thus, n24 hours , despite24 hours –31, with24 hours –34, whil24 hours . In addi persons , 37 ’ due to their unique ability to promote B-cell proliferation and antibody production via secretion of soluble pentraxin 3 and indicated cytokines [hi mature neutrophils and immotile Ly6Gmid immature neutrophils, have been reported in the splenic red pulp, with specialized functions in regulating pneumococcal clearance and emergency granulopoiesis [A growing number of studies have investigated the presence of neutrophil populations in different tissues. These tissue neutrophil populations can be resident or newly infiltrated, and they can change their phenotypes depending on the tissue microenvironment. Even at steady state, neutrophils can be detected at low levels in most tissues, excluding the brain and sex gonads. In contrast, the primary neutrophil pool is found in the bone marrow, spleen, and lung , 38. Impytokines , 46, whiopoiesis  Fig. 2)H cells)’opoiesis , therebyopoiesis . HoweverNeutrophils show altered heterogeneity in nonhomeostatic states, with rapidly changing phenotypic and functional properties. With the development of scRNA sequencing technology, neutrophils can now be efficiently captured for analysis, a previously challenging task. Recent studies have revealed that neutrophils in tumor tissue and adjacent normal tissue are distinct and highly heterogeneous at the level of single-cell transcriptomics. The transcriptomic signatures of tumor-associated neutrophils (TANs) and adjacent normal tissue-associated neutrophils (NANs) have been dissected in non-small cell lung carcinoma, and TANs can be further divided into four subpopulations that may acquire specific functional properties. Moreover, a tissue-resident neutrophil-derived gene signature is associated with immune checkpoint blockade failure . NeutropIn addition, neutrophils exhibit diversity in aging, autoimmune diseases such as systemic lupus erythematosus, cardiovascular diseases such as atherosclerosis and myocardial infarction, nervous system diseases such as degenerative diseases and stroke, and respiratory diseases such as COVID-19, chronic obstructive pulmonary disease, lung fibrosis, tuberculosis, or asthma , 50–54. Neutrophils are involved in promoting the resolution of inflammation and facilitating tissue repair in addition to their well-characterized proinflammatory function. There are three strategies adopted by neutrophils to promote tissue repair , 56: 1) Substantial gaps remain between the demands for transplant organs and supply from donors. To bridge the huge gap related to organ shortage and shorten the transplant waiting time for patients with end-stage disease, the proportion of marginal organs procured from extended criteria donors (ECDs) or donation after cardiac death (DCD) has increased considerably. However, organs from these donors tend to be more susceptible to ischemia-reperfusion injury (IRI), an inevitable pathogenic event following transplantation that can subsequently lead to worse outcomes.The accumulation of neutrophils in the kidney has been described both in animal models and in human acute kidney injury (AKI). Neutrophils are primary responders that are recruited from the circulation to the sites of injury. The proportion of neutrophils is increased, particularly in the renal interstitium, as early as 30 min after ischemia-reperfusion and reaches a peak at 24 h , 64. HowNeutrophils can form neutrophil extracellular traps (NETs), which are web-like structures composed of DNA, histones, and antimicrobial peptides such as MPO, elastase and cathepsin G , 78. NETNeutrophils are increasingly recognized as having the capacity to diversify , particuDelayed graft function (DGF) is a common complication of kidney transplantation and is associated with worse clinical outcomes. DGF is defined as the need for dialysis within the first week following transplantation. Ischemia-reperfusion injury and immune responses within transplants are recognized as major causes of DGF . Turunen+ T cells and allows alloreactive regulatory T cells (Tregs) to maintain long-term allograft survival [+ T cells [+ T cells via major histocompatibility complex II (MHCII) and cross-presenting to CD8+ T cells via MHCI, suggesting that neutrophils could also serve as antigen-presenting cells (APCs) [Neutrophils play a pivotal role in the initiation of acute cellular rejection. In a murine model of cardiac allograft rejection, blocking or lacking the neutrophil chemokine receptor CXCR2 significantly reduces neutrophil infiltration and inhibits T-cell infiltration into cardiac grafts. In addition, the combination of costimulatory blockade with peritransplant neutrophil depletion or anti-CXCL1/2 antibodies greatly enhances cardiac allograft survival, indicating that early neutrophil-mediated tissue damage may promote T-cell-mediated rejection . Anothersurvival . Fas lig T cells . On the s (APCs) , 100 (Fis (APCs) . In a mos (APCs) .In organ transplantation, the role of neutrophils is commonly related to antibody-mediated rejection . It was lo suppressive macrophages by producing CSF1, thereby promoting transplant tolerance in the context of CD40L blockade [It has long been recognized that neutrophils, as key mediators of ischemia-reperfusion injury, participate in early posttransplant innate immune responses, enhancing adaptive alloimmunity and ultimately impacting transplant outcomes. However, with the increased appreciation of the heterogeneity and diversity of neutrophils, it is important to assess whether neutrophil subpopulations that may alleviate graft injury and prevent rejection or re-establishment of tissue homeostasis exist after transplantation. Neutrophil-induced inhibition of T-cell proliferation might be essential to limit T-cell activation and maintain tolerance in inflammatory conditions. Studies have reported subsets of neutrophils that can suppress T-cell activation , 112. G-blockade  Fig. 3)lo suppreblockade . TargetiNeutrophils, a fundamental cellular component of innate immunity, are crucial in a wide range of protective and immune regulatory responses. Advances in multiomics technologies have helped in recognizing and understanding neutrophil heterogeneity, thus challenging the conventional view that neutrophils are a homogeneous population. Although some specialized neutrophil subpopulations have been described in homeostatic and pathological conditions, there is still a lack of precise criteria to define these neutrophil subsets at multilayered levels, including genomic, epigenomic, and protein features and functional phenotypes. In addition, existing studies have mainly explored the heterogeneity of neutrophils from the perspective of the single-cell transcriptome, which ignores the complex spatial information of neutrophil subpopulations and is unable to elucidate the interaction between neutrophil subsets and other cells in the context of the native tissue microenvironment.The adoption of tissue-specific phenotypes by neutrophils suggests that tissue niche cues may differentially condition neutrophils. Using multidimensional analytic techniques, it is evident that neutrophils also possess tissue-specific properties, similar to macrophages, which have been extensively studied for their tissue-specific characteristics in the past. Notably, tissue neutrophil heterogeneity and diversification studies are primarily conducted using preclinical mouse models; therefore, more investigations are required to better understand the diversity and plasticity of neutrophils in human tissues under healthy and pathological conditions, which is vital for comprehending the regulation of immune homeostasis. Therefore, we can reconsider the role of neutrophils from the point of view of single ‘microbial killers’ to include highly complex and finely regulated populations with diverse functions. We propose that neutrophil function could be ‘reprogrammed’ in numerous diseases, such as organ transplant complications. Exploration of the dynamic changes in the heterogeneity and plasticity of neutrophils under steady conditions and during disease development may lead to discovering novel therapeutic strategies that can ‘redirect’ neutrophil function back to a healthy state.


