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Epilepsy is a neurological disease characterised by recurrent seizures with complex aetiology. Temporal lobe epilepsy, the most common form in adults, can be acquired following brain insults including trauma, stroke, infection or sustained status epilepticus. The mechanisms that give rise to the formation and maintenance of hyperexcitable networks following acquired insults remain unknown, yet an extensive body of literature points towards persistent gene and epigenomic dysregulation as a potential mediator of this dysfunction. While much is known about the function of specific classes of epigenetic regulators (writers and erasers) in epilepsy, much less is known about the enzymes, which read the epigenome and modulate gene expression accordingly. Here, we explore the potential role for the epigenetic reader bromodomain and extra-terminal domain (BET) proteins in epilepsy. Using the intra-amygdala kainic acid model of temporal lobe epilepsy, we initially identified widespread dysregulation of important epigenetic regulators including EZH2 and REST as well as altered BRD4 expression in chronically epileptic mice. BRD4 activity was also notably affected by epilepsy-provoking insults as seen by elevated binding to and transcriptional regulation of the immediate early gene Fos. Despite influencing early aspects of epileptogenesis, blocking BET protein activity with JQ1 had no overt effects on epilepsy development in mice but did alter glial reactivity and influence gene expression patterns, promoting various neurotransmitter signalling mechanisms and inflammatory pathways in the hippocampus. Together, these results confirm that epigenetic reader activity is affected by epilepsy-provoking brain insults and that BET activity may exert cell-specific actions on inflammation in epilepsy., (© 2024 The Author(s). European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Application of 'omics' technology, and advances in in vitro methods for studying the growth of Fasciola hepatica, have highlighted the central role of migrating neoblasts in driving forward development and differentiation towards the adult-like form. Neoblast populations present molecular heterogeneity, morphological variation and changes associated with recruitment of these stem cells into their final tissue locations. However, terminal differentiation towards function, has received much less attention than has been the case for the free-living Platyhelminths. An actively replicating neoblast population, comprising cells with heterochromatic nuclei consistent with regulation of gene expression, has been identified in the parenchyma of juvenile Fasciola gigantica migrating in the liver of experimentally infected mice. In some of these cells, early cytoplasmic differentiation towards myocyte function was noted. Neoblasts have also been identified close to, and incorporated in, the subtegumental zone, the gastrodermis and the excretory ducts. In these locations, progressive morphological differentiation towards terminal function has been described. This includes the appearance of specific progenitors of type-1, type-2 and type-3 tegumental cells, the latter possibly contributing to tegumental spine development. 'Cryptic' surface molecular differentiation is postulated to account for recognition and 'docking' of migrating neoblasts with their final site for terminal differentiation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Objective: The coronavirus disease-2019 pandemic has facilitated the emergence of telerehabilitation, but it is unclear which patients are most likely to respond to physical therapy provided this way. The purpose of this study was to examine the relationship between individual patient factors and substantial clinical benefit from telerehabilitation among a cohort of patients with chronic low back pain (LBP)., Methods: This is a secondary analysis of data collected during a prospective longitudinal cohort study. Patients with chronic LBP (N = 98) were provided with a standardized physical therapy protocol adapted for telerehabilitation. We examined the relationship between patient factors and substantial clinical benefit with telerehabilitation, defined as a ≥50% improvement in disability at 10 weeks, measured using the Oswestry Disability Index., Results: Sixteen (16.3%) patients reported a substantial clinical benefit from telerehabilitation. Patients reporting substantial clinical benefit from telerehabilitation had lower initial pain intensity, lower psychosocial risk per the STarT Back Screening Tool, higher levels of pain self-efficacy, and reported higher therapeutic alliance with their physical therapist compared to other patients., Conclusion: Patients with lower psychosocial risk and higher pain-self efficacy experienced substantial clinical benefit from telerehabilitation for chronic LBP more often than other patients in our cohort. Therapeutic alliance was higher among patients who experienced a substantial clinical benefit compared to those who did not., Impact: This study indicates that psychosocial factors play an important role in the outcomes of patients receiving telerehabilitation for chronic LBP. Baseline psychosocial screening may serve as a method for identifying patients likely to benefit from this approach., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Physical Therapy Association. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

MicroRNAs have emerged as important regulators of the gene expression landscape in temporal lobe epilepsy. The mechanisms that control microRNA levels and influence target choice remain, however, poorly understood. RNA editing is a post-transcriptional mechanism mediated by the adenosine acting on RNA (ADAR) family of proteins that introduces base modification that diversifies the gene expression landscape. RNA editing has been studied for the mRNA landscape but the extent to which microRNA editing occurs in human temporal lobe epilepsy is unknown. Here, we used small RNA-sequencing data to characterize the identity and extent of microRNA editing in human temporal lobe epilepsy brain samples. This detected low-to-high editing in over 40 of the identified microRNAs. Among microRNA exhibiting the highest editing was miR-376a-3p, which was edited in the seed region and this was predicted to significantly change the target pool. The edited form was expressed at lower levels in human temporal lobe epilepsy samples. We modelled the shift in editing levels of miR-376a-3p in human-induced pluripotent stem cell-derived neurons. Reducing levels of the edited form of miR-376a-3p using antisense oligonucleotides resulted in extensive gene expression changes, including upregulation of mitochondrial and metabolism-associated pathways. Together, these results show that differential editing of microRNAs may re-direct targeting and result in altered functions relevant to the pathophysiology of temporal lobe epilepsy and perhaps other disorders of neuronal hyperexcitability., Competing Interests: K.L.E.H., J.C.K. and D.C.H. declare an invention under assessment for patent filing by RCSI. All other authors declare no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: Posttranscriptional mechanisms are increasingly recognized as important contributors to the formation of hyperexcitable networks in epilepsy. Messenger RNA (mRNA) polyadenylation is a key regulatory mechanism governing protein expression by enhancing mRNA stability and translation. Previous studies have shown large-scale changes in mRNA polyadenylation in the hippocampus of mice during epilepsy development. The cytoplasmic polyadenylation element-binding protein CPEB4 was found to drive epilepsy-induced poly(A) tail changes, and mice lacking CPEB4 develop a more severe seizure and epilepsy phenotype. The mechanisms controlling CPEB4 function and the downstream pathways that influence the recurrence of spontaneous seizures in epilepsy remain poorly understood., Methods: Status epilepticus was induced in wild-type and CPEB4-deficient male mice via an intra-amygdala microinjection of kainic acid. CLOCK binding to the CPEB4 promoter was analyzed via chromatin immunoprecipitation assay and melatonin levels via high-performance liquid chromatography in plasma., Results: Here, we show increased binding of CLOCK to recognition sites in the CPEB4 promoter region during status epilepticus in mice and increased Cpeb4 mRNA levels in N2A cells overexpressing CLOCK. Bioinformatic analysis of CPEB4-dependent genes undergoing changes in their poly(A) tail during epilepsy found that genes involved in the regulation of circadian rhythms are particularly enriched. Clock transcripts displayed a longer poly(A) tail length in the hippocampus of mice post-status epilepticus and during epilepsy. Moreover, CLOCK expression was increased in the hippocampus in mice post-status epilepticus and during epilepsy, and in resected hippocampus and cortex of patients with drug-resistant temporal lobe epilepsy. Furthermore, CPEB4 is required for CLOCK expression after status epilepticus, with lower levels in CPEB4-deficient compared to wild-type mice. Last, CPEB4-deficient mice showed altered circadian function, including altered melatonin blood levels and altered clustering of spontaneous seizures during the day., Significance: Our results reveal a new positive transcriptional-translational feedback loop involving CPEB4 and CLOCK, which may contribute to the regulation of the sleep-wake cycle during epilepsy., (© 2023 International League Against Epilepsy.)

The diagnosis of epilepsy is complex and challenging and would benefit from the availability of molecular biomarkers, ideally measurable in a biofluid such as blood. Experimental and human epilepsy are associated with altered brain and blood levels of various microRNAs (miRNAs). Evidence is lacking, however, as to whether any of the circulating pool of miRNAs originates from the brain. To explore the link between circulating miRNAs and the pathophysiology of epilepsy, we first sequenced argonaute 2 (Ago2)-bound miRNAs in plasma samples collected from mice subject to status epilepticus induced by intraamygdala microinjection of kainic acid. This identified time-dependent changes in plasma levels of miRNAs with known neuronal and microglial-cell origins. To explore whether the circulating miRNAs had originated from the brain, we generated mice expressing FLAG-Ago2 in neurons or microglia using tamoxifen-inducible Thy1 or Cx3cr1 promoters, respectively. FLAG immunoprecipitates from the plasma of these mice after seizures contained miRNAs, including let-7i-5p and miR-19b-3p. Taken together, these studies confirm that a portion of the circulating pool of miRNAs in experimental epilepsy originates from the brain, increasing support for miRNAs as mechanistic biomarkers of epilepsy., Competing Interests: YY and MV were employed by Omiics ApS. The remaining 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., (Copyright © 2023 Brindley, Heiland, Mooney, Diviney, Mamad, Hill, Yan, Venø, Reschke, Batool, Langa, Sanz-Rodriguez, Heller, Morris, Conboy, Kjems, Brennan and Henshall.)

