How completely are randomized controlled trials of non-pharmacological interventions following concussion reported? A systematic review

Purpose:The study aimed to examine the reporting completeness of randomized controlled trials(RCTs)of non-pharmacological interventions following concussion.Methods:We searched MEDLINE,Embase,PsycInfo,CINAHL,and Web of Science up to May 2022.Two reviewers independently screened studies and assessed reporting completeness using the Template for Intervention Description and Replication(TIDieR),Consensus on Exercise Reporting Template(CERT),and international Consensus on Therapeutic Exercise aNd Training(i-CONTENT)checklists.Additional information was sought my study authors where reporting was incomplete.Risk of bias(ROB)was assessed with the Cochrane ROB-2 Tool.RCTs examining non-pharmacological interventions following concussion.Results:We included 89 RCTs(n=53 high ROB)examining 11 different interventions for concussion:sub-symptom threshold aerobic exercise,cervicovestibular therapy,physical/cognitive rest,vision therapy,education,psychotherapy,hyperbaric oxygen therapy,transcranial magnetic stimulation,blue light therapy,osteopathic manipulation,and head/neck cooling.Median scores were:TIDieR 9/12(75%;interquartile range(IQR)=5;range:5-12),CERT 17/19(89%;IQR=2;range:10-19),and i-CONTENT 6/7(86%;IQR=1;range:5-7).Percentage of studies completely reporting all items was TIDieR 35%(31/89),CERT 24%(5/21),and i-CONTENT 10%(2/21).Studies were more completely reported after publication of TIDieR(t_(87)=2.08;p=0.04)and CERT(t_(19)=2.72;p=0.01).Reporting completeness was not strongly associated with journal impact factor(TIDieR:rs=0.27;p=0.01;CERT:r_(s)=-0.44;p=0.06;i-CONTENT:r_(s)=-0.17;p=0.48)or ROB(TIDieR:rs=0.11;p=0.31;CERT:rs=0.04;p=0.86;i-CONTENT:rs=0.12;p=0.60).Conclusion:RCTs of non-pharmacological interventions following concussion demonstrate moderate to good reporting completeness,but are often missing key components,particularly modifications,motivational strategies,and qualified supervisor.Reporting completeness improved after TIDieR and CERT publication,but publication in highly cited journals and low ROB do not guarantee reporting completeness.

Focus on the gut-brain axis: multiple sclerosis, the intestinal barrier and the microbiome

The brain-gut axis serves as the bidirectional connection between the gut microbiome, the intestinal barrier and the immune system that might be relevant for the pathophysiology of inflammatory demyelinating diseases. People with multiple sclerosis have been shown to have an altered microbiome, increased intestinal permeability and changes in bile acid metabolism. Experimental evidence suggests that these changes can lead to profound alterations of peripheral and central nervous system immune regulation. Besides being of pathophysiological interest, the brain-gut axis could also open new avenues of therapeutic targets. Modification of the microbiome, the use of probiotics, fecal microbiota transplantation, supplementation with bile acids and intestinal barrier enhancers are all promising candidates. Hopefully, pre-clinical studies and clinical trials will soon yield significant results.

An orbitofrontal cortex to midbrain projection modulates neuropathic pain

Neuropathic pain is a long term and common pain disorder in clinics that is refractory to treatment,however,the neural substrates and underlying mechanisms are poorly understood.Using the com bination of neuronal mapping,optogenetics,chemogenetics,eletrophysiological recording,in vivo fiber photometry and behavioral testing,we previously identified a new neural circuit of BLA-mPFC-vIPAG and its key role in encoding and modulation of the spared nerve injury(SNI)-induced neuropathic pain..Here we report that the V M-vlOFC-vIPAG circuit modulates neuropathic pain and dissects the underlying mechanisms at cellular and circuitry level.

步歌在帕金森病康复治疗中的应用

帕金森病(Parkinson's disease,PD)是一种重要神经系统退行性疾病.据欧洲机构的最新统计,中国PD患者目前占世界首位[1]。虽然PD的治疗可以有多种药物选择,但是随着药物效果的逐渐减弱和各种不良反应的增加,PD在中晚期会伴有多种并发症及高于正常人群的死亡率.

