19 results on '"Brennan GP"'
Search Results
2. Impact of JQ1 treatment on seizures, hippocampal gene expression, and gliosis in a mouse model of temporal lobe epilepsy.
- Author
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Harnett A, Mathoux J, Wilson MM, Heiland M, Mamad O, Srinivas S, Sanfeliu A, Sanz-Rodriguez A, How KLE, Delanty N, Cryan J, Brett FM, Farrell MA, O'Brien DF, Henshall DC, and Brennan GP
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- Animals, Mice, Male, Transcription Factors metabolism, Transcription Factors genetics, Epigenesis, Genetic drug effects, Mice, Inbred C57BL, Gene Expression drug effects, Nuclear Proteins metabolism, Nuclear Proteins genetics, Bromodomain Containing Proteins, Epilepsy, Temporal Lobe metabolism, Epilepsy, Temporal Lobe drug therapy, Epilepsy, Temporal Lobe genetics, Triazoles pharmacology, Hippocampus metabolism, Hippocampus drug effects, Azepines pharmacology, Seizures metabolism, Seizures drug therapy, Seizures genetics, Kainic Acid pharmacology, Gliosis metabolism, Gliosis drug therapy, Disease Models, Animal
- Abstract
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.)
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- 2024
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3. Fasciola gigantica: Ultrastructural localisation of neoblast recruitment in somatic tissues during growth and development in the hepatic parenchyma of experimentally infected mice.
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Hanna REB, Brennan GP, Robinson MW, Kajugu PE, and Quinn JM
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- Animals, Mice, Cell Differentiation, Fascioliasis parasitology, Fascioliasis veterinary, Liver parasitology, Fasciola physiology
- Abstract
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.)
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- 2024
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4. Examining the Relationship Between Individual Patient Factors and Substantial Clinical Benefit From Telerehabilitation Among Patients With Chronic Low Back Pain.
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McLaughlin KH, Fritz JM, Minick KI, Brennan GP, McGee T, Lane E, Thackeray A, Bardsley T, Wegener ST, Hunter SJ, and Skolasky RL
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- Humans, Prospective Studies, Longitudinal Studies, Physical Therapy Modalities, Low Back Pain therapy, Telerehabilitation, Chronic Pain
- Abstract
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.)
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- 2024
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5. Differential microRNA editing may drive target pathway switching in human temporal lobe epilepsy.
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Lau KEH, Nguyen NT, Kesavan JC, Langa E, Fanning K, Brennan GP, Sanz-Rodriguez A, Villegas-Salmerón J, Yan Y, Venø MT, Mills JD, Rosenow F, Bauer S, Kjems J, and Henshall DC
- Abstract
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.)
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- 2024
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6. CPEB4-CLOCK crosstalk during temporal lobe epilepsy.
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de Diego-Garcia L, Brennan GP, Auer T, Menendez-Mendez A, Parras A, Martin-Gil A, Mitra M, Ollà I, Villalba-Benito L, Gil B, Alves M, Lau K, Delanty N, Beausang A, Cryan J, Brett FM, Farrell MA, O'Brien DF, Mendez R, Carracedo-Rodríguez G, Henshall DC, Lucas JJ, and Engel T
- Subjects
- Animals, Humans, Male, Mice, Hippocampus, RNA, Messenger metabolism, Seizures, Transcription Factors metabolism, Drug Resistant Epilepsy, Epilepsy, Temporal Lobe metabolism, Melatonin blood, RNA-Binding Proteins genetics, RNA-Binding Proteins metabolism, Status Epilepticus chemically induced, Status Epilepticus genetics, CLOCK Proteins genetics
- Abstract
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.)
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- 2023
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7. Brain cell-specific origin of circulating microRNA biomarkers in experimental temporal lobe epilepsy.
- Author
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Brindley E, Heiland M, Mooney C, Diviney M, Mamad O, Hill TDM, Yan Y, Venø MT, Reschke CR, Batool A, Langa E, Sanz-Rodriguez A, Heller JP, Morris G, Conboy K, Kjems J, Brennan GP, and Henshall DC
- Abstract
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.)
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- 2023
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8. Significant Clinical Improvement Was Predicted in a Cohort of Patients With Low Back Pain Early in the Care Process.
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Brennan GP, Snow G, Minick KI, and Stevans JM
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- Humans, Retrospective Studies, Prognosis, Surveys and Questionnaires, Physical Therapy Modalities, Disability Evaluation, Low Back Pain rehabilitation
- Abstract
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.)
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- 2023
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9. Racial and Ethnic Disparities in the Incidence of High-Impact Chronic Pain Among Primary Care Patients with Acute Low Back Pain: A Cohort Study.