Objective: The purpose of this study was to determine the proportion of patients with low back pain who achieved clinical improvement in disability within 3 or 6 physical therapy visits, identify factors that predicted improvement, and predict the probability of improvement by the third and sixth visits., Methods: This retrospective, observational study looked at patients (N = 6523) who completed a numeric pain scale and Modified Low Back Disability Questionnaire (MDQ) at every visit. Four prediction models were developed: 30% improvement by visit 3 and by visit 6 and 50% improvement by visit 3 and by visit 6. A logistic regression model was fit to predict patients' improvement in disability using the MDQ. Predictive models used age, disability scores, sex, symptom duration, and payer type as factors. Receiver operating characteristic curves and area under the curve were computed for the models. Nomograms illustrate the relative impacts of the predictor variables., Results: Disability improved 30% in 42.7% of patients by visit 3 and 49% by visit 6. Disability improved 50% in 26% of patients by visit 3 and 32.9% by visit 6. First visit score (MDQ1) was strongest factor to predict 30% improvement by visit 3. The visit 3 score (MDQ3) was strongest factor to predict a 30% or 50% improvement by visit 6. The combination of MDQ1 and MDQ3 scores was strongest overall predictive factor for visit 6. The area under the curve values for models using only the MDQ1 and MDQ3 scores to predict 30% or 50% improvement by the sixth visit were 0.84 and 0.85, respectively, representing excellent overall diagnostic accuracy of the prediction models., Conclusion: Excellent discrimination to predict patients' significant clinical improvement by visit 6 using 2 outcome scores was demonstrated. Gathering outcomes routinely enhances assessment of prognosis and clinical decision making., Impact: Understanding prognosis of clinical improvement supports physical therapists' contribution to value-based care., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Physical Therapy Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: We assessed whether race or ethnicity was associated with the incidence of high-impact chronic low back pain (cLBP) among adults consulting a primary care provider for acute low back pain (aLBP)., Methods: In this secondary analysis of a prospective cohort study, patients with aLBP were identified through screening at seventy-seven primary care practices from four geographic regions. Incidence of high-impact cLBP was defined as the subset of patients with cLBP and at least moderate disability on Oswestry Disability Index [ODI >30]) at 6 months. General linear mixed models provided adjusted estimates of association between race/ethnicity and high-impact cLBP., Results: We identified 9,088 patients with aLBP (81.3% White; 14.3% Black; 4.4% Hispanic). Black/Hispanic patients compared to White patients, were younger and more likely to be female, obese, have Medicaid insurance, worse disability on ODI, and were at higher risk of persistent disability on STarT Back Tool (all P < .0001). At 6 months, more Black and Hispanic patients reported high-impact cLBP (30% and 25%, respectively) compared to White patients (15%, P < .0001, n = 5,035). After adjusting for measured differences in socioeconomic and back-related risk factors, compared to White patients, the increased odds of high-impact cLBP remained statistically significant for Black but not Hispanic patients (adjusted odds ration [aOR] = 1.40, 95% confidence interval [CI]: 1.05-1.87 and aOR = 1.25, 95%CI: 0.83-1.90, respectively)., Conclusions: We observed an increased incidence of high-impact cLBP among Black and Hispanic patients compared to White patients. This disparity was partly explained by racial/ethnic differences in socioeconomic and back-related risk factors. Interventions that target these factors to reduce pain-related disparities should be evaluated., Clinicaltrials.gov Identifier: NCT02647658., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

OBJECTIVE: To describe the variation in outcomes and number of visits before and after implementing a care guideline for total knee arthroplasty (TKA) rehabilitation. DESIGN: Nonrandomized intervention study. METHODS: We compared 2558 patients with TKA who received care that was not standardized (non-care guideline [NCG] group) to 9797 patients with TKA who received care according to the care guideline (CG). We fit 2 Bayesian hierarchical linear regression models using the Knee Outcome Survey - Activities of Daily Living (KOS-ADL) change score and number of physical therapy (PT) visits as the response variables, controlling for relevant predictor variables. We also compared the ratio of the standard deviations of the KOS-ADL change scores and the number of PT visits within and between clinics. RESULTS: The overall estimated mean improvement in KOS-ADL change score was 23.0 points (95% confidence interval [CI]: 20.3, 25.7) in the NCG group and 28.7 points (95% CI: 27.5, 29.7) in the CG group; the mean difference was 5.6 (2.7-8.6). Mean KOS-ADL change scores were higher in the CG group than the NCG group in every clinic, although only 8 clinics improved significantly. The number of PT visits did not change meaningfully (NCG: mean, 10.7 [95% CI: 9.9, 11.5]; CG: mean, 10.5 [95% CI: 9.9, 10.9]). Variation in KOS-ADL change score decreased by 4% within clinics (CG-NCG ratio: 0.96 [95% CI: 0.93, 0.99]) and 63% between clinics (CG-NCG ratio: 0.37 [95% CI: 0.21, 0.62]). Variation in number of visits decreased by 7% within clinics (CG-NCG ratio: 0.93 [95% CI: 0.90, 0.96]) and 19% between clinics (CG-NCG ratio: 0.81 [95% CI: 0.39, 1.49]). CONCLUSION: Implementing a care guideline for TKA rehabilitation may improve outcomes and reduce unwarranted variation in practice within clinics and especially between clinics within a large health care system. J Orthop Sports Phys Ther 2023;53(3):151-158. Epub: 12 December 2022. doi:10.2519/jospt.2022.11370 .

OBJECTIVE: To describe the application and examine the influence of a continuous quality improvement intervention, which had a goal of standardizing care to reduce the proportion of patients who do not have a meaningful improvement in patient-reported outcomes following total knee arthroplasty (TKA). DESIGN: Continuous quality improvement. METHODS: A physical therapy (PT) care guideline was initiated in 2013 for patients following TKA. The Knee Outcome Survey - Activities of Daily Living (KOS-ADL) was measured at every visit, and scores were extracted from a clinical outcomes database to calculate the proportion of patients who did not achieve a minimal clinically important difference. Based on logistic regression analysis, we compared the proportion of patients who did not progress on the KOS-ADL in a non-care guideline group (2008-2012) to a care guideline (CG) group (2014-2019). RESULTS: This study included 12 355 patients (aged 18-92 years) following TKA incurring at least 3 PT visits from 2008 to 2019. The percentage of patients who did not progress in the non-care guideline group was 25.8% and in the care guideline group 14.3% (P<0.001). The relationship between care guideline adherence and lack of progression on the KOS-ADL was statistically significant, X 2 ( df = 1) = 148.7, P<.001. CONCLUSION: The percentage of patients who did not achieve meaningful progress on the KOS-ADL declined significantly in the 6 years after implementing a TKA care guideline without an increase in the number of clinical visits. The standardized care guideline was associated with meaningful improvements for patients following TKA when applied in conjunction with PT access to outcome data, feedback through audits, performance goals, and financial incentives. J Orthop Sports Phys Ther 2023;53(3):143-150. Epub: 12 December 2022. doi:10.2519/jospt.2022.11369 .

Background: The OPTIMIZE trial is a multi-site, comparative effectiveness research (CER) study that uses a Sequential Multiple Assessment Randomized Trial (SMART) designed to examine the effectiveness of complex health interventions (cognitive behavioral therapy, physical therapy, and mindfulness) for adults with chronic low back pain. Modifications are anticipated when implementing complex interventions in CER. Disruptions due to COVID have created unanticipated challenges also requiring modifications. Recent methodologic standards for CER studies emphasize that fully characterizing modifications made is necessary to interpret and implement trial results. The purpose of this paper is to outline the modifications made to the OPTIMIZE trial using the Framework for Reporting Adaptations and Modifications to Evidence-Based Interventions (FRAME) to characterize modifications to the OPTIMIZE trial in response to the COVID pandemic and other challenges encountered., Methods: The FRAME outlines a strategy to identify and report modifications to evidence-based interventions or implementation strategies, whether planned or unplanned. We use the FRAME to characterize the process used to modify the aspects of the OPTIMIZE trial. Modifications were made to improve lower-than-anticipated rates of treatment initiation and COVID-related restrictions. Contextual modifications were made to permit telehealth delivery of treatments originally designed for in-person delivery. Training modifications were made with study personnel to provide more detailed information to potential participants, use motivational interviewing communication techniques to clarify potential participants' motivation and possible barriers to initiating treatment, and provide greater assistance with scheduling of assigned treatments., Results: Modifications were developed with input from the trial's patient and stakeholder advisory panels. The goals of the modifications were to improve trial feasibility without compromising the interventions' core functions. Modifications were approved by the study funder and the trial steering committee., Conclusions: Full and transparent reporting of modifications to clinical trials, whether planned or unplanned, is critical for interpreting the trial's eventual results and considering future implementation efforts., Trial Registration: ClinicalTrials.gov NCT03859713. Registered on March 1, 2019., (© 2023. The Author(s).)