细胞移植治疗脊髓损伤（英文）

Spinal cord injury can lead to severe motor,sensory and autonomic dysfunction.Currently,there is no effective treatment for the injured spinalcord.The transplantation of Schwann cells,neural stem cells or progenitor cells,olfactory ensheathing cells,oligodendrocyte precursor cells and mesenchymal stem cells has been investigated as potential therapies for spinal cord injury.However,little is known about the mechanisms through which these individual cell types promote repair and functional improvements.The five most commonly proposed mechanisms include neuroprotection,immunomodulation,axon regeneration,neuronal relay formation and myelin regeneration.A better understanding of the mechanisms whereby these cells promote functional improvements,as well as an appreciation of the obstacles in implementing these therapies and effectively modeling spinal cord injury,will be important to make cell transplantation a viable clinical option and may lead to the development of more targeted therapies.

Macrophage polarization in nerve injury： do Schwann cells play a role？

In response to peripheral nerve injury, the inflammatory response is almost entirely comprised of infiltrating macrophages. Macrophages are a highly plastic, heterogenic immune cell, playing an indispensable role in peripheral nerve injury, clearing debris and regulating the microenvironment to allow for efficient regeneration. There are several cells within the microenvironment that likely interact with macrophages to support their function – most notably the Schwann cell, the glial cell of the peripheral nervous system. Schwann cells express several ligands that are known to interact with receptors expressed by macrophages, yet the effects of Schwann cells in regulating macrophage phenotype remains largely unexplored. This review discusses macrophages in peripheral nerve injury and how Schwann cells may regulate their behavior.

Astrocyte in prion disease: a double-edged sword

Prion diseases are infectious protein misfolding disorders of the central nervous system that result from misfolding of the cellular prion protein(PrPC)into the pathologic isoform PrPSc.Pathologic hallmarks of prion disease are depositions of pathological prion protein PrPSc,neuronal loss,spongiform degeneration and astrogliosis in the brain.Prion diseases affect human and animals,there is no effective therapy,and they invariably remain fatal.For a long time,neuronal loss was considered the sole reason for neurodegeneration in prion pathogenesis,and the contribution of non-neuronal cells like microglia and astrocytes was considered less important.Recent evidence suggests that neurodegeneration during prion pathogenesis is a consequence of a complex interplay between neuronal and non-neuronal cells in the brain,but the exact role of these non-neuronal cells during prion pathology is still elusive.Astrocytes are non-neuronal cells that regulate brain homeostasis under physiological conditions.However,astrocytes can deposit PrPSc aggregates and propagate prions in prion-infected brains.Additionally,sub-populations of reactive astrocytes that include neurotrophic and neurotoxic species have been identified,differentially expressed in the brain during prion infection.Revealing the exact role of astrocytes in prion disease is hampered by the lack of in vitro models of prion-infected astrocytes.Recently,we established a murine astrocyte cell line persistently infected with mouse-adapted prions,and showed how such astrocytes differentially process various prion strains.Considering the complexity of the role of astrocytes in prion pathogenesis,we need more in vitro and in vivo models for exploring the contribution of sub-populations of reactive astrocytes,their differential regulation of signaling cascades,and the interaction with neurons and microglia during prion pathogenesis.This will help to establish novel in vivo models and define new therapeutic targets against prion diseases.In this review,we will discuss the complex role of astrocytes in prion disease,the existing experimental resources,the challenges to analyze the contribution of astrocytes in prion disease pathogenesis,and future strategies to improve the understanding of their role in prion disease.

应激诱导下星形胶质细胞的结构和功能修饰——进一步提示胶质细胞对应激的中枢反应

有机体的应激反应需要多个大脑区域的激活。这可能对突触传递和可塑性长期有益的影响。最近的证据证明,除神经元外,神经胶质细胞也参与调节应激的中枢反应。重复的或不受控制的应激与多种神经精神病症的出现密切相关。情绪和应激障碍(如严重抑郁症)状态下神经胶质细胞功能障碍在人类研究中一直被观察到,而有趣的是,应激的动物模型重现了与人类状况相当的神经胶质细胞异常,验证了啮齿动物模型在应激障碍研究中的可用性。在这篇综述中,我们将关注胶质细胞家族中的星形胶质细胞,并总结迄今为止将星形胶质细胞与可能的应激相关疾病联系起来的证据。

Towards a Theoretical Framework of Autonomous Systems Underpinned by Intelligence and Systems Sciences

Autonomous systems are an emerging AI technology functioning without human intervention underpinned by the latest advances in intelligence,cognition,computer,and systems sciences.This paper explores the intelligent and mathematical foundations of autonomous systems.It focuses on structural and behavioral properties that constitute the intelligent power of autonomous systems.It explains how system intelligence aggregates from reflexive,imperative,adaptive intelligence to autonomous and cognitive intelligence.A hierarchical intelligence model(HIM)is introduced to elaborate the evolution of human and system intelligence as an inductive process.The properties of system autonomy are formally analyzed towards a wide range of applications in computational intelligence and systems engineering.Emerging paradigms of autonomous systems including brain-inspired systems,cognitive robots,and autonomous knowledge learning systems are described.Advances in autonomous systems will pave a way towards highly intelligent machines for augmenting human capabilities.

