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Neuro‐immune interactions in health and disease: Insights from FENS‐Hertie 2022 Winter School
AbstractIn a great partnership, the Federation of European Neuroscience Societies (FENS) and the Hertie Foundation organized the FENS‐Hertie 2022 Winter School on ‘Neuro‐immune interactions in health and disease’. The school selected 27 PhD students and 13 postdoctoral fellows from 20 countries and involved 14 faculty members experts in the field. The Winter School focused on a rising field of research, the interactions between the nervous and both innate and adaptive immune systems under pathological and physiological conditions. A fine‐tuned neuro‐immune crosstalk is fundamental for healthy development, while disrupted neuro‐immune communication might play a role in neurodegeneration, neuroinflammation and aging. However, much is yet to be understood about the underlying mechanisms of these neuro‐immune interactions in the healthy brain and under pathological scenarios. In addition to new findings in this emerging field, novel methodologies and animal models were presented to foment research on neuro‐immunology. The FENS‐Hertie 2022 Winter School provided an insightful knowledge exchange between students and faculty focusing on the latest discoveries in the biology of neuro‐immune interactions while fostering great academic and professional opportunities for early‐career neuroscientists from around the world.
Leading in the development, standardised evaluation, and adoption of artificial intelligence in clinical practice: regional anaesthesia as an example.
A recent study by Suissa and colleagues explored the clinical relevance of a medical image segmentation metric (Dice metric) commonly used in the field of artificial intelligence (AI). They showed that pixel-wise agreement for physician identification of structures on ultrasound images is variable, and a relatively low Dice metric (0.34) correlated to a substantial agreement on subjective clinical assessment. We highlight the need to bring structure and clinical perspective to the evaluation of medical AI, which clinicians are best placed to direct.
Tumour irradiation combined with vascular-targeted photodynamic therapy enhances antitumour effects in pre-clinical prostate cancer
Abstract Background There is a need to improve the treatment of prostate cancer (PCa) and reduce treatment side effects. Vascular-targeted photodynamic therapy (VTP) is a focal therapy for low-risk low-volume localised PCa, which rapidly disrupts targeted tumour vessels. There is interest in expanding the use of VTP to higher-risk disease. Tumour vasculature is characterised by vessel immaturity, increased permeability, aberrant branching and inefficient flow. FRT alters the tumour microenvironment and promotes transient ‘vascular normalisation’. We hypothesised that multimodality therapy combining fractionated radiotherapy (FRT) and VTP could improve PCa tumour control compared against monotherapy with FRT or VTP. Methods We investigated whether sequential delivery of FRT followed by VTP 7 days later improves flank TRAMP-C1 PCa tumour allograft control compared to monotherapy with FRT or VTP. Results FRT induced ‘vascular normalisation’ changes in PCa flank tumour allografts, improving vascular function as demonstrated using dynamic contrast-enhanced magnetic resonance imaging. FRT followed by VTP significantly delayed tumour growth in flank PCa allograft pre-clinical models, compared with monotherapy with FRT or VTP, and improved overall survival. Conclusion Combining FRT and VTP may be a promising multimodal approach in PCa therapy. This provides proof-of-concept for this multimodality treatment to inform early phase clinical trials.
Two sample Mendelian Randomisation using an outcome from a multilevel model of disease progression.
Identifying factors that are causes of disease progression, especially in neurodegenerative diseases, is of considerable interest. Disease progression can be described as a trajectory of outcome over time-for example, a linear trajectory having both an intercept (severity at time zero) and a slope (rate of change). A technique for identifying causal relationships between one exposure and one outcome in observational data whilst avoiding bias due to confounding is two sample Mendelian Randomisation (2SMR). We consider a multivariate approach to 2SMR using a multilevel model for disease progression to estimate the causal effect an exposure has on the intercept and slope. We carry out a simulation study comparing a naïve univariate 2SMR approach to a multivariate 2SMR approach with one exposure that effects both the intercept and slope of an outcome that changes linearly with time since diagnosis. The simulation study results, across six different scenarios, for both approaches were similar with no evidence against a non-zero bias and appropriate coverage of the 95% confidence intervals (for intercept 93.4-96.2% and the slope 94.5-96.0%). The multivariate approach gives a better joint coverage of both the intercept and slope effects. We also apply our method to two Parkinson's cohorts to examine the effect body mass index has on disease progression. There was no strong evidence that BMI affects disease progression, however the confidence intervals for both intercept and slope were wide.