MicroRNAs are key posttranscriptional regulators of protein levels in cells. The brain is particularly enriched in microRNAs, and important roles have been demonstrated for these noncoding RNAs in various neurological disorders. To this end, visualization of microRNAs in specific cell types and subcellular compartments within tissue sections provides researchers with essential insights that support understanding of the cell and molecular mechanisms of microRNAs in brain diseases. In this chapter we describe an in situ hybridization protocol for the detection of microRNAs in mouse brain sections, which provides cellular resolution of the expression of microRNAs in the brain., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Abstract: Treatment effect modifiers identify patient characteristics associated with treatment responses. The purpose of this secondary analysis was to identify potential treatment effect modifiers for disability from the TARGET trial that compared usual care (control) with usual care + psychologically informed physical therapy (PIPT). The sample consisted of a STarT Back tool identified high-risk patients with acute low back pain that completed Oswestry Disability Index (ODI) data at index visit and 6 months later (n = 1250). Candidate treatment effect modifiers were identified a priori and informed by the literature. Linear mixed models tested for treatment effect modification through tests of statistical interaction. All statistical interactions ( P ≤ 0.20) were stratified by modifier to inspect for specific effects ( P ≤ 0.05). Smoking was identified as a potential effect modifier (treatment * smoking interaction, P = 0.08). In participants who were smokers, the effect of PIPT was (ODI = 5.5; 95% CI: 0.6-10.4; P = 0.03) compared with usual care. In participants who were nonsmokers, the effect of PIPT was (ODI = 1.5; 95% CI: -1.4 to 4.4; P = 0.31) compared with usual care. Pain medication was also identified as a potential effect modifier (treatment × pain medication interaction, P = 0.10). In participants prescribed ≥3 pain medications, the effect of PIPT was (ODI = 7.1; 95% CI: -0.1 to 14.2; P = 0.05) compared with usual care. The PIPT effect for participants prescribed no pain medication was (ODI = 3.5; 95% CI: -0.4 to 7.4; P = 0.08) and for participants prescribed 1 to 2 pain medications was (ODI = 0.6; 95% CI: -2.5 to 3.7; P = 0.70) when compared with usual care. These findings may be used for generating hypotheses and planning future clinical trials investigating the effectiveness of tailored application of PIPT., (Copyright © 2022 International Association for the Study of Pain.)

Brain development occurs until adulthood, with time-sensitive processes happening during embryo development, childhood, and puberty. During early life and childhood, dynamic changes in the brain are critical for physiological brain maturation, and these changes are tightly regulated by the expression of specific regulatory genetic elements. Early life insults, such as hypoxia, can alter the course of brain maturation, resulting in lifelong neurodevelopmental conditions. MicroRNAs are small non-coding RNAs, which regulate and coordinate gene expression. It is estimated that one single microRNA can regulate the expression of hundreds of protein-coding genes.. Uncovering the miRNome and microRNA-regulated transcriptomes may help to understand the patterns of genes regulating brain maturation, and their contribution to neurodevelopmental pathologies following hypoxia at Postnatal day 7. Here, using a PCR-based platform, we analyzed the microRNA profile postnatally in the hippocampus of control mice at postnatal day 8, 14, and 42 and after hypoxia at postnatal day 7, to elucidate the set of microRNAs which may be key for postnatal hippocampus maturation. We observed that microRNAs can be divided in four groups based on their temporal expression. Further after an early life insult, hypoxia at P7, 15 microRNAs showed a misregulation over time, including Let7a. We speculated that the transcriptional regulator c-myc is a contributor to this process. In conclusion, here, we observed that microRNAs are regulated postnatally in the hippocampus and alteration of their expression after hypoxia at birth may be regulated by the transcriptional regulator c-myc.

The International League Against Epilepsy/American Epilepsy Society (ILAE/AES) Joint Translational Task Force established the TASK3 working groups to create common data elements (CDEs) for various preclinical epilepsy research disciplines. This is the second in a two-part series of omics papers, with the other including genomics, transcriptomics, and epigenomics. The aim of the CDEs was to improve the standardization of experimental designs across a range of epilepsy research-related methods. We have generated CDE tables with key parameters and case report forms (CRFs) containing the essential contents of the study protocols for proteomics, lipidomics, and metabolomics of samples from rodent models and people with epilepsy. We discuss the important elements that need to be considered for the proteomics, lipidomics, and metabolomics methodologies, providing a rationale for the parameters that should be documented., (© 2022 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: To describe the feasibility of an evidence-based physical therapy (PT) program for persons with chronic low back pain (LBP) originally designed for in-person delivery, adapted for telehealth using videoconferencing., Design: Prospective, longitudinal cohort., Setting: Three health care systems in the United States., Participants: Adults, aged 18-64 years (N=126), with chronic LBP recruited from August through December 2020., Intervention: Up to 8 weekly sessions of telehealth PT., Main Outcome Measures: Follow-up assessments were 10 and 26 weeks after baseline. Participant outcomes collected were the Oswestry Disability Index, Patient-Reported Outcomes Measurement Information System-29 health domains, and pain self-efficacy. Implementation outcomes included acceptability, adoption, feasibility, and fidelity assessed using participant surveys and compliance with session attendance., Results: We enrolled 126 participants (mean age, 51.5 years; 62.7% female). Baseline perceptions about telehealth were generally positive. Eighty-eight participants (69.8%) initiated telehealth PT, with a median of 5 sessions attended. Participants in telehealth PT were generally satisfied (76.3%), although only 39.5% perceived the quality equal to in-person PT. Telehealth PT participants reported significant improvement in LBP-related disability, pain intensity, pain interference, physical function, and sleep disturbance at 10- and 26-week follow-ups., Conclusions: The findings generally support the feasibility of telehealth PT using videoconferencing. Implementation and participant outcomes were similar to in-person PT as delivered in the participating health care systems. We identified barriers that may detract from the patient experience and likelihood of benefitting from telehealth PT. More research is needed to optimize and evaluate the most effective strategies for providing telehealth PT for patients with chronic LBP., (Copyright © 2022 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

The International League Against Epilepsy/American Epilepsy Society (ILAE/AES) Joint Translational Task Force established the TASK3 working groups to create common data elements (CDEs) for various preclinical epilepsy research disciplines. The aim of the CDEs is to improve the standardization of experimental designs across a range of epilepsy research-related methods. Here, we have generated CDE tables with key parameters and case report forms (CRFs) containing the essential contents of the study protocols for genomics, transcriptomics, and epigenomics in rodent models of epilepsy, with a specific focus on adult rats and mice. We discuss the important elements that need to be considered for genomics, transcriptomics, and epigenomics methodologies, providing a rationale for the parameters that should be collected. This is the first in a two-part series of omics papers with the second installment to cover proteomics, lipidomics, and metabolomics in adult rodents., (© 2022 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: This study sought to develop and validate an original prediction formula that estimated the probability of success for patients with low back pain (LBP) to achieve a minimal clinically important difference (MCID) on the Modified Low Back Disability Questionnaire (MDQ)., Methods: Patients were 10 to 90 years old in this retrospective cohort study. Data were extracted from Intermountain Healthcare's registry, Rehabilitation Outcomes Management System: 62,858 patients admitted to physical therapy from 2002 to 2013 formed the training dataset, and 15,128 patients admitted 2015 to 2016 formed the verification dataset. Predicted probability to achieve MCID was compared with the actual percentage who succeeded. Two models were developed: 6-point improvement and 30% improvement. MDQ assessed disability, and numeric pain score assessed pain intensity. Predictive models used restricted cubic splines on age, initial pain, and disability scores for non-linear effects. Sex, symptom duration, and payer type were included as indicator variables. Predicted chance of success was compared with the actual percentage of patients that succeeded. Relative change in R-squared was calculated to assess variable importance in predicting success. Odds ratios for duration of injury and payer were calculated., Results: A positive trend was observed in both models between predicted and actual success achieved. Both "verification" models appear accurate and closely approximate the "training dataset." Baseline MDQ score was the most important factor to predict a 6-point improvement. Payer type and injury duration were important factors to predict 30% improvement. Best odds to achieve an MCID was having a workers compensation insurance payer and seeking care within 14 days., Conclusion: The 2 models demonstrated an accurate visualization of the chance of patients achieving significant improvement compared with the usual representation of the average rate of improvement for all patients., Impact: Enhancing physical therapists' understanding of the probability of a patient achieving significant clinical improvement can enhance decision-making processes and help physical therapists manage a patient's care more effectively., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Physical Therapy Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The preparation of unique wet and dry wound dressing products derived from unprocessed human amniotic membrane (UP-HAM) is described. The UP-HAM was decellularized, and the constituent proteins were cross-linked and stabilized before being trimmed and packed in sterile Nucril-coated laminated aluminium foil pouches with isopropyl alcohol to manufacture processed wet human amniotic membrane (PW-HAM). The dry type of PD-HAM was prepared by decellularizing the membrane, UV irradiating it, lyophilizing/freeze-drying it, sterilizing it, and storing it at room temperature. The UP-HAM consists of a translucent yellowish mass of flexible membranes with an average thickness of 42 μm. PW-HAM wound dressings that had been processed, decellularized, and dehydrated had a thinner average thickness of 30 μm and lacked nuclear-cellular structures. Following successful decellularization, discrete bundle of fibrous components in the stromal spongy layers, microvilli and reticular ridges were still evident on the surface of the processed HAM, possibly representing the location of the cells that had been removed by the decellularization process. Both wet and dry HAM wound dressings are durable, portable, have a shelf life of 3-5 years, and are available all year. A slice of HAM dressing costs 1.0 US$/cm 2 . Automation and large-scale HAM membrane preparation, as well as storage and transportation of the dressings, can all help to establish advanced technologies, improve the efficiency of membrane production, and reduce costs. Successful treatment of wounds to the cornea of the eye was achieved with the application of the HAM wound dressings. The HAM protein analysis revealed 360 μg proteins per gram of tissue, divided into three main fractions with MWs of 100 kDa, 70 kDa, and 14 kDa, as well as seven minor proteins, with the 14 kDa protein displaying antibacterial properties against human pathogenic bacteria. A wide range of antibacterial activity was observed after treatment with 75 μg/ml zinc oxide nanoparticles derived from human amniotic membrane proteins (HAMP-ZnO NP), including dose-dependent biofilm inhibition and inhibition of Gram-positive ( S. aureus, S. mutans, E. faecalis , and L. fusiformis ) and Gram-negative bacteria ( S. sonnei, P. aeruginosa, P. vulgaris, and C. freundii)., Competing Interests: RK was employed by company Cologenesis Healthcare Pvt. Ltd. The remaining 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., (Copyright © 2021 Ramasamy, Krishnakumar, Rekha, Vaseeharan, Saraswathi, Raj, Hanna, Brennan, Dayanithi and Vijayakumar.)