Peptide aptamer-mediated modulation of prion protein α-cleavage as treatment strategy for prion and other neurodegenerative diseases

Despite intensive research,most neurodegenerative diseases cannot be cured and for some of them no treatment is available to increase survival or quality of life.Among the latter are prion diseases,fatal and transmissible neurodegenerative diseases of humans and other animals.

Development and pilot implementation of a patient-oriented discharge summary for critically Ill patients

BACKGROUND Patients leaving the intensive care unit(ICU)often experience gaps in care due to deficiencies in discharge communication,leaving them vulnerable to increased stress,adverse events,readmission to ICU,and death.To facilitate discharge communication,written summaries have been implemented to provide patients and their families with information on medications,activity and diet restrictions,follow-up appointments,symptoms to expect,and who to call if there are questions.While written discharge summaries for patients and their families are utilized frequently in surgical,rehabilitation,and pediatric settings,few have been utilized in ICU settings.AIM To develop an ICU specific patient-oriented discharge summary tool(PODS-ICU),and pilot test the tool to determine acceptability and feasibility.METHODS Patient-partners(i.e.,individuals with lived experience as an ICU patient or family member of an ICU patient),ICU clinicians(i.e.,physicians,nurses),and researchers met to discuss ICU patients’specific informational needs and design the PODS-ICU through several cycles of discussion and iterative revisions.Research team nurses piloted the PODS-ICU with patient and family participants in two ICUs in Calgary,Canada.Follow-up surveys on the PODS-ICU and its impact on discharge were administered to patients,family participants,and ICU nurses.RESULTS Most participants felt that their discharge from the ICU was good or better(n=13;87.0%),and some(n=9;60.0%)participants reported a good understanding of why the patient was in ICU.Most participants(n=12;80.0%)reported that they understood ICU events and impacts on the patient’s health.While many patients and family participants indicated the PODS-ICU was informative and useful,ICU nurses reported that the PODS-ICU was“not reasonable”in their daily clinical workflow due to“time constraint”.CONCLUSION The PODS-ICU tool provides patients and their families with essential information as they discharge from the ICU.This tool has the potential to engage and empower patients and their families in ensuring continuity of care beyond ICU discharge.However,the PODS-ICU requires pairing with earlier discharge practices and integration with electronic clinical information systems to fit better into the clinical workflow for ICU nurses.Further refinement and testing of the PODS-ICU tool in diverse critical care settings is needed to better assess its feasibility and its effects on patient health outcomes.

Enhanced liver X receptor signalling reduces brain injury and promotes tissue regeneration following experimental intracerebral haemorrhage:roles of microglia/macrophages

background Inflammation-exacerbated secondary brain injury and limited tissue regeneration are barriers to favourable prognosis after intracerebral haemorrhage(ICH).As a regulator of inflammation and lipid metabolism,Liver X receptor(LXR)has the potential to alter microglia/macrophage(M/M)phenotype,and assist tissue repair by promoting cholesterol efflux and recycling from phagocytes.To support potential clinical translation,the benefits of enhanced LXR signalling are examined in experimental ICH.Methods Collagenase-induced ICH mice were treated with the LXR agonist GW3965 or vehicle.Behavioural tests were conducted at multiple time points.Lesion and haematoma volume,and other brain parameters were assessed using multimodal MRI with T2-weighted,diffusion tensor imaging and dynamic contrast-enhanced MRI sequences.The fixed brain cryosections were stained and confocal microscopy was applied to detect LXR downstream genes,M/M phenotype,lipid/cholesterol-laden phagocytes,oligodendrocyte lineage cells and neural stem cells.Western blot and real-time qPCR were also used.CX3CR1^(CreER):Rosa26^(iDTR) mice were employed for M/M-depletion experiments.results GW3965 treatment reduced lesion volume and white matter injury,and promoted haematoma clearance.Treated mice upregulated LXR downstream genes including ABCA1 and Apolipoprotein E,and had reduced density of M/M that apparently shifted from proinflammatory interleukin-1β+to Arginase1+CD206+regulatory phenotype.Fewer cholesterol crystal or myelin debris-laden phagocytes were observed in GW3965 mice.LXR activation increased the number of Olig2+PDGFRα+precursors and Olig2+CC1+mature oligodendrocytes in perihaematomal regions,and elevated SOX2+or nestin+neural stem cells in lesion and subventricular zone.MRI results supported better lesion recovery by GW3965,and this was corroborated by return to pre-ICH values of functional rotarod activity.The therapeutic effects of GW3965 were abrogated by M/M depletion in CX3CR1^(CreER):Rosa26^(iDTR) mice.Conclusions LXR agonism using GW3965 reduced brain injury,promoted beneficial properties of M/M and facilitated tissue repair correspondent with enhanced cholesterol recycling.