Transitioning from Subtyping to Precision Medicine in Parkinson's Disease: A Purpose-Driven Approach.
The International Parkinson and Movement Disorder Society (MDS) created a task force (TF) to provide a critical overview of the Parkinson's disease (PD) subtyping field and develop a guidance on future research in PD subtypes. Based on a literature review, we previously concluded that PD subtyping requires an ultimate alignment with principles of precision medicine, and consequently novel approaches were needed to describe heterogeneity at the individual patient level. In this manuscript, we present a novel purpose-driven framework for subtype research as a guidance to clinicians and researchers when proposing to develop, evaluate, or use PD subtypes. Using a formal consensus methodology, we determined that the key purposes of PD subtyping are: (1) to predict disease progression, for both the development of therapies (use in clinical trials) and prognosis counseling, (2) to predict response to treatments, and (3) to identify therapeutic targets for disease modification. For each purpose, we describe the desired product and the research required for its development. Given the current state of knowledge and data resources, we see purpose-driven subtyping as a pragmatic and necessary step on the way to precision medicine. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Supraglottic Airway Devices: Present State and Outlook for 2050.
Correct placement of supraglottic airway devices (SGDs) is crucial for patient safety and of prime concern of anesthesiologists who want to provide effective and efficient airway management to their patients undergoing surgery or procedures requiring anesthesia care. In the majority of cases, blind insertion of SGDs results in less-than-optimal anatomical and functional positioning of the airway devices. Malpositioning can cause clinical malfunction and result in interference with gas exchange, loss-of-airway, gastric inflation, and aspiration of gastric contents. A close match is needed between the shape and profile of SGDs and the laryngeal inlet. An adequate first seal (with the respiratory tract) and a good fit at the second seal of the distal cuff and the gastrointestinal tract are most desirable. Vision-guided insertion techniques are ideal and should be the way forward. This article recommends the use of third-generation vision-incorporated-video SGDs, which allow for direct visualization of the insertion process, corrective maneuvers, and, when necessary, insertion of a nasogastric tube (NGT) and/or endotracheal tube (ETT) intubation. A videoscope embedded within the SGD allows a visual check of the glottis opening and position of the epiglottis. This design affords the benefit of confirming and/or correcting a SGD's position in the midline and rotation in the sagittal plane. The first clinically available video laryngeal mask airways (VLMAs) and multiple prototypes are being tested and used in anesthesia. Existing VLMAs are still not perfect, and further improvements are recommended. Additional modifications in multicamera technology, to obtain a panoramic view of the SGD sitting correctly in the hypopharynx and to prove that correct sizes have been used, are in the process of production. Ultimately, any device inserted orally-SGD, ETT, NGT, temperature probe, transesophageal scope, neural integrity monitor (NIM) tubes-could benefit from correct vision-guided positioning. VLMAs also allow for automatic recording, which can be documented in clinical records of patients, and could be valuable during teaching and research, with potential value in case of legal defence (with an airway incident). If difficulties occur with the airway, documentation in the patient's file may help future anesthesiologists to better understand the real-time problems. Both manufacturers and designers of SGDs may learn from optimally positioned SGDs to improve the design of these airway devices.
Temporal lobe epilepsy in cats.
In recent years there has been increased attention to the proposed entity of feline temporal lobe epilepsy (TLE). Epileptic discharges in certain parts of the temporal lobe elicit very similar semiology, which justifies grouping these epilepsies under one name. Furthermore, feline TLE patients tend to have histopathological changes within the temporal lobe, usually in the hippocampus. The initial aetiology is likely to be different but may result in hippocampal necrosis and later hippocampal sclerosis. The aim of this article was not only to summarise the clinical features and the possible aetiology, but also being work to place TLE within the veterinary epilepsy classification. Epilepsies in cats, similar to dogs, are classified based on the aetiology into idiopathic epilepsy, structural epilepsy and unknown cause. TLE seems to be outside of this classification, as it is not an aetiologic category, but a syndrome, associated with a topographic affiliation to a certain anatomical brain structure. Magnetic resonance imaging, histopathologic aspects and current medical therapeutic considerations will be summarised, and emerging surgical options are discussed.