Brain imaging and electrophysiology have significantly enhanced our current understanding of stroke-related changes in brain structure and function and their implications for recovery processes. In the motor domain, most studies have focused on key motor areas of the frontal lobe including the primary and secondary motor cortices. Time- and recovery-dependent alterations in regional anatomy, brain activity and inter-regional connectivity have been related to recovery. In contrast, the involvement of posterior parietal cortical areas in stroke recovery is poorly understood although these regions are similarly important for important aspects of motor functioning in the healthy brain. Just in recent years, the field has increasingly started to explore to what extent posterior parietal cortical areas might undergo equivalent changes in task-related activation, regional brain structure and inter-regional functional and structural connectivity after stroke. The aim of this scoping review is to give an update on available data covering these aspects and thereby providing novel insights into parieto-frontal interactions for systems neuroscience stroke recovery research in the upper limb motor domain. et al. give an update on posterior parietal cortical areas and their changes in brain activation, regional brain structure and inter-regional structural, functional and effective connectivity and show how these changes relate to recovery processes after motor stroke.Reibelt   Studies in the motor domain have illustrated how multiple brain areas of both hemispheres undergo time-dependent changes not only in brain structure and regional activation but also in multi-site inter-regional structural and functional connectivity and related these changes to recovery processes.4-9 Most evidence for recovery-related dynamics in regional and network brain structure and function is available for key motor areas of the frontal lobe, comprising the primary motor cortices (M1), the dorsal and ventral premotor cortices (PMC), and the supplementary motor areas (SMA). For instance, it has been shown that a stroke leads to early upregulation of ipsilesional and contralesional motor cortices with an extended recruitment of brain regions particularly in more impaired patients. Resting-state and task-related functional MRI studies have found alterations in the connectivity and information flow between these key motor areas and have linked them to recovery.4Ischaemic stroke is one of the leading causes for persistent, long-term disability in western, industrialized countries.10 significantly involve interactions between posterior parietal cortical areas and frontal motor areas. For instance, the anterior portion of the lateral bank of the IPS has been found to contribute to grasping,12 precision grip13 and grip force adaption.14 It provides PMC with visual information about object properties and influences PMC-M1 interactions to generate task-specific motor commands. Also, more posterior cortices along the IPS have been reported to show grasp-related activations15 and encode spatial object features relevant for movement planning and execution.17 Another study has related the success in motor skill acquisition to the state of parieto-frontal functional networks.18 One important structural substrate of these interactions is dense connections between M1, ventral PMC and anterior and caudal IPS via the superior longitudinal fascicles. These pathways have been traced in animals20 and humans.21-23In comparison to key motor areas of the frontal lobe, the involvement of posterior parietal cortical areas and their contribution to stroke recovery has not been in the focus for many years although these regions are similarly important for motor function in the healthy human brain. Recently, the field has increasingly started to explore to what extent posterior parietal cortical areas including areas along the intraparietal sulcus (IPS) on the superior (SPL) and inferior parietal lobules (IPL) might undergo equivalent changes after stroke in regional brain structure, task-related activation and inter-regional functional and structural connectivity. Studies in healthy participants have already evidenced that skilled voluntary movements of the upper limb, including reaching, gasping, object manipulation and tool use,Collectively, as posterior parietal regions contribute to dexterity and skilled hand and arm movements in healthy participants and as they are connected to key motor areas of the frontal lobe, it has been hypothesized that these parietal brain areas might be also involved in recovery processes after stroke. The aim of this article was to review the available literature on stroke-related changes in regional and inter-regional brain function, structure and connectivity of posterior parietal cortical areas and their association with motor recovery after stroke.For this scoping review article, PubMed database was scanned for primary and secondary literature including systematic reviews and meta-analyses with the date of publication in 2000 and later. Literature selection was biased towards studies on ischaemic stroke patients, the upper limb motor domain and the posterior parietal cortex. Hence, studies on aphasia or neglect and studies involving global network/connectome analyses were not in the scope of the present work. Study selection was finalized based on data quality, methods, and novelty. Results are organized and presented with a focus on three distinct aspects, (i) changes in regional brain activation and regional transcranial magnetic stimulation (TMS) inference of causal involvement, (ii) structural connectivity analyses, and (iii) functional and effective connectivity analyses.Data sharing is not applicable to this article as no new data were created or analysed in this study.25 Overactivation early after stroke, observed both in the ipsilesional and contralesional hemispheres and particularly in more severely impaired patients, normalizes over time. Normalizing activation patterns have been associated to motor recovery.Most evidence for time- and recovery-dependent alterations in focal brain activation has been accumulated for key motor areas of the frontal lobe, comprising M1, dorsal and ventral PMC and SMA, as reported by systematic meta-analyses.25 an in-depth analysis on the single study level seems to be warranted to draw a more finely grained picture of changes in brain activation in posterior parietal cortical areas after stroke. In fact, taking all stroke patients and time points into account, one meta-analysis found an increased brain activation in bilateral precentral gyrus, left postcentral gyrus and right superior frontal gyrus, cingulate gyrus and the paracentral lobule. Interestingly, when biasing the analysis towards patients with subcortical lesions and intact cortices, upregulated active regions additionally comprised the right supramarginal gyrus and IPL. Moreover, when contrasting the activation in the acute stage after stroke with data from the chronic stage, not only the precentral and postcentral gyrus showed an overactivation in the acute stage but also the left IPL.25 Such meta-analyses are based on multimodal approaches whose details are worth noting. For instance, positron emission tomography data have shown an overactivation particularly early after subcortical stroke in bilateral ipsilesional and contralesional SPL and IPL.26-28 Functional MRI has similarly reported a task-related bilateral overactivation in posterior parietal cortical areas,29-34 and some studies have evidenced correlations between regional activations and subsequent amount of recovery. For example, activation in the contralesional IPL and ipsilesional IPS negatively related to recovery.35 One recent study has emphasized that posterior parietal brain activation might depend on the level of impairment by showing an overactivation specifically in the contralesional parietal lobe in hemiplegic chronic stroke patients with a positive association with motor functions.36 Most studies have found an early overactivation with subsequent normalization over time. However, there are also contradictory data. For example, one longitudinal study in patients with isolated subcortical lesions reported an increasing activation in the ipsilesional inferior parietal cortex as time proceeded.37 In summary, most task-related brain activation studies have argued that posterior parietal cortical areas might activate more strongly early after stroke and most likely in patients with more severe deficits and, speculatively, the highest need of secondary motor areas to compensate for motor deficits. Compared to frontal motor areas, posterior parietal involvement appears to be much more variable and inconsistent across studies and different patient cohorts. Differences in the level of impairment, lesion locations, and selection of regions within the complex functional anatomy of the posterior parietal cortex might be influential factors.38 Also, inter-study variability might lie in the kind of motor tasks used which may drastically differ regarding their recruitment of parietal resources. Hence, this might result in highly variable findings, especially since most studies rely on relatively simple motor tasks rather than complex tasks involving reach and grasp components or fine motor skills of dexterity. In meta-analyses, this might explain the absence of consistent posterior parietal brain activation across studies, which, in turn, might also explain the absence of associations with behaviour.Compared to frontal motor areas, meta-analyses have reported only limited evidence of stroke-related dynamics in posterior parietal brain activation. As large inter-subject variability in stroke cohorts, e.g. regarding the level of impairment, lesion locations and motor tasks, might have biased the findings of activation likelihood estimations towards the frontal lobe,39 In contrast, in the acute phase of stroke, stimulation of the contralesional anterior IPS led to the opposite effect with an improvement in motor functions in 14 patients with cortical stroke.40 Such data further indicate that the contribution of posterior parietal cortical areas might be time-sensitive and specific to lesion locations and regions tested. To what extent beneficial effects under online perturbation can really be interpreted as a positive effect of stopping an ongoing maladaptive process is still under debate.41 Regarding prospective aspects of recovery over time, there are no TMS studies which, for instance, have probed the effect of repetitive perturbation or up- or downregulation of posterior parietal cortical areas early after stroke and followed the clinical course of recovery thereafter. Only such approaches will be able to answer whether posterior parietal areas might causally drive recovery or whether they might support recovered motor functions without driving recovery itself.Brain activation studies have the important limitation that their results cannot be interpreted as causal. In other words, longitudinal changes in brain activation can be driven by recovery rather than