A systematic review investigating fatigue, psychological and cognitive impairment following TIA and minor stroke:protocol paper

Approximately 20,000 people have a transient ischemic attack (TIA) and 23,375 have a minor stroke in England each year. Fatigue, psychological and cognitive impairments are well documented post-stroke. Evidence suggests that TIA and minor stroke patients also experience these impairments; however, they are not routinely offered relevant treatment. This systematic review aims to: (1) establish the prevalence of fatigue, anxiety, depression, post-traumatic stress disorder (PTSD) and cognitive impairment following TIA and minor stroke and to investigate the temporal course of these impairments; (2) explore impact on quality of life (QoL), change in emotions and return to work; (3) identify where further research is required and to potentially inform an intervention study

Phase II randomised controlled trial of a 6-month self-managed community exercise program for people with Parkinson’s disease

Background Evidence for longer-term exercise delivery for people with Parkinsons Disease (pwP) is deficient. Aim Evaluate safety and adherence to a minimally supported community exercise intervention and estimate effect sizes (ES). Methods Two arm parallel phase II randomised controlled trial with blind assessment. PwP able to walk ≥100meters and with no contraindication to exercise were recruited from the Thames valley, UK and randomised (1:1) to intervention (exercise) or control (handwriting) groups, via a concealed computer-generated list. Groups received a six month, twice weekly program. Exercise was undertaken in community facilities (30minutes aerobic and 30minutes resistance) and handwriting at home, both were delivered through workbooks with monthly support visits. Primary outcome was a 2minute walk, with motor symptoms (MDS-UPDRS III), fitness, health and wellbeing measured. Results Between December 2011 and August 2013, n=53 (n=54 analysed) were allocated to exercise and n=52 (n=51 analysed) to handwriting. n=37 adhered to the exercise, most attending ≥1 session/week. Aerobic exercise was performed in 99% of attended sessions and resistance in 95%. Attrition and adverse events (AE) were similar between groups, no Serious AEs (n=2 exercise, n=3 handwriting) were related, exercise group related AEs (n=2) did not discontinue intervention. Largest effects were for motor symptoms (2minute walk ES= 0.20 (95%CI=-0.44:0.45) and MDS-UPDRS III ES=-0.30 (95%CI=0.07:0.54)) in favour of exercise over the 12month follow-up period. Some small effects were observed in fitness and wellbeing measures (ES >0.1). Conclusion pwP exercised safely and the possible long-term benefits observed support a substantive evaluation of this community program.(ClinicalTrials.Gov:NCT01439022)

A long term self-managed handwriting intervention for people with Parkinson’s: Results from the control group of a phase II randomised controlled trial

Objective: To report on the control group of a trial primarily designed to investigate exercise for improving mobility in people with Parkinson’s Disease (pwP). The control group undertook a handwriting intervention to control for attention and time spent practising a specific activity. Design: Secondary analysis of a two arm parallel phase II randomised controlled trial with blind assessment. Setting: Community Participants: PwP able to walk ≥100meters and with no contraindication to exercise recruited from the Thames valley, UK and randomised (1:1) to exercise or handwriting, via a concealed computer-generated list. Intervention: Handwriting was undertaken at home and exercise in community facilities, both were delivered through workbooks with monthly support visits and involved practice for one hour, twice weekly, over six months. Main measures: Handwriting was assessed, at baseline, 3, 6 and 12months, using a pangram giving writing speed, amplitude (area) and progressive reduction in amplitude (ratio). The MSD-UPDRS item 2.7 (UPDRS-2.7) measured self-reported handwriting deficits. Results: 105 pwP were recruited (analysed: n=51 handwriting, n=54 exercise). Forty pwP adhered to the handwriting program most completing ≥1 session/week. Moderate effects were found for amplitude (total area: d=0.32 95%CI -0.11:0.7, p=0.13) in favour of handwriting over 12months, effects for writing speed and ratio parameters were small ≤0.11. Self-reported handwriting difficulties also favoured handwriting (UPDRS-2.7: OR= 0.55 95%CI 0.34:0.91, p=0.02). No adverse effects were reported Conclusion PwP generally adhere to self-directed home handwriting which may provide benefit with minimal risk. Encouraging effects were found in writing amplitude and, moreover, perceived ability. (ClinicalTrials.Gov:NCT01439022)