Autoimmune Encephalitis Misdiagnosis in Adults.
IMPORTANCE: Autoimmune encephalitis misdiagnosis can lead to harm. OBJECTIVE: To determine the diseases misdiagnosed as autoimmune encephalitis and potential reasons for misdiagnosis. DESIGN, SETTING, AND PARTICIPANTS: This retrospective multicenter study took place from January 1, 2014, to December 31, 2020, at autoimmune encephalitis subspecialty outpatient clinics including Mayo Clinic (n = 44), University of Oxford (n = 18), University of Texas Southwestern (n = 18), University of California, San Francisco (n = 17), University of Washington in St Louis (n = 6), and University of Utah (n = 4). Inclusion criteria were adults (age ≥18 years) with a prior autoimmune encephalitis diagnosis at a participating center or other medical facility and a subsequent alternative diagnosis at a participating center. A total of 393 patients were referred with an autoimmune encephalitis diagnosis, and of those, 286 patients with true autoimmune encephalitis were excluded. MAIN OUTCOMES AND MEASURES: Data were collected on clinical features, investigations, fulfillment of autoimmune encephalitis criteria, alternative diagnoses, potential contributors to misdiagnosis, and immunotherapy adverse reactions. RESULTS: A total of 107 patients were misdiagnosed with autoimmune encephalitis, and 77 (72%) did not fulfill diagnostic criteria for autoimmune encephalitis. The median (IQR) age was 48 (35.5-60.5) years and 65 (61%) were female. Correct diagnoses included functional neurologic disorder (27 [25%]), neurodegenerative disease (22 [20.5%]), primary psychiatric disease (19 [18%]), cognitive deficits from comorbidities (11 [10%]), cerebral neoplasm (10 [9.5%]), and other (18 [17%]). Onset was acute/subacute in 56 (52%) or insidious (>3 months) in 51 (48%). Magnetic resonance imaging of the brain was suggestive of encephalitis in 19 of 104 patients (18%) and cerebrospinal fluid (CSF) pleocytosis occurred in 16 of 84 patients (19%). Thyroid peroxidase antibodies were elevated in 24 of 62 patients (39%). Positive neural autoantibodies were more frequent in serum than CSF (48 of 105 [46%] vs 7 of 91 [8%]) and included 1 or more of GAD65 (n = 14), voltage-gated potassium channel complex (LGI1 and CASPR2 negative) (n = 10), N-methyl-d-aspartate receptor by cell-based assay only (n = 10; 6 negative in CSF), and other (n = 18). Adverse reactions from immunotherapies occurred in 17 of 84 patients (20%). Potential contributors to misdiagnosis included overinterpretation of positive serum antibodies (53 [50%]), misinterpretation of functional/psychiatric, or nonspecific cognitive dysfunction as encephalopathy (41 [38%]). CONCLUSIONS AND RELEVANCE: When evaluating for autoimmune encephalitis, a broad differential diagnosis should be considered and misdiagnosis occurs in many settings including at specialized centers. In this study, red flags suggesting alternative diagnoses included an insidious onset, positive nonspecific serum antibody, and failure to fulfill autoimmune encephalitis diagnostic criteria. Autoimmune encephalitis misdiagnosis leads to morbidity from unnecessary immunotherapies and delayed treatment of the correct diagnosis.
Distributional reinforcement learning in prefrontal cortex
AbstractThe prefrontal cortex is crucial for learning and decision-making. Classic reinforcement learning (RL) theories center on learning the expectation of potential rewarding outcomes and explain a wealth of neural data in the prefrontal cortex. Distributional RL, on the other hand, learns the full distribution of rewarding outcomes and better explains dopamine responses. In the present study, we show that distributional RL also better explains macaque anterior cingulate cortex neuronal responses, suggesting that it is a common mechanism for reward-guided learning.