they are the cause of recovery. The same holds true for recovered hand function when addressed cross-sectionally. Hence, activity changes in posterior parietal areas might be simply an epiphenomenon without any functional importance for recovery or recovered hand function after stroke. Regarding this critical issue, few TMS studies have aimed at probing the influence of posterior parietal regions on recovered hand function by the perturbation of ongoing local activity. Contralesional SPL stimulation led to functional deficits of timing and accuracy in seven patients three months after isolated subcortical stroke.6 More recently, motor networks such as alternate corticofugal motor fibres, cortico-cerebellar networks and networks on the cortico-cortical level have gained an increasing interest in the field. For the latter and similarly to functional imaging data, most studies have addressed structural brain changes in frontal motor areas.Structural imaging has significantly contributed to stroke recovery research in recent years. The main focus of such analyses has been M1 and the corticospinal tract (CST), the main outflow tract of the human motor system.42 Ipsilesional cortical grey matter atrophy in the angular gyrus and the SPL has been linked with unfavourable recovery in a longitudinal study.43 Patients exhibiting lesions which extended from the primary sensorimotor cortices into more parietal areas have been reported to be at risk of retaining more severe chronic motor deficits.44 Similar findings have been obtained by a recent lesion mapping study in chronic stroke patients which correlated lesions affecting white-matter tracts below posterior parietal cortical areas with reduced treatment gains in motor rehabilitation.45 Structural connectivity analyses have also been conducted to investigate to what extent the integrity of motor pathways linking posterior parietal cortical areas with key areas of the frontal lobe might influence recovery. For example, one study in 26 chronic stroke patients reconstructed parieto-frontal motor connections between the ipsilesional anterior IPS and the ventral PMC and found that the structural integrity of this connection positively correlated with recovered hand function in addition to the well-established influence of the integrity of the CST.22 Likewise, in a longitudinal setting, another study reconstructed the superior longitudinal fascicle and reported a positive correlation between its microstructural state after three weeks and recovery until twelve weeks.46 Other studies have argued that such structure–behaviour relationships might be particularly relevant in more severely impaired patients, e.g. with larger lesion loads to the CST.48 Such findings have been recently extended by analyses linking the connectivity of specific brain areas within larger brain networks. One analysis trained support vector machine classifiers to separate patients with natural recovery, as defined by the proportional recovery model,49 from patients without natural recovery. The authors found that a stronger connectivity between ipsilesional posterior parietal cortices with the global connectome, assessed two weeks after stroke, was positively associated with a larger likelihood of exhibiting subsequent natural recovery.50 A synopsis of structural analyses including structural connectivity studies is given in More recently, studies have increasingly explored posterior parietal brain regions and their structural connections with frontal motor areas. For instance, it has been shown that subcortical strokes lead to atrophy and cortical thinning not only in ipsilesional M1, retrogradely affected by the lesion, but also in posterior parietal cortical areas along the IPS.68Aside from structural analyses, a variety of functional imaging studies have investigated the inter-regional interplay of posterior parietal cortical areas with other areas of the distributed motor network, particularly in the frontal lobe. Methodologically, functional connectivity (FC) analyses can be differentiated from effective connectivity (EC) analyses. FC describes the temporal relationship between spatially distant neurophysiological events. Most calculations are based on correlations between time series of functional MRI BOLD data or correlations of oscillations between different brain regions in task-free EEG data. Coupling strengths, e.g. between different motor areas, are non-directional and do not inform about the direction of interactions or causality. In contrast, EC calculations are mostly derived from task-related time series data and carry directional information about how brain activity in one region might influence the activity in another region.51 A subsequent EEG study in a similar cohort of patients, three months after stroke, has found a significant upregulation in task-related FC between the same regions, the ipsilesional anterior IPS and M1. Moreover, patients with larger deficits exhibited stronger parieto-frontal communication.52 Further MRI studies provided additional insights particularly for the acute stage and patients with severe deficits.53-55 Well-recovered stroke patients, measured acutely after stroke, exhibited a significant EC from ipsilesional AIP to dorsal PMC modulated by hand tapping which was not evident in healthy controls. Moreover, the strength of this parieto-frontal coupling could predict the effect of a TMS perturbation paradigm of the contralesional anterior IPS which was found to improve hand motor performance, potentially via the modulation of interhemispheric coupling.33 Another MRI study investigated severely impaired acute stroke patients. These patients exhibited a strong upregulation in parieto-frontal FC between ipsilesional anterior IPS and M1. Importantly though, the extent of this early upregulation was associated with larger persistent deficits after three to six months.53 It has been speculated that posterior parietal cortical areas upregulate after stroke and activate their interactions with frontal key motor areas to support motor output. However, this upregulation seems to be largely insufficient since a persistent upregulation over time, particularly in severely impaired patients, has been evidenced by FC54 and recent EC analyses.55There are already some studies which have provided valuable insights into ipsilesional parieto-frontal connectivity after stroke. In well-recovered chronic stroke patients, task-related functional MRI combined with dynamic causal modelling for EC analysis found an increase in reciprocal information flow between ipsilesional anterior IPS and M1 during a simple hand grip task. However, the extent of this upregulation could not be linked to persistent motor deficits.56 or have found a reduced FC between ipsilesional anterior IPS and dorsal PMC in less-recovered patients when compared to patients with a good outcome.41 Another study combined functional and structural imaging and TMS and observed that patients with an extensive lesion load to the CST exhibited higher FC in ipsilesional parieto-frontal networks.48 Patients with extensive CST damage showed a positive correlation between parieto-frontal FC and motor performance which might contrast with previous studies.52However, drawing conclusions on the impact of the parietal cortices in motor recovery after stroke remains a challenge, as current studies give a complex picture of parieto-frontal interactions after stroke -activate frontal premotor–motor networks which in turn could result in a reduced need for additional parietal input, i.e. a re-balancing of parieto-frontal and frontal functional motor networks could parallel motor training after stroke. Similarly, most likely supportive contributions have been previously suggested for prefrontal cortices by FC analyses for the contralesional hemisphere59 and by EC analyses during a motor imagery task for the ipsilesional hemisphere.70 Again and in line with brain activation studies, these considerations remain speculative as they remain associative in nature and do not prove any causality. Interventional studies probing the up- or downregulation of specific connections and analysing treatment effects would be needed to investigate whether parieto-frontal connectivity would exert driving influences or show specific or even unspecific changes because of training. Thereby and to make the situation even more difficult, parieto-frontal network involvement might be treatment specific. One study has investigated the addition of motor imagery training in chronic stroke patients and has found an upregulation of coupling strengths between ipsilesional parietal areas and M1 under motor imagery when compared to conventional rehabilitative treatment over four weeks.63 Another study has explored brain computer interface–guided robotic hand training and has found a treatment-associated increase in FC between bilateral SPL and ipsilesional SMA.64 Finally, the prediction of treatment gains has also been explored by several studies. For instance, one resting-state EEG study conducted early after stroke has reported that stronger baseline FC in the high beta band between ipsilesional posterior parietal leads and M1 positively contributed to motor improvement while stronger coupling between M1 and SMA was negatively related to functional improvement.65 A similar association between stronger baseline coherence in the high beta band between ipsilesional parietal leads and M1 has been related to improvement in a visuomotor tracking paradigm.67 Another study investigated a complex, gamified reaching task in the chronic stage of recovery. The training led to an increase in FC between left supramarginal gyrus and left SMA. The treatment effect itself was positively associated with the coupling strength between left angular gyrus and left M1.66 As a consequence, future studies will have to acknowledge that precise characteristics of experimental setups, motor task or training paradigms as well as outcome measures have a relevant influence on brain–behaviour associations, whether causal or not. An overview of functional and effective connectivity studies is given in Connectivity–behaviour relationships for ipsilesional parieto-frontal connectivity have been investigated for motor training after stroke. One EEG study has assessed changes in resting-state FC between frontal motor and multiple other brain regions during an intervention of home-based upper limb training over 28 days. It found that functional improvement was accompanied by decreases in FC between ipsilesional parietal cortices and M1 while FC values between M1 and PMC increased at the same time.38 were not in the focus of the present work. For aphasia and neglect, the interested reader is referred to relevant and informative primary research and reviews.71-77 In this regard, the network–outcome inferences in the present report are dominated by motor aspects. However, neglect and aphasia are critical influential factors for recovered motor functions and the success of rehabilitation.78 Hence, to what extent the associations between posterior parietal cortical areas and recovery