The Comprehensive Post-Acute Stroke Services (COMPASS) study: design and methods for a cluster-randomized pragmatic trial

Background: Patients discharged home after stroke face significant challenges managing residual neurological deficits, secondary prevention, and pre-existing chronic conditions. Post-discharge care is often fragmented leading to increased healthcare costs, readmissions, and sub-optimal utilization of rehabilitation and community services. The COMprehensive Post-Acute Stroke Services (COMPASS) Study is an ongoing cluster-randomized pragmatic trial to assess the effectiveness of a comprehensive, evidence-based, post-acute care model on patient-centered outcomes. Methods: Forty-one hospitals in North Carolina were randomized (as 40 units) to either implement the COMPASS care model or continue their usual care. The recruitment goal is 6000 patients (3000 per arm). Hospital staff ascertain and enroll patients discharged home with a clinical diagnosis of stroke or transient ischemic attack. Patients discharged from intervention hospitals receive 2-day telephone follow-up; a comprehensive clinic visit within 2 weeks that includes a neurological evaluation, assessments of social and functional determinants of health, and an individualized COMPASS Care PlanTM integrated with a community-specific resource database; and additional follow-up calls at 30 and 60 days post-stroke discharge. This model is consistent with the Centers for Medicare and Medicaid Services transitional care management services provided by physicians or advanced practice providers with support from a nurse to conduct patient assessments and coordinate follow-up services. Patients discharged from usual care hospitals represent the control group and receive the standard of care in place at that hospital. Patient-centered outcomes are collected from telephone surveys administered at 90 days. The primary endpoint is patient-reported functional status as measured by the Stroke Impact Scale 16. Secondary outcomes are: caregiver strain, all-cause readmissions, mortality, healthcare utilization, and medication adherence. The study engages patients, caregivers, and other stakeholders (including policymakers, advocacy groups, payers, and local community coalitions) to advise and support the design, implementation, and sustainability of the COMPASS care model. Discussion: Given the high societal and economic burden of stroke, identifying a care model to improve recovery, independence, and quality of life is critical for stroke survivors and their caregivers. The pragmatic trial design provides a real-world assessment of the COMPASS care model effectiveness and will facilitate rapid implementation into clinical practice if successful

Fatigue after Stroke: Baseline Predictors and Influence on Survival. Analysis of Data from UK Patients Recruited in the International Stroke Trial

Little is known about the associations of post-stroke fatigue or its influence on survival. The vitality component of the Short Form 36 (SF-36) is a valid and reliable measure of post-stroke fatigue. We sought to identify associates of post-stroke fatigue and determine whether fatigue predicted survival.We used SF-36 vitality scores obtained by postal questionnaires from 1080 UK patients randomised in the International Stroke Trial, at a mean of 64 weeks after stroke onset. We used logistic regression to explore factors at randomisation which predicted SF-36 vitality at follow-up, and the relationship between SF-36 vitality and both SF-36 mental health and SF-36 emotional role function at follow-up. We used Cox proportional hazards to explore the influence of SF-36 vitality at follow-up on subsequent survival, using four different statistical models for handling missing data.Female sex, increasing age, lower mental health and lower emotional role function scores were associated with greater degrees of fatigue after stroke (i.e. lower vitality scores) but these factors explained <30% of the variance (R(2)) in fatigue. In two models, fatigue at follow-up was associated with shorter subsequent survival.Increasing age, female sex, emotional role function and mental health were associated with increased fatigue at a mean of 64 weeks after stroke onset, but explained less than 30% of the variance. Fatigue was associated with reduced subsequent long-term survival in 2/4 models. Further work is needed to identify the biological substrate of fatigue and to clarify its influence on survival

NUDT2 Disruption Elevates Diadenosine Tetraphosphate (Ap4A) and Down-Regulates Immune Response and Cancer Promotion Genes.