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Roseen EJ, Smith CN, Essien UR, Cozier YC, Joyce C, Morone NE, Phillips RS, Gergen Barnett K, Patterson CG, Wegener ST, Brennan GP, Delitto A, Saper RB, Beneciuk JM, and Stevans JM
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- Adult, United States, Humans, Female, Male, Cohort Studies, Prospective Studies, Incidence, Primary Health Care, Chronic Pain epidemiology, Low Back Pain epidemiology
- Abstract
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.)
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- 2023
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10. Variation in Outcomes and Number of Visits Following Care Guideline Implementation: Part 2 of an Analysis of 12 355 Patients After Total Knee Arthroplasty.
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Capin JJ, Minick KI, Stevens-Lapsley JE, Snow GL, Woodfield D, Dibblee P, Brennan GP, and Hunter SJ
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- Humans, Activities of Daily Living, Bayes Theorem, Knee Joint, Physical Therapy Modalities, Treatment Outcome, Arthroplasty, Replacement, Knee rehabilitation, Osteoarthritis, Knee
- Abstract
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 .
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- 2023
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11. Improved Outcomes Following a Care Guideline Implementation: Part 1 of an Analysis of 12 355 Patients After Total Knee Arthroplasty.
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Minick KI, Hunter SJ, Capin JJ, Stevens-Lapsley JE, Snow GL, Woodfield D, Dibblee P, and Brennan GP
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- Humans, Activities of Daily Living, Treatment Outcome, Knee Joint, Physical Therapy Modalities, Arthroplasty, Replacement, Knee rehabilitation, Osteoarthritis, Knee etiology
- Abstract
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 .- Published
- 2023
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12. Characterizing modifications to a comparative effectiveness research study: the OPTIMIZE trial-using the Framework for Reporting Adaptations and Modifications to Evidence-based Interventions (FRAME).
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Fritz JM, Greene T, Brennan GP, Minick K, Lane E, Wegener ST, and Skolasky RL
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- Adult, Humans, Comparative Effectiveness Research, Evidence-Based Medicine, Pandemics, COVID-19, Low Back Pain
- Abstract
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).)
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- 2023
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13. Detection of MicroRNAs in Brain Slices Using In Situ Hybridization.
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Quinlan S, Henke C, Brennan GP, Henshall DC, and Jimenez-Mateos EM
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- Animals, Mice, Humans, In Situ Hybridization, Brain, Research Personnel, MicroRNAs genetics, Brain Diseases
- Abstract
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.)
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- 2023
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14. Treatment effect modifiers for individuals with acute low back pain: secondary analysis of the TARGET trial.
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Beneciuk JM, George SZ, Patterson CG, Smith CN, Brennan GP, Wegener ST, Roseen EJ, Saper RB, and Delitto A
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- Humans, Physical Therapy Modalities, Pain Measurement, Physical Examination, Disability Evaluation, Low Back Pain drug therapy, Acute Pain drug therapy
- Abstract
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.)
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- 2023
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15. Editorial: The molecular mechanisms of epilepsy and potential therapeutics.
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Engel T, Brennan GP, and Soreq H
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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.
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- 2022
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16. MicroRNA Profiling Shows a Time-Dependent Regulation within the First 2 Months Post-Birth and after Mild Neonatal Hypoxia in the Hippocampus from Mice.
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Leavy A, Brennan GP, and Jimenez-Mateos EM
- Abstract
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.
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- 2022
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17. A companion to the preclinical common data elements for proteomics, lipidomics, and metabolomics data in rodent epilepsy models. A report of the TASK3-WG4 omics working group of the ILAE/AES joint translational TASK force.
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Bindila L, Eid T, Mills JD, Hildebrand MS, Brennan GP, Masino SA, Whittemore V, Perucca P, Reid CA, Patel M, Wang KK, and van Vliet EA
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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.)
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- 2022
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18. Outcomes of Telehealth Physical Therapy Provided Using Real-Time, Videoconferencing for Patients With Chronic Low Back Pain: A Longitudinal Observational Study.
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Fritz JM, Minick KI, Brennan GP, McGee T, Lane E, Skolasky RL, Thackeray A, Bardsley T, Wegener ST, and Hunter SJ
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- Adult, Female, Humans, Male, Middle Aged, Physical Therapy Modalities, Prospective Studies, Videoconferencing, Chronic Pain rehabilitation, Low Back Pain rehabilitation, Telemedicine
- Abstract
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.)
- Published
- 2022
- Full Text
- View/download PDF
19. A companion to the preclinical common data elements for genomics, transcriptomics, and epigenomics data in rodent epilepsy models. A report of the TASK3-WG4 omics working group of the ILAE/AES joint translational TASK force.
- Author
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van Vliet EA, Hildebrand MS, Mills JD, Brennan GP, Eid T, Masino SA, Whittemore V, Bindila L, Wang KK, Patel M, Perucca P, and Reid CA
- Abstract
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.)
- Published
- 2022
- Full Text
- View/download PDF
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