after motor stroke might be mediated by an impact on neglect and speech disturbances remains undiscussed. An integrative review covering all domains would be warranted to address this further and systematically. Third, the authors fully recognize that the posterior parietal cortex comprises multiple functionally and structurally defined areas. Also, findings were organized for the ipsilesional and contralesional hemisphere, but not for the right and left, or dominant and non-dominant hemispheres, an approach that might be particularly intuitive for language recovery research. Thus, the picture presented in this work, particularly the synopsis given in The aim of the present work was to provide a scoping review of posterior parietal cortical areas and their contribution to recovery after motor stroke. Three limitations are worth noting: First, the authors do neither claim any completeness nor have they utilized any objective assessment of the methodological quality of the selected studies. Hence, particularly the small sample sizes should be considered with caution when inferring any conclusions from the presented data. Second, study selection was biased towards the motor domain and, for connectivity studies, towards parieto-frontal connections. Studies with a focus on other domains of deficits, such as aphasia or neglect, and connectivity within posterior parietal brain regions themselves4 As discussed, the present picture appears rather complex and simple conclusions are still difficult to draw. It was not the aim of the present work to provide novel mechanistic or causal explanations of how precisely posterior parietal cortical areas may influence motor recovery after stroke. Brain–behaviour associations derived from functional and structural brain imaging remain associative in nature and do not evidence any causality. Notwithstanding these difficulties, the review aims at providing an integrative, illustrative and informative synopsis over the current body of literature to help other researchers to detect yet hidden patterns of alterations in the parieto-frontal network, to develop novel hypotheses, and to design appropriate studies which will have to combine, at best, imaging, behaviour and interventional approaches. For instance, the literature suggests that posterior parietal cortical areas might be most likely recruited in patients with severe deficits and higher lesion loads. On a speculative note, in these patients, the core motor networks appear to exhibit a high demand for additional neuronal input from prefrontal and posterior parietal areas, potentially to enhance excitability and promote plasticity to compensate for the motor network disruption. However, whether changes in posterior parietal brain activity and connectivity are causally related to recovered function or even linked to long-term recovery, i.e. whether they might drive plasticity and recovery, remains unclear. If not, an unspecific epiphenomenon of the upregulated brain must be considered as well. There are different ways how future studies could investigate these alternative hypotheses. For instance, short interventional studies could use TMS or transcranial direct current stimulation (tDCS) to perturbate or up- and downregulate ongoing activity in posterior parietal brain areas and analyse subsequent changes in primary motor cortical excitability. Herein, the combined analysis of patients with minor and severe deficits could then inform about different causal roles of these areas in specific patient cohorts. When conducted at different time points, early or late after stroke, the aspect of time dependency could be addressed as well. Finally, when it comes to brain–behaviour relationships, studies will have to acknowledge that the selection of motor tasks, from simple tasks to very complex tasking including reach and grasp components, will have an important impact on activation, thereby influencing the susceptibility to perturbation. As another point, data in severely impaired patients with unfavourable outcome have indicated that a persisting overactivation in posterior parietal cortical activity or coupling over time might reflect a supportive, but futile attempt of the brain to activate available resources. However, there are also some TMS data which suggest that posterior parietal areas might be engaged in maladaptive processes. To better understand these discrepancies of supportive or maladaptive roles, we need prospective, interventional and well-powered TMS/tDCS studies on samples covering a broad spectrum of impairment from minor deficits to more severe impairment. Ultimately, to what extent an early additional upregulation of posterior parietal cortical areas, e.g. by means of activating TMS or tDCS,79 might promote future recovery in clinical cohorts has to be investigated prospectively and systematically. So far, appropriate cohorts have not been studied yet and posterior parietal stimulation data in clinical cohorts are limited.81Collectively, there is a growing body of literature indicating that posterior parietal cortices and their interactions to other motor areas clearly undergo stroke- and treatment-related changes that are associated with motor recovery processes. The present synopsis extends previous data on brain activity and connectivity changes after stroke which have largely focused on key motor areas of the frontal lobe.


Moreover, these innovations strive to optimize visual acuity and consequent patient satisfaction. With the Research Topic on Frontiers in Medicine titled “Recent advances in refractive surgery”, we gathered new sophisticated surgical approaches on state-of-the art technologies poised to contribute to the ongoing progression within the field of refractive surgery.Recently, there has been swift advancement in the realm of refractive surgical methodologies, resulting in the emergence of refractive procedures that are both enhanced in safety and heightened in efficacy. New developments in surgical methodologies, including laser Han et al. undertook an initial bibliometric assessment of SMILE surgery spanning the last 12 years. Their findings revealed that research terminology associated with SMILE can be categorized into six distinct clusters: femtosecond (FS) laser technology, dry eye, biomechanics, visual quality, complications, and hyperopia, and that these words are helpful for better understandings of major concerns of surgeons and researchers in consideration of the further development of SMILE surgery.The advent of SMILE over the past decade has introduced a viable substitute to LASIK for individuals seeking cornea laser refractive procedures. SMILE presents an innovative technique, relying exclusively on the femtosecond (FS) laser to shape an intrastromal lenticule that can be extracted through a minor incision. Presently, SMILE has solidified its status as a mainstream option among refractive interventions, catering to the management of mild to moderate myopia and myopic astigmatism. In a pioneering study, Cui et al. demonstrated, in their meta-analysis selecting 6 randomized clinical trials for high astigmatism of 2.0 D or more, that SMILE, FS-LASIK and photorefractive keratectomy demonstrated similar effectiveness and safety profiles in correcting high myopic astigmatism. However, it should be noted that SMILE induced more residual astigmatism and diminished precision in forecasting astigmatic outcomes, alongside reduced surgically induced spherical aberrations when compared to alternative surgical methods. These findings indicate that the astigmatic nomogram requires some adjustments, especially in consideration of a slight tendency toward undercorrection for high astigmatism.Based on the fact of the lack of an eye tracking system as well as a control of ocular cyclotorsion in current SMILE surgery, there are still ongoing concerns about astigmatic correction, especially in high astigmatic eyes. Wu et al. showed, using both AS-OCT and ultrasound biomicroscopy (UBM), that ICL size, ATA, and CLR, and ciliary sulcus angle (CSA) were essential for obtaining the optimal ICL vault, and that this derived formula outperformed the currently available NK and KS formulas. The combination of AS-OCT and UBM may hold a promise for further refinement of the optimal ICL size selection.The posterior chamber pIOL (EVO Visian ICL) is widely acknowledged on a global scale as a long-term safe and effective approach for correcting moderate to high ametropia. Nonetheless, a low vault may be linked to cataract development, while a high vault can lead to angle closure and consequent elevation in intraocular pressure. Consequently, the ability to anticipate the ideal ICL vault assumes paramount significance in the realm of clinical practice, particularly when prioritizing the safety of ICL surgery. At present, the majority of surgeons rely on the manufacturer's sizing nomogram derived from measurements like white-to-white and anterior chamber depth, or utilize predictive formulas grounded in the data acquired from anterior segment optical coherence tomography (AS-OCT), in order to ascertain the most suitable ICL size. Wang et al. observed a strong correlation between alternations in standard keratometry (SK) and total keratometry (TK), as measured by swept source OCT (IOL Master 700), following SMILE and FS-LASIK procedures. These changes were found to be closely associated with shifts in spherical equivalent at the corneal plane, exhibiting a high correlation coefficient of 0.97. Notably, the authors introduced a novel approach by combining telecentric keratectomy with anterior segment optical coherence tomography (AS-OCT) to simultaneously measure the anterior and posterior corneal surfaces, leading to a more accurate prediction of intraocular lens (IOL) power after myopic corneal refractive surgery compared to SK. This enhanced precision could be attributed to the fact that the anterior/posterior corneal radius (A/P) ratio deviates further from the normal range, and also due to the refined alignment of TK with SK. The novel TK parameter could potentially offer a precise and objective assessment of corneal power that closely tracks the alterations in refractive change in corneal refractive surgery, thereby facilitating the attainment of a more exact refraction outcome.Contemporary cataract surgery has garnered recognition as a form of refractive surgery due to the incorporation of optical biometry and the latest-generation IOL power calculation formulas. However, it is still difficult to accurately determine IOL power in eyes undergoing corneal refractive surgery, possibly due to a keratometric measurement errors as well as effective lens position prediction errors. In their study, In conclusion, this Research Topic provides us essential insights on refractive surgery for further refinement and offers the opportunity to contribute to the ongoing advancement of refractive surgical techniques. Modern refractive surgery has been become acknowledged as one of the most sophisticated surgical techniques in the field of ophthalmology.KK: Writing – original draft. KN: Writing – review and editing.