Ion Channel Dysregulation Following Intracerebral Hemorrhage

Injury to the brain after intracerebral hemorrhage(ICH)results from numerous complex cellular mechanisms.At present,effective therapy for ICH is limited and a better understanding of the mechanisms of brain injury is necessary to improve prognosis.There is increasing evidence that ion channel dysregulation occurs at multiple stages in primary and secondary brain injury following ICH.Ion channels such as TWIK-related K+channel 1,sulfonylurea 1 transient receptor potential melastatin 4 and glutamate-gated channels affect ion homeostasis in ICH.They in turn participate in the formation of brain edema,disruption of the blood-brain barrier,and the generation of neurotoxicity.In this review,we summarize the interaction between ions and ion channels,the effects of ion channel dysregulation,and we discuss some therapeutics based on ion-channel modulation following ICH.

Epitranscriptomic Regulation of NMDA Receptors Rears its Ugly Head in Chemotherapy-Induced Neuropathic Pain

A number of different cancer chemotherapy agents such as cisplatin,oxaliplatin,and paclitaxel can lead to nerve damage,thereby giving rise to neuropathic pain states that present with mechanical and cold allodynia[1].Although these pain conditions often resolve after completion of the chemotherapy,a significant portion of patients exhibit longlasting pain that can persist longer than 12 months with a negative impact on the quality of life of affected individuals[1].

Lesion-symptom mapping with NIHSS sub-scores in ischemic stroke patients

Background Lesion-symptom mapping(LSM)is a statistical technique to investigate the population-specific relationship between structural integrity and post-stroke clinical outcome.In clinical practice,patients are commonly evaluated using the National Institutes of Health Stroke Scale(NIHSS),an 11-domain clinical score to quantitate neurological deficits due to stroke.So far,LSM studies have mostly used the total NIHSS score for analysis,which might not uncover subtle structure–function relationships associated with the specific sub-domains of the NIHSS evaluation.Thus,the aim of this work was to investigate the feasibility to perform LSM analyses with sub-score information to reveal category-specific structure–function relationships that a total score may not reveal.Methods Employing a multivariate technique,LSM analyses were conducted using a sample of 180 patients with NIHSS assessment at 48-hour post-stroke from the ESCAPE trial.The NIHSS domains were grouped into six categories using two schemes.LSM was conducted for each category of the two groupings and the total NIHSS score.Results Sub-score LSMs not only identify most of the brain regions that are identified as critical by the total NIHSS score but also reveal additional brain regions critical to each function category of the NIHSS assessment without requiring extensive,specialised assessments.Conclusion These findings show that widely available sub-scores of clinical outcome assessments can be used to investigate more specific structure–function relationships,which may improve predictive modelling of stroke outcomes in the context of modern clinical stroke assessments and neuroimaging.

Intracerebral haemorrhage: from clinical settings to animal models

Spontaneous intracerebral haemorrhage(ICH)is a devastating type of stroke with high mortality and morbidity and for which no effective treatments are available to date.Much experimental and clinical research have been performed to explore its mechanisms regard the subsequent inflammatory cascade and to seek the potential therapeutic strategies.The aim of this review is to discuss insights from clinical settings that have led to the development of numerous animal models of ICH.Some of the current and future challenges for clinicians to understand ICH are also surveyed.