Oligonucleotide therapies offer precision treatments for a variety of neurological diseases, including epilepsy, but their deployment is hampered by the blood-brain barrier (BBB). Previous studies showed that intracerebroventricular injection of an antisense oligonucleotide (antagomir) targeting microRNA-134 (Ant-134) reduced evoked and spontaneous seizures in animal models of epilepsy. In this study, we used assays of serum protein and tracer extravasation to determine that BBB disruption occurring after status epilepticus in mice was sufficient to permit passage of systemically injected Ant-134 into the brain parenchyma. Intraperitoneal and intravenous injection of Ant-134 reached the hippocampus and blocked seizure-induced upregulation of miR-134. A single intraperitoneal injection of Ant-134 at 2 h after status epilepticus in mice resulted in potent suppression of spontaneous recurrent seizures, reaching a 99.5% reduction during recordings at 3 months. The duration of spontaneous seizures, when they occurred, was also reduced in Ant-134-treated mice. In vivo knockdown of LIM kinase-1 (Limk-1) increased seizure frequency in Ant-134-treated mice, implicating de-repression of Limk-1 in the antagomir mechanism. These studies indicate that systemic delivery of Ant-134 reaches the brain and produces long-lasting seizure-suppressive effects after systemic injection in mice when timed with BBB disruption and may be a clinically viable approach for this and other disease-modifying microRNA therapies., Competing Interests: Declaration of interests D.C.H. reports patent US9803200 B2 “Inhibition of microRNA-134 for the treatment of seizure-related disorders and neurologic injuries,” and D.C.H. and C.R.R. report patent WO2019219723A1 “Pharmaceutical compositions for treatment of microRNA related diseases.” The remaining authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

RNA modifications have emerged as an additional layer of regulatory complexity governing the function of almost all species of RNA. N 6 -methyladenosine (m 6 A), the addition of methyl groups to adenine residues, is the most abundant and well understood RNA modification. The current review discusses the regulatory mechanisms governing m 6 A, how this influences neuronal development and function and how aberrant m 6 A signaling may contribute to neurological disease. M 6 A is known to regulate the stability of mRNA, the processing of microRNAs and function/processing of tRNAs among other roles. The development of antibodies against m 6 A has facilitated the application of next generation sequencing to profile methylated RNAs in both health and disease contexts, revealing the extent of this transcriptomic modification. The mechanisms by which m 6 A is deposited, processed, and potentially removed are increasingly understood. Writer enzymes include METTL3 and METTL14 while YTHDC1 and YTHDF1 are key reader proteins, which recognize and bind the m 6 A mark. Finally, FTO and ALKBH5 have been identified as potential erasers of m 6 A, although there in vivo activity and the dynamic nature of this modification requires further study. M 6 A is enriched in the brain and has emerged as a key regulator of neuronal activity and function in processes including neurodevelopment, learning and memory, synaptic plasticity, and the stress response. Changes to m 6 A have recently been linked with Schizophrenia and Alzheimer disease. Elucidating the functional consequences of m 6 A changes in these and other brain diseases may lead to novel insight into disease pathomechanisms, molecular biomarkers and novel therapeutic targets., Competing Interests: 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., (Copyright © 2021 Mathoux, Henshall and Brennan.)

Background: Many patients with acute low back pain (LBP) first seek care from primary care physicians. Evidence is lacking for interventions to prevent transition to chronic LBP in this setting. We aimed to test if implementation of a risk-stratified approach to care would result in lower rates of chronic LBP and improved self-reported disability., Methods: We conducted a pragmatic, cluster randomized trial using 77 primary care clinics in four health care systems across the United States. Practices were randomly assigned to a stratified approach to care (intervention) or usual care (control). Using the STarTBack screening tool, adults with acute LBP were screened low, medium, and high-risk. Patients screened as high-risk were eligible. The intervention included electronic best practice alerts triggering referrals for psychologically informed physical therapy (PIPT). PIPT education was targeted to community clinics geographically close to intervention primary care clinics. Primary outcomes were transition to chronic LBP and self-reported disability at six months. Trial Registry: ClinicalTrials.gov NCT02647658., Findings: Between May 2016 and June 2018, 1207 patients from 38 intervention and 1093 from 37 control practices were followed. In the intervention arm, around 50% of patients were referred for physical therapy (36% for PIPT) compared to 30% in the control. At 6 months, 47% of patients reported transition to chronic LBP in the intervention arm (38 practices, n  = 658) versus 51% of patients in the control arm (35 practices, n  = 635; OR=0.83 95% CI 0.64, 1.09; p  = 0.18). No differences in disability were detected (difference -2·1, 95% CI -4.9-0.6; p  = 0.12). Opioids and imaging were prescribed in 22%-25% and 23%-26% of initial visits, for intervention and control, respectively. Twelve-month LBP utilization was similar in the two groups., Interpretation: There were no differences detected in transition to chronic LBP among patients presenting with acute LBP using a stratified approach to care. Opioid and imaging prescribing rates were non-concordant with clinical guidelines., Funding: Patient-Centered Outcomes Research Institute (PCORI) contract # PCS-1402-10867., Competing Interests: Dr. Delitto reports grants from PCORI, grants from NIH, grants from DOD, outside the submitted work; Dr. Patterson reports grants from Patient Centered Outcomes Research Institute, during the conduct of the study; Dr. Stevans reports grants from PCORI, during the conduct of the study; Dr. Khoja reports grants from PCORI, during the conduct of the study; Dr. Freel has nothing to disclose; Dr. Schneider reports grants from Patient Centered Outcomes Research Institute, during the conduct of the study; Dr. Greco reports grants from Patient-Centered Outcomes Research Institute, during the conduct of the study; Dr. Sowa reports grants from PCORI, during the conduct of the study; grants from NIH, USAMRMC, VA, The Pittsburgh Foundation, outside the submitted work; Dr. Brennan reports other institutional support from Patient Centered Outcomes Research Institute (PCORI), during the conduct of the study; other institutional support from Patient Centered Outcomes Research Institute (PCORI), outside the submitted work; Stephen J. Hunter has nothing to disclose; Dr. Minick has nothing to disclose; Dr. Wasan has nothing to disclose; Dr. Wegener reports grants from PCORI, during the conduct of the study; Ms. Ephraim has nothing to disclose; Dr. Freburger reports other from American Physical Therapy Association, outside the submitted work; Dr. Beneciuk reports grants from Patient-Centered Outcomes Research Institute, during the conduct of the study; Dr. George reports personal fees from Rehab Essentials, Inc, personal fees from Med Risk, LLC, grants from NIH, other from Duke University, all outside the submitted work; Dr. Saper has nothing to disclose., (© 2021 The Authors.)

Background and Rationale: Bi-directional neuronal-glial communication is a critical mediator of normal brain function and is disrupted in the epileptic brain. The potential role of aberrant microglia and astrocyte function during epileptogenesis is important because the mediators involved provide tangible targets for intervention and prevention of epilepsy. Glial activation is intrinsically involved in the generation of childhood febrile seizures (FS), and prolonged FS (febrile status epilepticus, FSE) antecede a proportion of adult temporal lobe epilepsy (TLE). Because TLE is often refractory to treatment and accompanied by significant memory and emotional difficulties, we probed the role of disruptions of glial-neuronal networks in the epileptogenesis that follows experimental FSE (eFSE). Methods: We performed a multi-pronged examination of neuronal-glia communication and the resulting activation of molecular signaling cascades in these cell types following eFSE in immature mice and rats. Specifically, we examined pathways involving cytokines, microRNAs, high mobility group B-1 (HMGB1) and the prostaglandin E2 signaling. We aimed to block epileptogenesis using network-specific interventions as well as via a global anti-inflammatory approach using dexamethasone. Results: (A) eFSE elicited a strong inflammatory response with rapid and sustained upregulation of pro-inflammatory cytokines. (B) Within minutes of the end of the eFSE, HMGB1 translocated from neuronal nuclei to dendrites, en route to the extracellular space and glial Toll-like receptors. Administration of an HMGB1 blocker to eFSE rat pups did not decrease expression of downstream inflammatory cascades and led to unacceptable side effects. (C) Prolonged seizure-like activity caused overall microRNA-124 (miR-124) levels to plunge in hippocampus and release of this microRNA from neurons via extra-cellular vesicles. (D) Within hours of eFSE, structural astrocyte and microglia activation was associated not only with cytokine production, but also with activation of the PGE 2 cascade. However, administration of TG6-10-1, a blocker of the PGE 2 receptor EP2 had little effect on spike-series provoked by eFSE. (E) In contrast to the failure of selective interventions, a 3-day treatment of eFSE-experiencing rat pups with the broad anti-inflammatory drug dexamethasone attenuated eFSE-provoked pro-epileptogenic EEG changes. Conclusions: eFSE, a provoker of TLE-like epilepsy in rodents leads to multiple and rapid disruptions of interconnected glial-neuronal networks, with a likely important role in epileptogenesis. The intricate, cell-specific and homeostatic interplays among these networks constitute a serious challenge to effective selective interventions that aim to prevent epilepsy. In contrast, a broad suppression of glial-neuronal dysfunction holds promise for mitigating FSE-induced hyperexcitability and epileptogenesis in experimental models and in humans., Competing Interests: 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., (Copyright © 2021 Brennan, Garcia-Curran, Patterson, Luo and Baram.)