Inflammatory processes are increased by stress and contribute to the pathology of mood disorders. Stress is thought to primarily induce inflammation through peripheral and central noradrenergic neurotransmission. In healthy individuals, these pro-inflammatory effects are countered by glucocorticoid signaling, which is also activated by stress. In chronically stressed individuals, the anti-inflammatory effects of glucocorticoids are impaired, allowing pro-inflammatory effects to go unchecked. Mechanisms underlying this glucocorticoid resistance are well understood, but the precise circuits and molecular mechanisms by which stress increases inflammation are not as well known. In this narrative review, we summarize the mechanisms by which chronic stress increases inflammation and contributes to the onset and development of stress-related mood disorders. We focus on the neural substrates and molecular mechanisms, especially those regulated by noradrenergic signaling, that increase inflammatory processes in stressed individuals. We also discuss key knowledge gaps in our understanding of the communication between nervous and immune systems during stress and considerations for future therapeutic strategies. Here we highlight the mechanisms by which noradrenergic signaling contributes to inflammatory processes during stress and how this inflammation can contribute to the pathology of stress-related mood disorders. Understanding the mechanisms underlying crosstalk between the nervous and immune systems may lead to novel therapeutic strategies for mood disorders and/or provide important considerations for treating immune-related diseases in individuals suffering from stress-related disorders. Stress is well known to initiate and exacerbate mood disorders like anxiety, depression, and posttraumatic stress disorder (PTSD). These disorders are serious public health concerns as the lifetime prevalence rates for major depressive disorder (MDD), anxiety disorders, and PTSD are estimated to be estimated to be 10%–20%, 25%–31%, and 6%–8%, respectively  noradrenergic signaling via the sympathetic nervous system and locus coeruleus  and (2) The main objectives of this narrative review are to: (1) summarize our current understanding of the mechanisms by which stress regulates inflammatory processes, (2) provide mechanisms by which inflammatory molecules can influence neuronal activity and mood, (3) describe how inflammatory pain might exacerbate inflammatory processes and contribute to negative mood, (4) highlight the role of glucocorticoid receptors in mitigating stress-induced inflammation, and (5) discuss knowledge gaps in our understanding of the neural circuits responsible for communication between immune and nervous systems. We discuss the physiological stress response, the effects of acute stress on inflammatory markers, and a key transcriptional mechanism underlying stress-induced inflammation. We then discuss the effects of inflammatory processes on neuronal activity and provide evidence that inflammation directly contributes to depression in certain individuals. We discuss how inflammation can be exacerbated by the neural substrates underlying nociception as inflammatory molecules sensitize pain-sensing neurons, which in turn release pro-inflammatory neuropeptides. We highlight the importance of glucocorticoids in mitigating inflammatory processes caused by stress and discuss how glucocorticoid signaling within the optimal range is necessary for resilience to the adverse effects of stress. We discuss key gaps in our understanding of the neural circuits and molecular mechanisms that contribute to stress-induced inflammation. We also discuss how this knowledge can potentially be used to develop novel therapeutic strategies, why this is currently challenging, and how these challenges might be overcome. Understanding the communication between the nervous and immune systems will allow basic scientists and clinicians to better understand this stress-immune axis and how it impacts biological processes, behavior, and patient outcomes.Stress can have profound effects on physiological, molecular, and neuronal mechanisms that lead to long-lasting changes in behavior. Physiological and psychological stressors activate multiple systems simultaneously, with one of the most immediate responses being increased noradrenergic signaling. In the periphery, norepinephrine is released from postganglionic neurons that regulate the sympathetic nervous system to increase heart rate and prime the organism for “fight or flight” . The priThe hypothalamic–pituitary–adrenal (HPA) axis represents the neuroendocrine branch of the stress response. Here, a stressor increases the activation of parvocellular neurons in the paraventricular nucleus of the hypothalamus (PVN), which release CRF , therebyThus, in humans and rodents, chronic stress activates both noradrenergic signaling and the HPA axis. Since a major result of noradrenergic signaling is an increase in inflammatory markers, an important role for GR signaling is the compensatory reduction of inflammatory processes . These sAcute stressful experiences result in increased inflammatory marker expression and other neurophysiological changes. The Trier Social Stress Test (TSST) is commonly used as an acute psychological stressor in humans . In thisA meta-analysis of 34 studies measuring circulating inflammatory markers indicate that in individuals exposed to acute stress under laboratory conditions, levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor α (TNFα) are increased . Acute sSingle and multiple stressors also increase inflammatory markers in rodents. In established rodent stress models, such as social defeat stress, inflammatory processes are activated in the brain and periphery. A single social defeat session in the resident-intruder paradigm increases IL-6 mRNA expression in the medial prefrontal cortex (mPFC), while increases in IL-1β and TNFα are only observed in the mPFC after at least 7 days of stress . The mPFMood disorders associated with chronic stress are also associated with increases in inflammatory markers in the blood , 79, 80 Inflammatory cytokines are not only increased by stress but contribute to the pathology of stress-related mood disorders. A broad range of social , anatomiFor example, a meta-analysis of 14 trials with 6,262 participants revealed that pharmacological cytokine inhibitors or non-steroidal anti-inflammatory drugs (NSAIDS) can reduce depression scores in adults with depressive symptoms compared to placebo controls . A subseConversely, treatments using exogenous cytokines increase symptoms of depression. Interferon-α (IFNα) exacerbates symptoms of depression when used to treat hepatitis C . IFNα alStudies in the absence of any treatments also support a relationship between stress-related mood disorders and immune dysfunction as depression and autoimmune disorders share comorbidity, common symptoms, and inflammatory processes . Diseaseq/11 protein coupled receptors (GPCRs) that activate phospholipase C β, which increases concentrations of diacylglycerol and inositol trisphosphate, thus activating protein kinase C signaling and increasing intracellular calcium concentrations. The β adrenergic receptors are GsPCRs that activate adenylyl cyclase, converting adenosine triphosphate to 3′,5′-cyclic adenosine monophosphate (cAMP), which activates protein kinase A signaling  are increased. IDO is responsible for catabolizing tryptophan into kynurenine, which further catabolizes into metabolites like quinolinic acid in microglia and kynurenic acid in astrocytes , 31, 115Increased serotonergic neurotransmission can facilitate neurogenesis in the subgranular zone of the dentate gyrus , which iThe neural substrates underlying pain represent an important, and often overlooked, system that can cause a positive feedback loop that increases inflammation during stress. A heightened sense of pain represents one of the most prominent symptoms caused by inflammation. Pain is an unpleasant sensory and emotional experience caused by actual or potential tissue damage. While the sensation originates with activation of nociceptors throughout the periphery, the signals are sent to the brain via the spinothalamic tract and further shaped by supraspinal brain regions that encode it with a negative emotional valence . InteresWhile nociceptors can be activated by noxious chemical, thermal, and mechanical stimuli at baseline, local inflammation from injury or infection can sensitize them. Mast cells, macrophages, and keratinocytes release inflammatory mediators such as TNF-α, IL-1β, and IL-6 that increase infiltration of immune cells that further promote inflammation . These mRepeated activation of these nociceptors under chronic pain conditions can also cause microglia reactivity, leading to central sensitization of nociceptive pathways. Here, microglia reactivity is thought to occur due to the release of the chemokine CCL2 from the chronically active nociceptor . Once reUnderstandably, treating inflammatory pain with non-selective COX inhibitors and other non-steroidal anti-inflammatory drugs (NSAIDs) is considered first-line therapy for clinicians . Other tImpairments in the anti-inflammatory mechanisms regulated by GRs can lead to systemic inflammation in chronically stressed individuals. Negative feedback of the HPA axis prevents continuous activity of itself during periods of prolonged stress. Here, negative feedback is mediated by glucocorticoids, which bind to glucocorticoid receptors in multiple tissues including the anterior pituitary , PVN 15, and PFCA number of factors can cause glucocorticoid resistance. Glucocorticoid signaling can be impaired by DNA methylation of the gene encoding GRs, thereby reducing GR expression . AdditioGlucocorticoid resistance can also be caused by NFkB, which impairs the ability of GRs to bind DNA and regulate gene expression , 164. NFAberrant glucocorticoid signaling is a hallmark of stress-related psychiatric disorders. MDD patients display increased salivary cortisol in the first hour of wakefulness, but salivary cortisol concentrations are similar to controls within 8 h of wakefulness . BecauseRecently, we found that GR expression is increased in the mPFC of rats resilient to the adverse behavioral effects of social defeat. We found that a specific target of GRs, sphingosine-1-phosphate receptor 3 (S1PR3), prevented anxiety- and depression-like behavior by mitigating stress-induced inflammation. S1PR3 mRNA was also reduced in the blood of veterans with PTSD , which iDecades of research has identified many key molecular mechanisms underlying the interplay among stress, inflammation, pain, and behavior. The nervous system is central to this interplay, but we have yet to identify many of the circuits responsible for this interplay. For example, we know that noradrenergic neurotransmission contributes to inflammatory processes in immune cells of the blood and brain using pharmacology. These noradrenergic neurons are likely postganglionic sympathetic neurons and locus coeruleus