Dynamic modulation of genomic enhancer elements in the suprachiasmatic nucleus, the site of the mammalian circadian clock
The mammalian suprachiasmatic nucleus (SCN), located in the ventral hypothalamus, synchronizes and maintains daily cellular and physiological rhythms across the body, in accordance with environmental and visceral cues. Consequently, the systematic regulation of spatiotemporal gene transcription in the SCN is vital for daily timekeeping. So far, the regulatory elements assisting circadian gene transcription have only been studied in peripheral tissues, lacking the critical neuronal dimension intrinsic to the role of the SCN as central brain pacemaker. By using histone-ChIP-seq, we identified SCN-enriched gene regulatory elements that associated with temporal gene expression. Based on tissue-specific H3K27ac and H3K4me3 marks, we successfully produced the first-ever SCN gene-regulatory map. We found that a large majority of SCN enhancers not only show robust 24-h rhythmic modulation in H3K27ac occupancy, peaking at distinct times of day, but also possess canonical E-box (CACGTG) motifs potentially influencing downstream cycling gene expression. To establish enhancer–gene relationships in the SCN, we conducted directional RNA-seq at six distinct times across the day and night, and studied the association between dynamically changing histone acetylation and gene transcript levels. About 35% of the cycling H3K27ac sites were found adjacent to rhythmic gene transcripts, often preceding the rise in mRNA levels. We also noted that enhancers encompass noncoding, actively transcribing enhancer RNAs (eRNAs) in the SCN, which in turn oscillate, along with cyclic histone acetylation, and correlate with rhythmic gene transcription. Taken together, these findings shed light on genome-wide pretranscriptional regulation operative in the central clock that confers its precise and robust oscillation necessary to orchestrate daily timekeeping in mammals.
DNA methylation changes induced by long and short photoperiods in Nasonia
Many organisms monitor the annual change in day length and use this information for the timing of their seasonal response. However, the molecular mechanisms underlying photoperiodic timing are largely unknown. The wasp Nasonia vitripennis is an emerging model organism that exhibits a strong photoperiodic response: Short autumnal days experienced by females lead to the induction of developmental arrest (diapause) in their progeny, allowing winter survival of the larvae. How female Nasonia control the developmental trajectory of their offspring is unclear. Here, we took advantage of the recent discovery that DNA methylation is pervasive in Nasonia and tested its role in photoperiodism. We used reduced representation bisulfite sequencing (RRBS) to profile DNA methylation in adult female wasps subjected to different photoperiods and identified substantial differential methylation at the single base level. We also show that knocking down DNA methyltransferase 1a (Dnmt1a), Dnmt3, or blocking DNA methylation pharmacologically, largely disrupts the photoperiodic diapause response of the wasps. To our knowledge, this is the first example for a role of DNA methylation in insect photoperiodic timing.
Ultrahigh frequencies of peripherally matured LGI1- and CASPR2-reactive B cells characterize the cerebrospinal fluid in autoimmune encephalitis
Intrathecal synthesis of central nervous system (CNS)-reactive autoantibodies is observed across patients with autoimmune encephalitis (AE), who show multiple residual neurobehavioral deficits and relapses despite immunotherapies. We leveraged two common forms of AE, mediated by leucine-rich glioma inactivated-1 (LGI1) and contactin-associated protein-like 2 (CASPR2) antibodies, as human models to comprehensively reconstruct and profile cerebrospinal fluid (CSF) B cell receptor (BCR) characteristics. We hypothesized that the resultant observations would both inform the observed therapeutic gap and determine the contribution of intrathecal maturation to pathogenic B cell lineages. From the CSF of three patients, 381 cognate-paired IgG BCRs were isolated by cell sorting and scRNA-seq, and 166 expressed as monoclonal antibodies (mAbs). Sixty-two percent of mAbs from singleton BCRs reacted with either LGI1 or CASPR2 and, strikingly, this rose to 100% of cells in clonal groups with ≥4 members. These autoantigen-reactivities were more concentrated within antibody-secreting cells (ASCs) versus B cells ( P < 0.0001), and both these cell types were more differentiated than LGI1- and CASPR2-unreactive counterparts. Despite greater differentiation, autoantigen-reactive cells had acquired few mutations intrathecally and showed minimal variation in autoantigen affinities within clonal expansions. Also, limited CSF T cell receptor clonality was observed. In contrast, a comparison of germline-encoded BCRs versus the founder intrathecal clone revealed marked gains in both affinity and mutational distances ( P = 0.004 and P < 0.0001, respectively). Taken together, in patients with LGI1 and CASPR2 antibody encephalitis, our results identify CSF as a compartment with a remarkably high frequency of clonally expanded autoantigen-reactive ASCs whose BCR maturity appears dominantly acquired outside the CNS.