Importance: Acute low back pain (LBP) is highly prevalent, with a presumed favorable prognosis; however, once chronic, LBP becomes a disabling and expensive condition. Acute to chronic LBP transition rates vary widely owing to absence of standardized operational definitions, and it is unknown whether a standardized prognostic tool (ie, Subgroups for Targeted Treatment Back tool [SBT]) can estimate this transition or whether early non-guideline concordant treatment is associated with the transition to chronic LBP., Objective: To assess the associations between the transition from acute to chronic LBP with SBT risk strata; demographic, clinical, and practice characteristics; and guideline nonconcordant processes of care., Design, Setting, and Participants: This inception cohort study was conducted alongside a multisite, pragmatic cluster randomized trial. Adult patients with acute LBP stratified by SBT risk were enrolled in 77 primary care practices in 4 regions across the United States between May 2016 and June 2018 and followed up for 6 months, with final follow-up completed by March 2019. Data analysis was conducted from January to March 2020., Exposures: SBT risk strata and early LBP guideline nonconcordant processes of care (eg, receipt of opioids, imaging, and subspecialty referral)., Main Outcomes and Measures: Transition from acute to chronic LBP at 6 months using the National Institutes of Health Task Force on Research Standards consensus definition of chronic LBP. Patient demographic characteristics, clinical factors, and LBP process of care were obtained via electronic medical records., Results: Overall, 5233 patients with acute LBP (3029 [58%] women; 4353 [83%] White individuals; mean [SD] age 50.6 [16.9] years; 1788 [34%] low risk; 2152 [41%] medium risk; and 1293 [25%] high risk) were included. Overall transition rate to chronic LBP at six months was 32% (1666 patients). In a multivariable model, SBT risk stratum was positively associated with transition to chronic LBP (eg, high-risk vs low-risk groups: adjusted odds ratio [aOR], 2.45; 95% CI, 2.00-2.98; P < .001). Patient and clinical characteristics associated with transition to chronic LBP included obesity (aOR, 1.52; 95% CI, 1.28-1.80; P < .001); smoking (aOR, 1.56; 95% CI, 1.29-1.89; P < .001); severe and very severe baseline disability (aOR, 1.82; 95% CI, 1.48-2.24; P < .001 and aOR, 2.08; 95% CI, 1.60-2.68; P < .001, respectively) and diagnosed depression/anxiety (aOR, 1.66; 95% CI, 1.28-2.15; P < .001). After controlling for all other variables, patients exposed to 1, 2, or 3 nonconcordant processes of care within the first 21 days were 1.39 (95% CI, 1.21-2.32), 1.88 (95% CI, 1.53-2.32), and 2.16 (95% CI, 1.10-4.25) times more likely to develop chronic LBP compared with those with no exposure (P < .001)., Conclusions and Relevance: In this cohort study, the transition rate to chronic LBP was substantial and increased correspondingly with SBT stratum and early exposure to guideline nonconcordant care.

Epileptic encephalopathies (EE) are severe epilepsy syndromes characterized by multiple seizure types, developmental delay and even regression. This class of disorders are increasingly being identified as resulting from de novo genetic mutations including many identified mutations in the family of chromodomain helicase DNA binding (CHD) proteins. In particular, several de novo pathogenic mutations have been identified in the gene encoding chromodomain helicase DNA binding protein 2 (CHD2), a member of the sucrose nonfermenting (SNF-2) protein family of epigenetic regulators. These mutations in the CHD2 gene are causative of early onset epileptic encephalopathy, abnormal brain function, and intellectual disability. Our understanding of the mechanisms by which modification or loss of CHD2 cause this condition remains poorly understood. Here, we review what is known and still to be elucidated as regards the structure and function of CHD2 and how its dysregulation leads to a highly variable range of phenotypic presentations.

Epilepsy is a network disorder driven by fundamental changes in the function of the cells which compose these networks. Driving this aberrant cellular function are large scale changes in gene expression and gene expression regulation. Recent studies have revealed rapid and persistent changes in epigenetic control of gene expression as a critical regulator of the epileptic transcriptome. Epigenetic-mediated gene output regulates many aspects of cellular physiology including neuronal structure, neurotransmitter assembly and abundance, protein abundance of ion channels and other critical neuronal processes. Thus, understanding the contribution of epigenetic-mediated gene regulation could illuminate novel regulatory mechanisms which may form the basis of novel therapeutic approaches to treat epilepsy. In this review we discuss the effects of epileptogenic brain insults on epigenetic regulation of gene expression, recent efforts to target epigenetic processes to block epileptogenesis and the prospects of an epigenetic-based therapy for epilepsy, and finally we discuss technological advancements which have facilitated the interrogation of the epigenome., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background : The efficiency and effectiveness of multiple physical therapy care delivery models can be measured using the value-based care paradigm. Entering physical therapy through direct access can decrease health-care utilization and improve patient outcomes. Limited evidence exists which compares direct access physical therapy to referral using the value-based care paradigm specific to cervical spine radiculopathy. Case Description : The patient was a 39-year-old woman who presented to physical therapy through physician referral with the diagnoses of acute cervical radiculopathy. The patient was evaluated, provided guideline adherent treatment and discharged with a home exercise program. Sixteen months from being discharged, the same patient returned through direct access due to an acute onset of cervical spine symptoms and was evaluated and provided treatment that same morning. Outcomes : Direct access physical therapy saved the patient and third-party payer $434.30 and $3264.75 respectively. A 5×'s higher efficiency per visit and a 6.2×'s higher value in reducing disability was demonstrated when the patient accessed physical therapy directly. Physician referral and direct access entry pathways demonstrated neck disability index improvements of 6% and 16%, respectively. Discussion : This case report describes a clinical example of previous research that demonstrates improved cost efficiency, outcomes, and increased value with a patient who presented to physical therapy with cervical radiculopathy through two different access to care models. The results of this case demonstrate a clinical example of the use of the value-based care paradigm in comparing value and efficiency of two access to care models in a patient with cervical radiculopathy without other neurological deficits.

Epilepsy diagnosis is complex, requires a team of specialists and relies on in-depth patient and family history, MRI-imaging and EEG monitoring. There is therefore an unmet clinical need for a non-invasive, molecular-based, biomarker to either predict the development of epilepsy or diagnose a patient with epilepsy who may not have had a witnessed seizure. Recent studies have demonstrated a role for microRNAs in the pathogenesis of epilepsy. MicroRNAs are short non-coding RNA molecules which negatively regulate gene expression, exerting profound influence on target pathways and cellular processes. The presence of microRNAs in biofluids, ease of detection, resistance to degradation and functional role in epilepsy render them excellent candidate biomarkers. Here we performed the first multi-model, genome-wide profiling of plasma microRNAs during epileptogenesis and in chronic temporal lobe epilepsy animals. From video-EEG monitored rats and mice we serially sampled blood samples and identified a set of dysregulated microRNAs comprising increased miR-93-5p, miR-142-5p, miR-182-5p, miR-199a-3p and decreased miR-574-3p during one or both phases. Validation studies found miR-93-5p, miR-199a-3p and miR-574-3p were also dysregulated in plasma from patients with intractable temporal lobe epilepsy. Treatment of mice with common anti-epileptic drugs did not alter the expression levels of any of the five miRNAs identified, however administration of an anti-epileptogenic microRNA treatment prevented dysregulation of several of these miRNAs. The miRNAs were detected within the Argonuate2-RISC complex from both neurons and microglia indicating these miRNA biomarker candidates can likely be traced back to specific brain cell types. The current studies identify additional circulating microRNA biomarkers of experimental and human epilepsy which may support diagnosis of temporal lobe epilepsy via a quick, cost-effective rapid molecular-based test., Competing Interests: Declaration of competing interest None., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Hypoxic ischemic encephalopathy (HIE) is the most frequent cause of acquired infant brain injury. Early, clinically relevant biomarkers are required to allow timely application of therapeutic interventions. We previously reported early alterations in several microRNAs (miRNA) in umbilical cord blood at birth in infants with HIE. However, the exact timing of these alterations is unknown. Here, we report serial changes in six circulating, cross-species/bridging biomarkers in a clinically relevant porcine model of neonatal HIE with functional analysis. Six miRNAs-miR-374a, miR-181b, miR-181a, miR-151a, miR-148a and miR-128-were significantly and rapidly upregulated 1-h post-HI. Changes in miR-374a, miR-181b and miR-181a appeared specific to moderate-severe HI. Histopathological injury and five miRNAs displayed positive correlations and were predictive of MRS Lac/Cr ratios. Bioinformatic analysis identified that components of the bone morphogenic protein (BMP) family may be targets of miR-181a. Inhibition of miR-181a increased neurite length in both SH-SY5Y cells at 1 DIV (days in vitro) and in primary cultures of rat neuronal midbrain at 3 DIV. In agreement, inhibition of miR-181a increased expression of BMPR2 in differentiating SH-SY5Y cells. These miRNAs may therefore act as early biomarkers of HIE, thereby allowing for rapid diagnosis and timely therapeutic intervention and may regulate expression of signalling pathways vital to neuronal survival.