Associations of AT(N) biomarkers with neuropsychiatric symptoms in prechnical Alzheimer’s disease and cognitively unimpaired individuals

The development of in vivo biomarkers of Alzheimer's disease(AD)has advanced the diagnosis of AD from a clinical syndrome to a biological construct.The preclinical stage of AD continuum is defined by the identification of AD biomarkers crossing the pathological threshold in cognitively unimpaired individuals.While neuropsychiatric symptoms(NPS)are non-cognitive symptoms that are increasingly recognized as early manifestations of AD,the associations of NPS with AD pathophysiology in preclinical AD remain unclear.Here,we review the associations between NPS and AD biomarkers amyloid-(3(Aβ),tau and neurodegeneration in preclinical AD and cognitivelyunimpaired individuals in 19 eligible English-language publications(8 cross-sectional studies,10 longitudinal,1 both cross-sectional and longitudinal).The cross-sectional studies have consistently shown that NPS,particularly depressive and anxiety symptoms,are associated with higher Aβ.The longitudinal studies have suggested that greater NPS are associated with higher Aβ and cognitive decline in cognitively unimpaired subjects over time.However,most of the studies have either cross-sectionally or longitudinally shown no association between NPS and tau pathology.For the association of NPS and neurodegeneration,two studies have shown that the cerebrospinal fluid total-tau is linked to longitudinal increase in NPS and that the NPS may predict longitudinal metabolic decline in preclinical AD,respectively.However,evidence for the association between atrophy and NPS in preclinical AD is less consistent.Therefore,future longitudinal studies with well-designed methodologies and NPS measurements are required not only to determine the relationship among AT(N)biomarkers,NPS and cognitive decline,but also to elucidate the contribution of comorbid pathology to preclinical AD.

Outcomes of Medicare beneficiaries hospitalised with transient ischaemic attack and stratification using the ABCD^(2) score

Background Long-term outcomes for Medicare beneficiaries hospitalised with transient ischaemic attack(TIA)and role of ABCD^(2) score in identifying high-risk individuals are not studied.Methods We identified 40825 Medicare beneficiaries hospitalised from 2011 to 2014 for a TIA to a Get With The Guidelines(GWTG)-Stroke hospital and classified them using ABCD^(2)s of mortality and rehospitalisation(all-cause,ischaemic stroke,haemorrhagic stroke,myocardial infarction,and gastrointestinal and intracranial haemorrhage)for high-risk versus low-risk groups adjusted for patient and hospital characteristics.Results Of the 40825 patients,35118(86%)were high risk(ABCD^(2)≥4)and 5707(14%)were low risk(ABCD^(2)=0-3).Overall rate of mortality during 1-year follow-up after hospital discharge for the index TIA was 11.7%,44.3% were rehospitalised for any reason and 3.6%were readmitted due to stroke.Patients with ABCD^(2) score≥4 had higher mortality at 1 year than not(adjusted HR 1.18,95%CI 1.07 to 1.30).Adjusted risks for ischaemic stroke,all-cause readmission and mortality/all-cause readmission at 1 year were also significantly higher for patients with ABCD^(2) score≥4 vs 0-3.In contrast,haemorrhagic stroke,myocardial infarction,gastrointestinal bleeding and intracranial haemorrhage risk were not significantly different by ABCD^(2) score.Conclusions This study validates the use of ABCD^(2) score for long-term risk assessment after TIA in patients aged 65 years and older.Attentive efforts for community-based follow-up care after TIA are needed for ongoing prevention in Medicare beneficiaries who were hospitalised for TIA.

大多数心房颤动患者在卒中发病前未接受预防性抗凝治疗

业已证实，抗栓治疗能显著降低心房颤动（atrial fibrillation，AF）患者的卒中风险，但在现实生活中AF患者的抗栓治疗率显著不足。因此，美国北卡罗莱那州杜克临床研究所的Xian等在既往有AF史的急性缺血性卒中患者中进行了一项回顾性研究，旨在检测卒中发病前未按照指南推荐接受适当抗栓治疗的患者比例，同时探讨先前接受抗栓治疗与卒中严重程度和院内转归的联系。

Profiling Chromatin Accessibility at Single-cell Resolution

How distinct transcriptional programs are enacted to generate cellular heterogeneity and plasticity,and enable complex fate decisions are important open questions.One key regulator is the cell’s epigenome state that drives distinct transcriptional programs by regulating chromatin accessibility.Genome-wide chromatin accessibility measurements can impart insights into regulatory sequences(in)accessible to DNA-binding proteins at a single-cell resolution.This review outlines molecular methods and bioinformatic tools for capturing cell-to-cell chromatin variation using single-cell assay for transposase-accessible chromatin using sequencing(scATAC-seq)in a scalable fashion.It also covers joint profiling of chromatin with transcriptome/proteome measurements,computational strategies to integrate multi-omic measurements,and predictive bioinformatic tools to infer chromatin accessibility from single-cell transcriptomic datasets.Methodological refinements that increase power for cell discovery through robust chromatin coverage and integrate measurements from multiple modalities will further expand our understanding of gene regulation during homeostasis and disease.