neurons. However, it is possible that certain subregions of these noradrenergic centers are more important for stress-induced inflammatory processes than others. For example, thoracic, but not lumbar, sympathetic neurons might underlie stress-induced inflammation. We know that norepinephrine induces microglia reactivity and cytokine production and assume this norepinephrine is derived from the locus coeruleus, but this has yet to be directly demonstrated. We also do not know if the pro-inflammatory effects of norepinephrine in microglia are due to NFkB-mediated transcription as they are in peripheral immune cells.The activity of noradrenergic neurons and specific neural circuits can be manipulated using chemogenetic or optogenetic methods. In particular, viral vectors expressing hyperpolarizing hM4D and depolarizing hM3D Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) under the control of the PRSx8 promoter have been developed . These cCross-talk between the nervous and immune systems during stress is complex and can have profound effects on behavior. Stress activates both the sympathetic nervous system and the HPA axis, which are generally pro- and anti-inflammatory, respectively , 60. EacNFkB and GRs represent two major transcription factors that regulate gene expression in response to activation of the sympathetic nervous system activation and the HPA axis, respectively. NFkB is a master transcriptional regulator of the inflammatory response whereas GRs are highly effective anti-inflammatory transcription factors, which is largely attributed to their inhibition of NFkB. GRs inhibit NFkB through direct interactions that prevent binding to DNA and indirect mechanisms, like increasing the transcription of proteins that prevent the nuclear translocation of NFkB. NFkB inhibits GRs through similar mechanisms , 38, 165Activation of GRs can cause a number of deleterious effects, such as reducing hippocampal volume , which cStress-induced inflammation affects neuronal activity in the brain. Within the brain, locus coeruleus activation increases noradrenergic neurotransmission, which can increase inflammatory processes. Peripheral cytokines can also influence brain activity through direct and indirect mechanisms. Cytokines can directly access the brain via humoral routes through circumventricular organs, blood–brain barriers with impaired integrity caused by stress, and/or specific cytokine transporters. Peripheral cytokines can also influence brain activity by modulating vagus nerve activity , 26, 114Most of what we know about the effects of norepinephrine-induced inflammation comes from pharmacological studies. The locus coruleus is the primary source of norepinephrine in the brain . In the Novel therapeutic strategies for treating stress-related disorders could target mechanisms by which stress induces inflammatory processes or the specific inflmamamtory processes changed by stress. Targeting specific cytokines, especially within specific cell types or tissues, might lead to efficacious treatments with minimal side effects. Targeting TNFα systemically has demonstrated considerable promise . Future The ultimate goal of understanding how inflammatory processes contribute to mental health is to develop novel treatments for stress-related mood disorders. This presents a considerable challenge as different individuals may have different pathologies driving inflammatory processes. For example, norepinephrine may be driving inflammation in some, whereas substance P may contribute to inflammation in others. A history of immune-related diseases may also complicate pathology. This challenge could potentially be overcome by using RNA sequencing to screen for changes in inflammatory transcripts. Transcriptional data could allow researchers to infer the signaling pathways that are driving inflammatory processes in stressed individuals. RNA sequencing technology is becoming more readily available and less expensive. Further, streamlined analysis pipelines are making it faster and easier to obtain meaningful results. This could help provide more personalized therapeutic strategies. Of course, this also has its own limitations as changes in transcription do not necessarily mean that changes in protein expression or function would be observed. Protein screens using multiplex enzyme-linked immunosorbent assays (ELISAs) might prove to be more useful, although they would not be able to screen as many targets as RNA sequencing would. Perhaps RNA sequencing of larger sample sizes scales could inform the development of more targeted and accurate multiplex ELISAs. Targeting differentially expressed proteins presents many of the same challenges as other brain disorders since the BBB limits the access of drugs to the brain. Targeting inflammatory cytokines in the periphery is more feasible, but their effects on mental health are more difficult to predict since not all of them directly contribute to the pathology of stress-related disorders.A comprehensive understanding of the mechanisms underlying stress-induced infalmamtory processes may lay the groundwork for more targeted therapeutic strategies in treating stress-related disorders. For example, identifying intracellular signaling pathways by which noreinephrine increases inflammation might allow for treatments that are more specific to stress-induced inflammation without affecting noradrenergic neurotransmission or aspects of the innate immune response. Understanding mechanisms contributing to stress-induced inflammation may also inform therapeutic strategies for disorders of the immune system. For example, understanding glucocorticoid resistance and the psychiatric history of a patient might inform treatment strategies or dosage because individuals diagnosed with depression are less responsive to glucocorticoids . AdrenerThis review examines the mechanisms by which stress affects inflammatory processes and how those inflammatory processes can alter behavior. Stress activates the HPA axis and sympathetic nervous system, which in turn activate anti-inflammatory GRs and pro-inflammatory NFkB, respectively. Stress-related mood disorders are characterized by glucocorticoid resistance and/or excess noradrenergic signaling, causing an imbalance that leads to increases in inflammatory processes. Preclinical work from our labs and others, as well as some human studies, has demonstrated that vulnerability to chronic stress is associated with inflammatory processes in the brain and periphery. These inflammatory processes contribute to anxiety- and depression-like behavior in rodents and depression severity scores in humans. Here, we review neuro-immune interactions and how they relate to pain circuitry as nociceptive signaling has an emotional component, which we believe should be thoughtfully considered in models of inflammatory effects on mental health. Additionally, a more comprehensive understanding of the specific cell types, circuits, and intracellular signaling mechanisms responsible for the inflammatory effects caused by norepinephrine is needed. In sum, this review aims to summarize our current understanding of how the immune and nervous systems respond to stress, communicate with one another, and regulate behavior. Understanding the pathology of stress-related mood disorders could lead to more personalized, efficacious treatments.RT, UK, LG, FH, NF, and BC performed literature searches and wrote the text. NF provided oversight on sections regarding pain. BC provided general oversight for this review. All authors contributed to the article and approved the submitted version.This work was funded in part by a Brain and Behavior Research Foundation (fka NARSAD) Young Investigator Award #29185, which was awarded to BC.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Emergency medical services (EMS) are a unique workforce providing 24/7 emergencycare across high-income countries (HICs) and low- and middle-income countries(LMICs). Although traditionally perceived as first responders to traumatic andmedical emergencies, EMS scope of practice has evolved to respond to thechanging needs of communities, including a growing demand for community-basedpalliative care. Public health provides a useful framework to conceptualisepalliative and end-of-life care in community-based settings. However, countrieslack public policy frameworks recognising the role EMS can play in initiatingpalliative approaches in the community, facilitating goals of care at end oflife and transporting patients to preferred care settings. This article aims toexplore the potential role of EMS in a public health palliative care approach ina critical discussion essay format by (1) discussing the utility of EMS within apublic health palliative care approach, (2) identifying the current barrierspreventing public health approaches to EMS palliative care provision and (3)outlining a way forward through priorities for future research, policy,education and practice. EMS facilitate equitable access, early provision, expertcare and efficacious integration of community-based palliative care. However,numerous structural, cultural and practice barriers exist, appearing ubiquitousacross both HICs and LMICs. A Public Health Palliative Care approach to EMSFramework highlights the opportunity for EMS to work as a linking asset to buildcapacity and capability to support palliative care in place; connect patients tohealth and community supports; integrate alternative pathways by engagingmultidisciplinary teams of care; and reduce avoidable hospital admissions byfacilitating home-based deaths. This article articulates a public healthapproach to EMS palliative and end-of-life care provision and offers apreliminary framework to illustrate the components of a potential implementationand policy strategy. However, as a result of global populations living longer and with morechronic progressive diseases, the EMS scope of practice has evolved to respond tothese changing needs of communities. Ageing populations and increasing preferences to die at home have resulted ina growing demand for community-based palliative care.Emergency medical services (EMS) are specifically staffed, designed and equipped forthe emergency care of patients across metropolitan, regional, rural and remotesettings 24 h a day, 7 days a week (24/7). EMS are traditionally perceived as firstresponders to traumatic and medical emergencies, typically motor vehicle accidentsor cardiac arrests.An approach that improves the quality of life for patients and their familieswho are facing problems associated with life-limiting illnesses, through theprevention and relief of suffering by means of early identification, correctassessment and treatment of pain and other problems, whether physical,psychosocial or spiritual.The World Health Organization (WHO) defines palliative care asEnd-of-life care (EoLC) typically refers to assessment, care and treatment ofpatients in their final 12 months prior to death. As a result, EMS have emerged as ‘gap-fillers’, providing palliative and EoLCto patients in community-based settings when other services