Seizures result from hypersynchronous, abnormal firing of neuronal populations and are the primary clinical symptom of the epilepsies. Brain tissue from animal models and patients with acquired forms of epilepsy commonly features selective neuronal loss, gliosis, inflammatory markers and microscopic and macroscopic reorganization of networks. The gene expression landscape is a critical driver of these changes, and gene expression is fine tuned by small, non-coding RNAs called microRNAs (miRNAs). miRNAs inhibit the function of protein-coding transcripts, resulting in changes in multiple aspects of cell structure and function, including axonal and dendritic structure and the repertoire of neurotransmitter receptors, ion channels and transporters that establish neurophysiological functions. Dysregulation of the miRNA system has emerged as a mechanism that underlies epileptogenesis. Given that miRNAs can act on multiple mRNA targets, their manipulation offers a novel, multi-targeting approach to correct disturbed gene expression patterns. Targeting of some miRNAs has also been used to selectively upregulate individual transcripts, offering the possibility of precision therapy approaches for disorders of haploinsufficiency. In this Review, we discuss how miRNAs determine and control neuronal and glial functions, how this process is altered in states associated with hyperexcitability, and the prospects for miRNA targeting for the treatment of epilepsy.

MicroRNAs perform important roles in the post-transcriptional regulation of gene expression. Sequencing as well as functional studies using antisense oligonucleotides indicate important roles for microRNAs during the development of epilepsy through targeting transcripts involved in neuronal structure, gliosis and inflammation. MicroRNA-22 (miR-22) has been reported to protect against the development of epileptogenic brain networks through suppression of neuroinflammatory signalling. Here, we used mice with a genetic deletion of miR-22 to extend these insights. Mice lacking miR-22 displayed normal behaviour and brain structure and developed similar status epilepticus after intraamygdala kainic acid compared to wildtype animals. Continuous EEG monitoring after status epilepticus revealed, however, an accelerated and exacerbated epilepsy phenotype whereby spontaneous seizures began sooner, occurred more frequently and were of longer duration in miR-22-deficient mice. RNA sequencing analysis of the hippocampus during the period of epileptogenesis revealed a specific suppression of inflammatory signalling in the hippocampus of miR-22-deficient mice. Taken together, these findings indicate a role for miR-22 in establishing early inflammatory responses to status epilepticus. Inflammatory signalling may serve anti-epileptogenic functions and cautions the timing of anti-inflammatory interventions for the treatment of status epilepticus.

Temporal lobe epilepsy is the most common drug-resistant form of epilepsy in adults. The reorganization of neural networks and the gene expression landscape underlying pathophysiologic network behavior in brain structures such as the hippocampus has been suggested to be controlled, in part, by microRNAs. To systematically assess their significance, we sequenced Argonaute-loaded microRNAs to define functionally engaged microRNAs in the hippocampus of three different animal models in two species and at six time points between the initial precipitating insult through to the establishment of chronic epilepsy. We then selected commonly up-regulated microRNAs for a functional in vivo therapeutic screen using oligonucleotide inhibitors. Argonaute sequencing generated 1.44 billion small RNA reads of which up to 82% were microRNAs, with over 400 unique microRNAs detected per model. Approximately half of the detected microRNAs were dysregulated in each epilepsy model. We prioritized commonly up-regulated microRNAs that were fully conserved in humans and designed custom antisense oligonucleotides for these candidate targets. Antiseizure phenotypes were observed upon knockdown of miR-10a-5p, miR-21a-5p, and miR-142a-5p and electrophysiological analyses indicated broad safety of this approach. Combined inhibition of these three microRNAs reduced spontaneous seizures in epileptic mice. Proteomic data, RNA sequencing, and pathway analysis on predicted and validated targets of these microRNAs implicated derepressed TGF-β signaling as a shared seizure-modifying mechanism. Correspondingly, inhibition of TGF-β signaling occluded the antiseizure effects of the antagomirs. Together, these results identify shared, dysregulated, and functionally active microRNAs during the pathogenesis of epilepsy which represent therapeutic antiseizure targets., Competing Interests: Competing interest statement: D.C.H. reports US Patent No. US 9,803,200 B2 “Inhibition of microRNA-134 for the treatment of seizure-related disorders and neurologic injuries.”, (Copyright © 2020 the Author(s). Published by PNAS.)

Liver flukes include Fasciola hepatica, Fasciola gigantica, Clonorchis sinensis, Opisthorchis spp., Fascioloides magna, Gigantocotyle explanatum and Dicrocoelium spp. The two main species, F. hepatica and F. gigantica, are major parasites of livestock and infections result in huge economic losses. As with C. sinensis, Opisthorchis spp. and Dicrocoelium spp., they affect millions of people worldwide, causing severe health problems. Collectively, the group is referred to as the Food-Borne Trematodes and their true significance is now being more widely recognised. However, reports of resistance to triclabendazole (TCBZ), the most widely used anti-Fasciola drug, and to other current drugs are increasing. This is a worrying scenario. In this review, progress in understanding the mechanism(s) of resistance to TCBZ is discussed, focusing on tubulin mutations, altered drug uptake and changes in drug metabolism. There is much interest in the development of new drugs and drug combinations, the re-purposing of non-flukicidal drugs, and the development of new drug formulations and delivery systems; all this work will be reviewed. Sound farm management practices also need to be put in place, with effective treatment programmes, so that drugs can be used wisely and their efficacy conserved as much as is possible. This depends on reliable advice being given by veterinarians and other advisors. Accurate diagnosis and identification of drug-resistant fluke populations is central to effective control: to determine the actual extent of the problem and to determine how well or otherwise a treatment has worked; for research on establishing the mechanism of resistance (and identifying molecular markers of resistance); for informing treatment options; and for testing the efficacy of new drug candidates. Several diagnostic methods are available, but there are no recommended guidelines or standardised protocols in place and this is an issue that needs to be addressed., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Repetitive or prolonged seizures (status epilepticus) can damage neurons within the hippocampus, trigger gliosis, and generate an enduring state of hyperexcitability. Recent studies have suggested that microvesicles including exosomes are released from brain cells following stimulation and tissue injury, conveying contents between cells including microRNAs (miRNAs). Here, we characterized the effects of experimental status epilepticus on the expression of exosome biosynthesis components and analyzed miRNA content in exosome-enriched fractions. Status epilepticus induced by unilateral intra-amygdala kainic acid in mice resulted in acute subfield-specific, bi-directional changes in hippocampal transcripts associated with exosome biosynthesis including up-regulation of endosomal sorting complexes required for transport (ESCRT)-dependent and -independent pathways. Increased expression of exosome components including Alix were detectable in samples obtained 2 weeks after status epilepticus and changes occurred in both the ipsilateral and contralateral hippocampus. RNA sequencing of exosome-enriched fractions prepared using two different techniques detected a rich diversity of conserved miRNAs and showed that status epilepticus selectively alters miRNA contents. We also characterized editing sites of the exosome-enriched miRNAs and found six exosome-enriched miRNAs that were adenosine-to-inosine (ADAR) edited with the majority of the editing events predicted to occur within miRNA seed regions. However, the prevalence of these editing events was not altered by status epilepticus. These studies demonstrate that status epilepticus alters the exosome pathway and its miRNA content, but not editing patterns. Further functional studies will be needed to determine if these changes have pathophysiological significance for epileptogenesis., (Copyright © 2020 Batool, Hill, Nguyen, Langa, Diviney, Mooney, Brennan, Connolly, Sanz-Rodriguez, Cavanagh and Henshall.)