Regulation of gene expression is one of several roles proposed for the stress-induced nucleotide diadenosine tetraphosphate (Ap4A). We have examined this directly by a comparative RNA-Seq analysis of KBM-7 chronic myelogenous leukemia cells and KBM-7 cells in which the NUDT2 Ap4A hydrolase gene had been disrupted (NuKO cells), causing a 175-fold increase in intracellular Ap4A. 6,288 differentially expressed genes were identified with P < 0.05. Of these, 980 were up-regulated and 705 down-regulated in NuKO cells with a fold-change ≥ 2. Ingenuity® Pathway Analysis (IPA®) was used to assign these genes to known canonical pathways and functional networks. Pathways associated with interferon responses, pattern recognition receptors and inflammation scored highly in the down-regulated set of genes while functions associated with MHC class II antigens were prominent among the up-regulated genes, which otherwise showed little organization into major functional gene sets. Tryptophan catabolism was also strongly down-regulated as were numerous genes known to be involved in tumor promotion in other systems, with roles in the epithelial-mesenchymal transition, proliferation, invasion and metastasis. Conversely, some pro-apoptotic genes were up-regulated. Major upstream factors predicted by IPA® for gene down-regulation included NFκB, STAT1/2, IRF3/4 and SP1 but no major factors controlling gene up-regulation were identified. Potential mechanisms for gene regulation mediated by Ap4A and/or NUDT2 disruption include binding of Ap4A to the HINT1 co-repressor, autocrine activation of purinoceptors by Ap4A, chromatin remodeling, effects of NUDT2 loss on transcript stability, and inhibition of ATP-dependent regulatory factors such as protein kinases by Ap4A. Existing evidence favors the last of these as the most probable mechanism. Regardless, our results suggest that the NUDT2 protein could be a novel cancer chemotherapeutic target, with its inhibition potentially exerting strong anti-tumor effects via multiple pathways involving metastasis, invasion, immunosuppression and apoptosis

Synthesis Paper: Targeted Livestock Grazing: Prescription for Healthy Rangelands

Targeted livestock grazing is a proven tool for manipulating rangeland vegetation, and current knowledge about targeted livestock grazing is extensive and expanding rapidly. Targeted grazing prescriptions optimize the timing, frequency, intensity, and selectivity of grazing (or browsing) in combinations that purposely exert grazing/browsing pressure on specific plant species or portions of the landscape. Targeted grazing differs from traditional grazing management in that the goal of targeted grazing is to apply defoliation or trampling to achieve specific vegetation management objectives, whereas the goal of traditional livestock grazing management is generally the production of livestock commodities. A shared aim of targeted livestock grazing and traditional grazing management is to sustain healthy soils, flora, fauna, and water resources that, in turn, can sustain natural ecological processes (e.g., nutrient cycle, water cycle, energy flow). Targeted grazing prescriptions integrate knowledge of plant ecology, livestock nutrition, and livestock foraging behavior. Livestock can be focused on target areas through fencing, herding, or supplement placement. Although practices can be developed to minimize the impact of toxins contained in target plants, the welfare of the animals used in targeted grazing must be a priority. Monitoring is needed to determine if targeted grazing is successful and to refine techniques to improve efficacy and efficiency. Examples of previous research studies and approaches are presented to highlight the ecological benefits that can be achieved when targeted grazing is applied properly. These cases include ways to suppress invasive plants and ways to enhance wildlife habitat and biodiversity. Future research should address the potential to select more adapted and effective livestock for targeted grazing and the associated animal welfare concerns with this practice. Targeted livestock grazing provides land managers a viable alternative to mechanical, chemical, and prescribed fire treatments to manipulate rangeland vegetation