Search

STUDY DESIGN: Retrospective cohort study. OBJECTIVES: To describe the clinical outcomes following outpatient physical therapy for postoperative rehabilitation in 4 categories of shoulder surgery. Furthermore, we sought to determine if differences in outcomes between genders existed. BACKGROUND: Improving the quality of care for patients following shoulder surgery requires an understanding of the clinical outcomes resulting from current clinical practice. METHODS: This study included 856 patients (43.7% female; mean +/- SD age, 51.8 +/- 14.2 years) who received outpatient physical therapy following shoulder surgery. Standardized methods for classification of patients to type of shoulder surgery and collection of outcome variables were used. Data were gathered from 57 therapists working in 12 clinics. Patients included had been classified into 1 of 4 surgical categories: repair of a unidirectional instability, rotator cuff repair, rotator cuff repair with a subacromial decompression, or subacromial decompression alone. Descriptive statistics were calculated for baseline characteristics of patients in each surgical category. For all patients, scores on the Disability of the Arm Shoulder and Hand (DASH) questionnaire and a numeric pain rating scale (NPRS) were obtained at the initial and final physical therapy visits, and the change between visits was calculated. Data on number of physical therapy sessions and length of stay (LOS) were collected. For each surgical category, independent-samples t tests were used to determine differences between genders for each initial and final clinical outcome of pain and disability, change scores, utilization of visits, and LOS. The percentage of patients who achieved a minimal clinically important difference (MCID) on the DASH was also determined for each surgical group. For each gender in each surgical category, paired t tests were used to determine if patients achieved significant change in pain and disability. RESULTS: Means for each clinical outcome for the initial and final pain and disability scores, change scores, and the percentage of patients that achieved an MCID are provided. Significant differences were observed between genders for clinical outcomes. In the group treated with unilateral instability repair, women reported significantly greater initial disability than men, and their DASH change scores were significantly greater. In the group that had rotator cuff repairs, women reported significantly greater disability initially and at the final follow-up. In the group that had rotator cuff repairs combined with subacrominal decompression, women reported significantly greater disability initially and greater change in DASH scores. Females also reported greater change in their pain scores than males (P<.05). There were no significant differences between men and women in the subacromial decompression group (P<.05). There were no significant differences between genders for number of physical therapy visits or LOS. Men and women in each surgical category achieved clinically meaningful and statistically significant improvement for pain and disability during treatments (P<.01). Greater than 75% of patients achieved an MCID (15 points) on the DASH score in each surgical category (range, 75.6%-94.5%). CONCLUSIONS: Differences were observed between men and women in 4 postoperative surgical categories in each of the clinical outcomes but not for number of physical therapy visits or LOS. Statistically significant and clinically meaningful pain and disability improvements were reported for each gender within each shoulder category. Results from this study may help therapists estimate the prognosis of males and females receiving nonstandardized postoperative physical therapy in 4 different shoulder surgical categories. LEVEL OF EVIDENCE: Therapy, level 2b. J Orthop Sports Phys Ther 2010;40(1):20-29, Epub 7 December 2009. doi:10.2519/jospt.2010.3043. [ABSTRACT FROM AUTHOR]

BACKGROUND AND PURPOSE: Physical therapists frequently attend continuing education courses with the goal of providing better care, yet the effectiveness of continuing education for improving outcomes has not been examined. SUBJECTS: Data were obtained for all eligible patients (n=1,365; mean age=42.1 years, SD=14.0 years; 69.9% female) with a chief complaint of neck pain who were treated in 13 physical therapy clinics over a 24-month period. Disability data (Neck Disability Index scores) from the initial and final therapy sessions were recorded from clinical databases. METHODS: Thirty-four of 57 physical therapists employed within the 13 clinics attended a 2-day continuing education course. Eleven of the 34 attendees also participated in an ongoing clinical improvement project for patients with neck pain. Clinical outcomes were compared in the pre- and post-course periods for therapists attending or not attending the course, and for therapists participating or not participating in the ongoing project. RESULTS: There were no differences in clinical outcomes based on attendance at the continuing education course. There was an interaction between time and participation in the ongoing project, such that participants achieved greater change in disability after the course. The percentage of patients achieving at least the minimum detectable amount of change in disability with treatment increased significantly for participants after the course. DISCUSSION AND CONCLUSION: Attendance at a 2-day continuing education course was not associated with improvement in clinical outcomes, but participation in an ongoing improvement project did result in greater clinical improvement for patients with neck pain. Further investigation of educational methods to improve clinical outcomes is needed. These results suggest that traditional continuing education formats may not be effective for improving patient care. [ABSTRACT FROM AUTHOR]

STUDY DESIGN: Randomized clinical trial. OBJECTIVE: Compare outcomes of patients with low back pain receiving treatments matched or unmatched to their subgrouping based on initial clinical presentation. SUMMARY OF BACKGROUND DATA: Patients with 'nonspecific' low back pain are often viewed as a homogeneous group, equally likely to respond to any particular intervention. Others have proposed methods for subgrouping patients as a means for determining the treatment most likely to benefit patients with particular characteristics. METHODS: Patients with low back pain of less than 90 days' duration referred to physical therapy were examined before treatment and classified into one of three subgroups based on the type of treatment believed most likely to benefit the patient (manipulation, stabilization exercise, or specific exercise). Patients were randomly assigned to receive manipulation, stabilization exercises, or specific exercise treatment during a 4-week treatment period. Disability was assessed in the short-term (4 weeks) and long-term (1 year) using the Oswestry. Comparisons were made between patients receiving treatment matched to their subgroup, versus those receiving unmatched treatment. RESULTS: A total of 123 patients participated (mean age, 37.7 +/- 10.7 years; 45% female). Patients receiving matched treatments experienced greater short- and long-term reductions in disability than those receiving unmatched treatments. After 4 weeks, the difference favoring the matched treatment group was 6.6 Oswestry points (95% CI, 0.70-12.5), and at long-term follow-up the difference was 8.3 points (95% CI, 2.5-14.1). Compliers-only analysis of long-term outcomes yielded a similar result. CONCLUSIONS: Nonspecific low back pain should not be viewed as a homogenous condition. Outcomes can be improved when subgrouping is used to guide treatment decision-making. [ABSTRACT FROM AUTHOR]

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.