Cytochemical staining techniques were carried out en bloc with in vitro excysted and gut-penetrated Fasciola gigantica larvae in order to visualise the glycocalyx of the tegument, a structure which comprises the parasite component of the host-parasite interface, yet is incompletely preserved by conventional fixation and preparation techniques for electron microscopy. Positive reactivity with ruthenium red and periodic acid-thiocarbohydrazine-osmium (PATCO) techniques revealed that the glycocalyx is polyanionic and carbohydrate-rich throughout its depth. It comprises a trilaminate arrangement, with a thin dense zone and fibrillar layer closely apposed to the outer aspect of the apical plasma membrane, invested by an irregular thick mucopolysaccharide capsule. The latter, not recorded in adult flukes, may represent a specific adaptation to facilitate invasion in the face of host immunity, and may also protect the parasite surface from the action of host- and parasite-derived proteases. Early in the invasion of a naïve host, the glycocalyx may be partly responsible for triggering the responses of innate immunity, while later in infection, or when an anamnestic response is initiated in an immunocompetent host, the antibodies and activated lymphocytes of specific acquired immunity are invoked to interact with the parasite surface. The cytochemical properties of the glycocalyx, together with its potential for dynamic turnover due to exocytosis of the T0 tegumental secretory bodies, are likely to aid neutralisation of potentially damaging immune effectors and ensure their removal from the vicinity of the parasite by sloughing in complex with glycocalyx components., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Low back pain (LBP) is one of the most prevalent and potentially disabling conditions for which people seek health care. Patients, providers, and payers agree that greater effort is needed to prevent acute LBP from transitioning to chronic LBP., Methods and Study Design: The TARGET (Targeted Interventions to Prevent Chronic Low Back Pain in High-Risk Patients) Trial is a primary care-based, multisite, cluster randomized, pragmatic trial comparing guideline-based care (GBC) to GBC + referral to Psychologically Informed Physical Therapy (PIPT) for patients presenting with acute LBP and identified as high risk for persistent disabling symptoms. Study sites include primary care clinics within each of five geographical regions in the United States, with clinics randomized to either GBC or GBC + PIPT. Acute LBP patients at all clinics are risk stratified (high, medium, low) using the STarT Back Tool. The primary outcomes are the presence of chronic LBP and LBP-related functional disability determined by the Oswestry Disability Index at 6 months. Secondary outcomes are LBP-related processes of health care and utilization of services over 12 months, determined through electronic medical records. Study enrollment began in May 2016 and concluded in June 2018. The trial was powered to include at least 1860 high-risk patients in the randomized controlled trial cohort. A prospective observational cohort of approximately 6900 low and medium-risk acute LBP patients was enrolled concurrently., Discussion: The TARGET pragmatic trial aims to establish the effectiveness of the stratified approach to acute LBP intervention targeting high-risk patients with GBC and PIPT., Trial Registration: ClinicalTrials.govNCT02647658 Registered Jan. 6, 2016., (Copyright © 2019. Published by Elsevier Inc.)

Mesial temporal lobe epilepsy (mTLE) is a chronic neurological disease characterized by recurrent seizures. The antiepileptic drugs currently available to treat mTLE are ineffective in one-third of patients and lack disease-modifying effects. miRNAs, a class of small noncoding RNAs which control gene expression at the post-transcriptional level, play a key role in the pathogenesis of mTLE and other epilepsies. Although manipulation of miRNAs at acute stages has been reported to reduce subsequent spontaneous seizures, it is uncertain whether targeting miRNAs at chronic stages of mTLE can also reduce seizures. Furthermore, the functional role and downstream targets of most epilepsy-associated miRNAs remain poorly understood. Here, we show that miR-135a is selectively upregulated within neurons in epileptic brain and report that targeting miR-135a in vivo using antagomirs after onset of spontaneous recurrent seizures can reduce seizure activity at the chronic stage of experimental mTLE in male mice. Further, by using an unbiased approach combining immunoprecipitation and RNA sequencing, we identify several novel neuronal targets of miR-135a , including Mef2a Mef2 proteins are key regulators of excitatory synapse density. Mef2a and miR-135a show reciprocal expression regulation in human (of both sexes) and experimental TLE, and miR-135a regulates dendritic spine number and type through Mef2. Together, our data show that miR-135a is target for reducing seizure activity in chronic epilepsy, and that deregulation of miR-135a in epilepsy may alter Mef2a expression and thereby affect synaptic function and plasticity. SIGNIFICANCE STATEMENT miRNAs are post-transcriptional regulators of gene expression with roles in the pathogenesis of epilepsy. However, the precise mechanism of action and therapeutic potential of most epilepsy-associated miRNAs remain poorly understood. Our study reveals dramatic upregulation of the key neuronal miRNA miR-135a in both experimental and human mesial temporal lobe epilepsy. Silencing miR-135a in experimental temporal lobe epilepsy reduces seizure activity at the spontaneous recurrent seizure stage. These data support the exciting possibility that miRNAs can be targeted to combat seizures after spontaneous seizure activity has been established. Further, by using unbiased approaches novel neuronal targets of miR-135a , including members of the Mef2 protein family, are identified that begin to explain how deregulation of miR-135a may contribute to epilepsy., (Copyright © 2019 the authors.)

Using in vitro procedures to prepare newly excysted metacercariae and gut-penetrated juvenile Fasciola gigantica, the ultrastructural features of the tegumental syncytium and perikarya of these ephemeral stages in the host-invasion process were compared. The T0-type tegumental cells in newly excysted metacercariae are packed with stored T0 granules which, following transport to the surface membrane of the syncytium, discharge by exocytosis to maintain the glycocalyx. The T0 cells become depleted of T0 granules during the penetration process, shrink in size, and initiate autophagy in the cytoplasm to facilitate metamorphosis from a storage function to active biosynthesis. The novel products appear to include lysosomes which contribute to the autophagosomes, and T1 granules, necessary for maintenance of the glycocalyx and immunoprotection, as the invasion process continues into the host liver. Residual bodies, the end-products of autophagy, are eliminated from the apical membrane of the tegumental syncytium into the host-parasite interface. There they may present a transient source of parasite-derived molecules, including lysosomal cathepsin-type proteases, with potential for interaction with the host's immune system, and so might be exploited as targets for vaccinal and immunomodulatory studies., (Copyright © 2018 Elsevier B.V. All rights reserved.)

MicroRNAs are a class of small non-coding RNA that regulate gene expression at a post-transcriptional level. MicroRNAs have been identified in various body fluids under normal conditions and their stability as well as their dysregulation in disease has led to ongoing interest in their diagnostic and prognostic potential. Circulating microRNAs may be valuable predictors of early-life complications such as birth asphyxia or neonatal seizures but there are relatively few data on microRNA content in plasma from healthy babies. Here we performed small RNA-sequencing analysis of plasma processed from umbilical cord blood in a set of healthy newborns. MicroRNA levels in umbilical cord plasma of four male and four female healthy babies, from two different centres were profiled. A total of 1,004 individual microRNAs were identified, which ranged from 426 to 659 per sample, of which 269 microRNAs were common to all eight samples. Many of these microRNAs are highly expressed and consistent with previous studies using other high throughput platforms. While overall microRNA expression did not differ between male and female cord blood plasma, we did detect differentially edited microRNAs in female plasma compared to male. Of note, and consistent with other studies of this type, adenylation and uridylation were the two most prominent forms of editing. Six microRNAs, miR-128-3p, miR-29a-3p, miR-9-5p, miR-218-5p, 204-5p and miR-132-3p were consistently both uridylated and adenylated in female cord blood plasma. These results provide a benchmark for microRNA profiling and biomarker discovery using umbilical cord plasma and can be used as comparative data for future biomarker profiles from complicated births or those with early-life developmental disorders., Competing Interests: The authors have declared that no competing interests exist.

Background: There are no blood-based molecular biomarkers of temporal lobe epilepsy (TLE) to support clinical diagnosis. MicroRNAs are short noncoding RNAs with strong biomarker potential due to their cell-specific expression, mechanistic links to brain excitability, and stable detection in biofluids. Altered levels of circulating microRNAs have been reported in human epilepsy, but most studies collected samples from one clinical site, used a single profiling platform or conducted minimal validation., Method: Using a case-control design, we collected plasma samples from video-electroencephalogram-monitored adult TLE patients at epilepsy specialist centers in two countries, performed genome-wide PCR-based and RNA sequencing during the discovery phase and validated findings in a large (>250) cohort of samples that included patients with psychogenic non-epileptic seizures (PNES)., Findings: After profiling and validation, we identified miR-27a-3p, miR-328-3p and miR-654-3p with biomarker potential. Plasma levels of these microRNAs were also changed in a mouse model of TLE but were not different to healthy controls in PNES patients. We determined copy number of the three microRNAs in plasma and demonstrate their rapid detection using an electrochemical RNA microfluidic disk as a prototype point-of-care device. Analysis of the microRNAs within the exosome-enriched fraction provided high diagnostic accuracy while Argonaute-bound miR-328-3p selectively increased in patient samples after seizures. In situ hybridization localized miR-27a-3p and miR-328-3p within neurons in human brain and bioinformatics predicted targets linked to growth factor signaling and apoptosis., Interpretation: This study demonstrates the biomarker potential of circulating microRNAs for epilepsy diagnosis and mechanistic links to underlying pathomechanisms., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Inhibition of microRNA-134 by an oligonucleotide antagomir (ant-134) has been shown to produce powerful antiseizure effects in multiple models of epilepsy. However, to successfully translate the treatment to the clinic, it is important to assess what potential adverse effects it may have on naive brain tissue., Methods: To investigate this, adult male Sprague-Dawley rats were treated with either ant-134 or a scrambled control sequence. Animals were later assessed for spatial navigation, before ex vivo slices were taken to assess the effects of microRNA-134 knockdown on well-defined measures of intrinsic and synaptic properties., Results: Hippocampal field potential recordings determined that silencing of microRNA-134 by ant-134 injection was associated with a reduction in epileptiform activity following application of 9 mmol/L K + . Nevertheless, rats performed normally in the novel object location test. Action potential waveforms and miniature excitatory synaptic currents recorded in CA1 pyramidal neurons were unaffected by ant-134., Significance: These results demonstrate that ant-134 confers a seizure-protective effect without obvious interference with hippocampal neuronal properties or network function. These findings support further development of this novel approach to epilepsy treatment., (© 2018 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.)