are unavailable, aspalliative emergencies arise. This shifting practice of EMS is apparent across both high-income countries(HIC) and low- and middle-income countries (LMIC).712Specialist palliative care services are not able to fulfil the needs of thesepatients in isolation, particularly after hours.1315 recognisingthat health is determined by a range of social and structural factors impacting onequity of access to palliative care,17 while highlighting theintersecting role of health services and citizens in delivering holistic EoLC, andrecognising everyone has a role to play in EoLC.Public health provides a useful framework to conceptualise palliative and EoLC incommunity-based settings,20 However, internationally, countries lack public policyframeworks that acknowledge the unique role EMS can play in initiating palliativeapproaches in the community, facilitating goals of care at end of life andtransporting patients to preferred care settings. Furthermore, the WHO neglects to recognise the role of EMS in key policydocuments despite highlighting ‘palliative care requires a broad multidisciplinary approach’, in addition to ‘multisectoral policy and action to address broaderdeterminants of health’.Palliative care networks have made significant progress to integratemultidisciplinary teams into their provision of care, including emergencydepartments (EDs).25 However, in this discussion essay, we will argue for a broaderapproach – at a national and global level – which implements integrative policy tocompliment education and clinical practice guidelines. To address these gaps, thisarticle aims to explore the potential role of EMS in a public health palliative careapproach by (1) discussing the utility of EMS within a public health palliative careapproach, (2) identifying the current barriers preventing public health approachesto EMS palliative care provision and (3) outlining a way forward through prioritiesfor future research, policy, education and practice.Current attempts to integrate EMS with palliative care are predominately focussed onprotocols and training.EMS are uniquely positioned in healthcare systems as they provide a link betweencommunity-based patients and in-hospital settings. This position can be leveraged inthe provision of palliative care through EMS facilitating equitable access, earlyprovision, expert care and efficacious integration. EMS also offer significant adjunct in-home support to community-basedpalliative care patients during out-of-hours times when other palliative careservices are often unavailable.28EMS provide access to healthcare through their mobility and round the clockavailability. In addition to the provision of traditional emergency care, EMS candeliver palliative care to patients in community-based settings and transport thoserequiring further specialist care to alternative destinations beyond the ED,including in-patient palliative care units. living in regional, rural and remote areas; living with disability; LGBTQI+ identifying; First Nations identifying; culturally and linguistically diverse; and incarcerated. Targeted initiatives to broaden access to such groups to address theseinequities could be facilitated through the provision of EMS palliative carereaching diverse global communities. These groups are often picked up in crisissituations as a direct result of inequitable access.37Internationally, people of low socioeconomic status (SES) and those marginalised frommainstream society are particularly susceptible to experience barriers in receivingpalliative care in keeping with the disproportionate challenges they face accessingservices in general. Such marginalised and underserved groups may include, but arenot limited to, people who are homeless or at risk of homelessness; and are therefore well-positioned to initiate early palliative care at home. This potential benefit for patient comfort, early identification and reliefof suffering is significant. As many palliative patients wish to receive care in their homes and avoidtransportation to hospitals, with appropriate clinical support, EMS can providecommunity-based palliative care that ensures patient wishes and autonomy are respected.EMS may be the first point of medical contact for palliative care patients, A recent study implementing a specialist EMS palliative care programmeresulted in high patient and family satisfaction, and greater consumer recognitionof the compassion and skill of EMS personnel when providing palliative symptommanagement. In addition, the knowledge of the 24/7 availability of the EMS providersin this programme provided confidence and peace of mind for patients, their familiesand carers, facilitating early grief support and reducing avoidable hospital admissions.The early and timely provision of community-based palliative care has been shown topositively impact both patients and their conditions, improving patient and familyquality of life (QoL) satisfaction and confidence.43 Alarming conditions such as acute pain, dyspnoea, convulsionsand sudden loss of consciousness are well documented reasons for EMS attendance topalliative patients.45 These conditions, inter alia, may causesignificant distress for patients, their families and caregivers; however, they also represent areas of EMS expertise which can be readilyresolved. As out-of-hospital specialists, EMS are well trained and experienced inmanaging these emergencies in community-based settings. As such, EMS are well-equipped to attend to palliative care patients in thelikely event they deteriorate and require immediate care, especially when onlygeneralist palliative care capacity is required out-of-hours.As palliative care patients advance in age, EoLC emergencies are more likely, forwhich EMS are often called. However, the EMS discipline represents a field which is rarely involved informal palliative care partnerships, despite regularly interacting with thesepatients.47 Integrating EMS with other palliative care service providersoffers a range of compelling opportunities to enhance public health responses topalliative care. EMS could initiate palliative care to unidentified patients whowould benefit from this approach to care. In doing so, EMS personnel are in a uniqueposition to gather first-hand insight into patients’ social and structuraldeterminants of health, which may inform future palliative care planning andmanagement. EMS could also connect patients, their families and carers with otherrelevant community services, including social workers and bereavement groups,thereby activating integrated healthcare pathways. In this way, EMS has the opportunity to provide efficacious integrationthrough a ‘treat and refer’ function.Palliative care is, by its very nature, multidisciplinary.Based on these unique abilities of EMS and the resulting benefits to palliative careprovision, a public health approach to EMS palliative care is warranted. Targetedpublic health policy may assist in the integration of EMS with other healthcaresystems working within palliative care service provision. Interdisciplinarypartnerships could facilitate the delivery of early and home-based palliative care,respect of patient autonomy, improved patient and family QoL, increased patient andfamily satisfaction and confidence, decreased healthcare costs and enhancedfulfilment of community preferences to die at home.LMICs may particularly benefit from strengthening public health policy relating toEMS and palliative care system integration. The potential decreased healthcare costsconferred by integrating already existing systems  wouldrepresent an efficient use of scarce resources, especially when avoidable hospitaladmissions are significantly reduced in preference for community-based care. as illustrated by the case study vignette. These barriers, which appearubiquitous across both HICs and LMICs,45 may be divided into threecategories: structural, cultural and practice. We argue changes to public healthpolicy could assist in overcoming many of these barriers.Despite the aforementioned utility of integrating EMS and palliative care systemsthrough a public health policy approach, several common barriers exist that oftenresult in lamentable patient care, However, for patients at end of life, transportation is often undesired and inappropriate. Despite patient and family wishes often contradicting this trajectory, EMSregularly convey palliative patients to a medical facility, and due to a lack of alternate pathways, this almost invariably involves anED. Murphy-Jones and Timmons described patient transport as a default ‘safety net’for EMS providers when managing palliative patients. Where EMS providers deviate from standard practice, there is a perceived lackof legal support and fear of litigation.EMS systems are traditionally designed and perceived by consumers to provideemergency treatment and patient conveyance to tertiary facilities. Structural and individual inequities also influence a palliative care patientand their family and carers’ capacity to facilitate a home-based death. Literature suggests greater hospital use in the last year of life of patientsliving in more disadvantaged socioeconomic positions. As a result, EMS ought to be cognisant of these disparities and have theability to make holistic assessments when considering the need to transport apalliative care patient to hospital.However, family members may also call EMS during a palliative care emergency toprevent the dying process of their loved one, and advocate for a patient to be takento the hospital even if preferences and plans to die at home have been documented.55 Despite this intent, wherethese documents do exist, they tend to cause greater confusion for EMS providers asthere are no clear guidelines for their use and the validity of such documentationin emergency scenarios is questioned.56Medico-legal documentation represents a further challenge to EMS providerdecision-making in palliative situations. Advance directives (AD) and do notresuscitate (DNR) orders, for example, are designed to assist decision-making inthese scenarios. However, they are largely unavailable.EMS system rigidity and the fear of medico-legal repercussions act as significantstructural barriers preventing EMS personnel from challenging the traditionalexpectations of hospital-based care, and pursuing alternative pathways. EMS providers are trained to intervene, often invasively, in life-threateningsituations and convey their patients to a medical facility for definitive care. In this manner, EMS providers are predisposed to perform curativeinterventions with the aim of ‘saving lives’.55 As a result, the EMS cultureis death averse, clearly distinguished from the more holistic palliative approachprimarily concerned with the prevention and relief of suffering. Palliative therapeutic goals may, therefore, come into conflict with EMStherapeutic goals.58 Thus, when EMS providers are confronted with palliativepatients, their interventions may be inappropriate and even harmful.The typical focus of EMS involves immediate measures to preserve life or limb untildefinitive care is reached.et