Temporal lobe epilepsy is a common and often drug-resistant seizure disorder. The underlying pathological processes which give rise to the development of spontaneous seizures include neuroinflammation, cell loss, neurogenesis and dendritic abnormalities and many of these are driven by insult-induced changes in gene expression and gene expression regulation. MicroRNAs are powerful modulators of post-transcriptional gene expression which are dysregulated during epileptogenesis. The advent of locked nucleic acid (LNA) based inhibitory methods and mimic technology has facilitated in vivo functional assessment of these molecules in epilepsy. Here we review recent advances in our understanding of the role of these short non-coding RNAs in the pathophysiology of epilepsy., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: The Centers for Medicare and Medicaid Services (CMS) require physical therapists document patients' functional limitations. The process is not standardized. 
A systematic approach to determine a patient's functional limitations and responsiveness to change is needed., Objective: The purpose of this study is to compare patient-reported outcomes (PROs) responsiveness to change using 7-level severity/complexity modifier scale proposed by Medicare to a derived scale implemented by Intermountain Healthcare's Rehabilitation Outcomes Management System (ROMS)., Design: This was a retrospective, observational cohort design., Methods: 165,183 PROs prior to July 1, 2013, were compared to 46,334 records from July 1, 2013, to December 31, 2015. Histograms and ribbon plots illustrate distribution and change of patients' scores. ROMS raw score ranges were calculated and compared to CMS' severity/complexity levels based on score percentage. Distribution of the population was compared based on the 2 methods. Sensitivity and specificity were compared for responsiveness to change based on minimal clinically important difference (MCID)., Results: Histograms demonstrated few patient scores placed in CMS scale levels at the extremes, whereas the majority of scores placed in 2 middle levels (CJ, CK). ROMS distributed scores more evenly across levels. Ribbon plots illustrated advantage of ROMS' using narrower score ranges. Greater chance for patients to change levels was observed with ROMS when an MCID was achieved. ROMS narrower scale levels resulted in greater sensitivity and good specificity., Limitations: Geographic representation for the United States was limited. Without patients' global rating of change, a reference standard to gauge validation of improvement could not be provided., Conclusions: ROMS provides a standard approach to identify accurately functional limitation modifier levels and to detect improvement more accurately than a straight across transposition using the CMS scale., (© 2017 American Physical Therapy Association)

An in vivo study in the laboratory rat model has been carried out to monitor changes to the tegument and gut of adult Fasciola hepatica following treatment with myrrh ('Mirazid'). Rats infected with the triclabendazole-resistant Dutch isolate were dosed orally with Mirazid at a concentration of 250 mg/kg and flukes recovered 2, 3 and 7 days post-treatment (pt). The flukes were processed for examination by scanning and transmission electron microscopy. A variety of changes to the external surface were observed, culminating in the sloughing of the tegumental syncytium. Internal changes to the syncytium and tegumental cell bodies were more severe and were evident from 2 days pt onwards. Swelling of the basal infolds (leading to flooding of the surface layer) and a decline in secretory body production were the major changes seen. The gastrodermal cells were less severely affected than the tegument, pointing to a trans-tegumental route of uptake for Mirazid by the fluke. Some loss of muscle fibres in the main somatic muscle layers was observed, which may be correlated with the decline in movement of flukes seen at recovery.

Background: To address a lack of information on the control of ovine helminth parasites in Northern Ireland (NI), a number of research projects have been undertaken, dealing with gastrointestinal nematodes, tapeworms and liver fluke. This investigation concerns Nematodirus and concentrates on three aspects of disease: farm management strategies for its control, derived from the results of a Questionnaire; the efficacy of treatment used by farmers, as determined by a coprological survey; and the hatching requirements of Nematodirus eggs, that is, whether prolonged chilling is a pre-requisite for hatching., Results: A Questionnaire was sent to 252 sheep farmers in NI in March 2012 (covering the years 2009-2012) and replies were received from 228 farmers. Under-dosing, inaccurate calibration of equipment and inappropriate product choice were poor practices identified. Following this survey, the efficacy of treatment of Nematodirus spp. in sheep flocks was evaluated in April and May 2012. Sampling kits were sent to 51 flock owners, all of whom returned pre- and post-anthelmintic dosing faecal samples to the laboratory for analysis. At the time of treatment, 41 flocks were positive for Nematodirus (as diagnosed by the presence of eggs). Reduced benzimidazole efficacy was detected in 35.7% of flocks tested ( n  = 28). Although only involving a small number of flocks, reduced efficacy of levamisole treatment was detected in 50%, of avermectins in 33% and of moxidectin in 75% of flocks tested (n = 2, 6 and 4, respectively). In the egg hatch experiment, carried out under "chilled" and "non-chilled" conditions, 43% of the eggs in the "non-chilled" group were able to hatch, compared to 100% in the "chilled" group., Conclusions: The identification of inefficient control strategies argues for continued education of stockholders, in order to improve their management programmes. This is particularly important where the practices might impact on the development of anthelmintic resistance, which has been shown to exist on NI farms. The appropriate choice of anthelmintic is a vital part of this plan. The ability of eggs to hatch under non-chilled conditions demonstrates a flexibility in hatching behaviour. This may represent an adaptation to climate change and account for the recent emergence of a second, autumnal peak of infection.

Synaptic downscaling is a homeostatic mechanism that allows neurons to reduce firing rates during chronically elevated network activity. Although synaptic downscaling is important in neural circuit development and epilepsy, the underlying mechanisms are poorly described. We performed small RNA profiling in picrotoxin (PTX)-treated hippocampal neurons, a model of synaptic downscaling. Thereby, we identified eight microRNAs (miRNAs) that were increased in response to PTX, including miR-129-5p, whose inhibition blocked synaptic downscaling in vitro and reduced epileptic seizure severity in vivo Using transcriptome, proteome, and bioinformatic analysis, we identified the calcium pump Atp2b4 and doublecortin (Dcx) as miR-129-5p targets. Restoring Atp2b4 and Dcx expression was sufficient to prevent synaptic downscaling in PTX-treated neurons. Furthermore, we characterized a functional crosstalk between miR-129-5p and the RNA-binding protein (RBP) Rbfox1. In the absence of PTX, Rbfox1 promoted the expression of Atp2b4 and Dcx. Upon PTX treatment, Rbfox1 expression was downregulated by miR-129-5p, thereby allowing the repression of Atp2b4 and Dcx. We therefore identified a novel activity-dependent miRNA/RBP crosstalk during synaptic scaling, with potential implications for neural network homeostasis and epileptogenesis., (© 2017 The Authors.)

An in vitro study has been carried out to monitor changes to the female reproductive system in adult triclabendazole (TCBZ)-resistant Fasciola hepatica following treatment with a commercial preparation of myrrh ("Mirazid"). Flukes were immersed for 6 h and 24 h in myrrh extract at a concentration of 200 µg/ml, then processed for histological and transmission electron microscope (TEM) examination of the uterus, Mehlis' gland, ovary and vitellaria. Egg production had become abnormal at 6 h post-treatment (pt), with the uterine lumen being filled with free vitelline cells and masses of shell protein material; few eggs were present. At 24 h pt, no eggs were present. Distinct changes to the ovary and Mehlis' gland were only observed after 24 h incubation in Mirazid. The ovary contained numbers of apoptotic oogonia and oocytes. In the Mehlis' gland, the S1 cells were disorganised and the processes from them were vacuolated, although the disruption was not significant. More severe changes were observed in the vitelline cells and follicles. After 6 h incubation in Mirazid, although the gross organisation of the vitelline follicles appeared to be normal, nuclear changes indicative of the early stages of apoptosis were observed in the stem cells and shell protein production by the mature cells had decreased. At 24 h pt, a distinct shift in cell population was evident, with the follicles containing mainly mature cells and spaces were present between the cells. The shell globule clusters in the mature cells were disorganised. In more severely-affected follicles, cells were seen to be breaking down, with karyolytic nuclei and disintegrating cytoplasm. Overall, the results have shown that exposure to Mirazid treatment had a severe impact on egg production by TCBZ-resistant flukes, an effect that was mediated by disruption of the vitelline cells and of the mechanism co-ordinating egg formation in the ootype.

Although there have been extensive studies on the larval adhesion of acorn barnacles over the past few decades, little is known about stalked barnacles. For the first time, we describe the larval adhesive systems in the stalked barnacle, Octolasmis angulata and the findings differ from previous reports of the temporary (antennulary) and cement glands in thoracican barnacles. We have found that the temporary adhesives of cyprid are produced by the clustered temporary adhesive glands located within the mantle, instead of the specialised hypodermal glands in the second antennular segment as reported in the acorn barnacles. The temporary adhesive secretory vesicles (TASV) are released from the gland cells into the antennule via the neck extensions of the glands, and surrounded with microtubules in the attachment disc. Cement glands undergo a morphological transition as the cyprid grows. Synthesis of the permanent adhesives only occurs during the early cyprid stage, and is terminated once the cement glands reach maximum size. Evidence of the epithelial invaginations on the cement glands supports the involvement of exocytosis in the secretion of the permanent adhesives. This study provides new insight into the larval adhesives system of thoracican barnacles.