al. recommended first identifying ‘EMS-palliative care champions’ within serviceswho have a strong affinity and willingness to build capacity within services.Despite possible heterogeneity of EMS views and opinions, EMS systems have playedincreasingly prominent roles in the provision of community-based care. Within this model, there has been a greater recognition of the capacity andcapability of EMS to support palliative care in place, and facilitate alternativereferral pathways to other health providers when required.49Because of these disparities, some EMS systems and individual EMS personnel may notidentify palliative care as part of their role. To combat this cultural barrier,Lamba Structural and cultural barriers facing EMS and palliative care system integrationdirectly impact practice. In the case study vignette, the structural barriers ofcompulsory patient transport and lack of legal documentation, alongside the culturalbarrier of death adversity among EMS personnel, resulted in poor practice by the EMSsystem. Futile interventions were performed, and patient autonomy was ignored. Toovercome these barriers, EMS could have access to a 24/7 palliative care specialistvia telehealth, who could reassure the EMS personnel to take a palliative approachto care and provide the necessary medico-legal documentation to verify this courseof action. As a result, the EMS personnel could administer an opioid to relieve thedyspnoea, provide reassurance to the patient and their family, and leave them athome with follow-up referral to a community palliative care team during regularhours. As a result of this change in practice, a desirable outcome for the patient,their family and the broader healthcare system could be achieved. While several HICs with sufficient resources have developed specialist EMSpersonnel roles integrating the provision of palliative care , LMICs lack the necessary resources to develop these novel roles and requireindividualised approaches given their disparate contexts. Furthermore, not all EMSpersonnel fall within the same scope of practice. Those with generalist training maybe constrained in their ability to practice palliative care, such as a limited scopeto administer opioids, especially through the preferred subcutaneous route forpalliative patients. The out-of-hospital setting may further challenge EMS’ ability to practicepalliative care given the uncontrolled and unpredictable environment, oftenresulting in a dearth of information available to EMS personnel.46While structural and cultural barriers must be overcome to improve practice, uniquebarriers remain regarding the availability of resources, EMS scope of practice andcomplex nature of the community-based setting.Despite the advances made to connect multidisciplinary teams across palliative caresettings, too often the potential for EMS integration is missed. Throughout thisdiscourse, a prominent question has been raised: how can EMS better engage withcommunity networks and health/social services to deliver improved outcomes forpalliative care patients, families and carers, and empower EMS personnel toconfidently adopt palliative approaches to care? However, as a result of increasingly prevalent mental health emergencies inHIC communities,64 coupled with the de-institutionalisation of mental healthcareleading to a greater focus on person-centred community-based care, EMS and otherfirst responder services have adapted their attitudes and approach. Integratedmodels of mental health emergency first responder care are emerging across HICs,which place mental health workers in police or ambulance call centres, orco-response mobile crisis services alongside police officers and EMS personnel. Specialist mental health workers can provide expert assessment to patients atpoint of care, reducing the need to invoke involuntary detention on the patient andavoidable transportation to hospital for further assessment.In the past, mental health emergencies have also been perceived as beyond thetraditional scope of practice for EMS. The pilot programme in one Australian jurisdiction saw 90% of patientsassessed by the PACER team able to stay in the community, with only 12% of peoplerequiring transport to the ED – a significant decrease from 56% previously.Police, ambulance, clinician early response (PACER) is an Australian tri-responsemobile service which teams a mental health clinician, police officer and EMSpersonnel together in a first responder vehicle to attend mental health crisis inthe community. However, limitations to both models must be recognised, especially in LMICsand regional, rural and remote areas of HICs, where resources can be scarce.Given integrated models of care can have a significant impact on improving timelinessof care pathways and diversions from EDs, a palliative care co-response mobileservice could potentially better facilitate community preferences to die at home andengender stronger public health approaches to palliative care, if partnerships withcommunity networks were also pursued. Literature supports the notion that carebegins when the emergency number is dialled, highlighting opportunities forpalliative care specialists to also be integrated into EMS call centres.18 partnership framework todevelop a preliminary Public Health Palliative Care approach to Emergency MedicalServices Framework (Framework) proposal for consideration deration .This Framework aims to identify EMS as an asset capable of linking formal  and informal (community) networks of palliative care to produceequitable access for marginalised and underserved groups in both HICs and LMICs;early provision and referral; expert care and place-based assessment; andefficacious integration. The Framework recognises that structural, cultural andpractice barriers must be overcome, through the integration of health and socialservices with community networks, to produce desirable and sustainable outcomes. Asa result, a public health palliative care approach to EMS could facilitate capacityand capability to support palliative care in place; connect patients to health andcommunity supports; integrate alternative pathways; engage multidisciplinary teamsof care; reduce avoidable hospital admissions; and facilitate home-based deaths. Those exhibiting a particular aptitude or passion for palliative care needaccess to further opportunities to gain advanced practical training in palliativecare with specialists, allowing these EMS personnel to become champions within theirrespective service and contribute to the ongoing sustainability of palliative care expertise.To overcome the significant cultural barriers facing EMS in delivering palliativecare, clinician attitudes and perceptions regarding the role of EMS must firstevolve. Palliative care fundamentals ought to be imbued in education offerings toall EMS personnel, beginning at an undergraduate/student curriculum level andextending to ongoing mandated professional development training for established EMS personnel.Social attitudes to receiving palliative care help may be a barrier tobuilding collaborative communities, which has profound implications forimplementing public health approaches, such as compassionate communities. Tobe effective, any public health practice model must attempt to modify thesesocial norms. The goals of a public health approach should be to createsustainable community environments with the capacity to engage in end oflife discussion, support and practical care, whilst developing communitynorms that ensure citizens know about and can draw upon these assets when needed.Patients, families and carers’ attitudes and perceptions of the potential function ofEMS in community-based palliative care must also be addressed, given their importantrole in initiating EMS involvement in care with their call to emergency services.Previous studies that informed the development of the HELP framework highlighted: around death literacy and the role of EMS in palliative care provision. Deathliteracy is defined as ‘a set of knowledge and skills that make it possible to gainaccess to understand and act upon end-of-life and death care options’. EMS also have the unique opportunity to engage patients and their familiesand carers in palliative care health promotion, and sign-post locally providedhealth and community supports.Shifting societal attitudes to accept EMS as an asset of community-based palliativecare, beyond their traditional hospital conveyance role, will require a targetedbehaviour change campaignInvesting in the research and implementation of alternate referral pathways for EMScaring for palliative patients in the community must also be prioritised.Initiatives such as the PACER model could be adapted to a palliative care context;however, this would likely be resource intensive and only feasible in metropolitansettings of HICs. A pilot programme should first be conducted to investigate theefficacy of such a partnership, and pending evaluation success, this model of carecould be implemented in suitable settings with adequate funding allowing forsustainable provision. A recent study confirmed Australian EMS have a high level of intention to usea specialist palliative care telehealth service if it were made available to them.Other avenues to establish integrated models of community-based palliative care,harnessing the assets of health and social service workforces with communitynetworks, must also be developed and piloted. The COVID-19 pandemic has highlightedsignificant opportunities for integrating specialist support into otherwisegeographically inaccessible settings, and proven healthcare systems are adaptive to change.EMS chaplains can offer another avenue of integrated support for community-basedpalliative care patients and their families and carers. Chaplains can deliverreactive scene support to EMS personnel during palliative care call-outs, providingextended continuity of care and early bereavement to families and carers when thepatient dies, allowing EMS to reduce time on scene and be dispatched to other patients.Future research could investigate key gaps in the current literature, including thedifferences in context between LMICs and HICs; underserved populations’ access andusage of palliative care EMS; and patient, family and carer perspectives.Embedding a public health palliative care approach to EMS into health systems willultimately facilitate community preferences to die in place and avoidhospitalisation where appropriate: a goal all countries, regardless of their SES,are likely aspiring towards.A public health approach to palliative and EoLC acknowledges and facilitates thecontribution everyone can make in improving the experiences of seriously ill anddying people. The EMS sector, in particular, offers valuable resources and skillsdistinct from other services that positions them to provide expertise and support insituations that would otherwise go unmet. This article articulates a public healthapproach to EMS palliative and EoLC provision and offers a preliminary framework toillustrate the components of a potential implementation and policy strategy.