A population based study of the prevalence of fatigue following transient ischaemic attack and minor stroke

BACKGROUND AND PURPOSE: Fatigue is common after stroke and can be attributable to the increased physical effort associated with severe neurological deficits; however, its presence in those with little motor deficit raises the possibility of confounding by other factors, such as comorbidity, anxiety, and medication. To control for such factors and determine the extent of stroke-specific fatigue, we compared patients with minor stroke who had little or no residual neurological deficit with patients with TIA; both groups had undergone similar investigations and treatment. METHODS: The prevalence of fatigue 6 months after TIA or minor stroke was assessed in consecutive patients using the Chalder fatigue scale in a population-based incidence study (Oxford Vascular Study). Patients were included if they were independent in self-care Barthel Index (>or=18/20) and without major cognitive impairment (Mini-Mental State Examination >or=24/30). Stroke severity at baseline was assessed with the National Institute of Health Stroke Scale (NIHSS). Other potential causes of fatigue were assessed including anxiety, depression, recent life events, medication, and abnormalities in biochemistry or hematologic tests. RESULTS: Seventy-six participants had minor stroke (mean age, 74.1 years; 42 men) and 73 had TIA (mean age, 72.5 years; 40 men). At 6-month follow-up, median Barthel Index score was 20 (interquartile range, 20-20) in both groups. However, fatigue was more common after stroke than TIA (56% vs 29%; OR, 3.14; 95% CI, 1.51-6.57; P=0.0008). This difference was present both in patients with modified Rankin score of 0 at 6 months (23.8% vs 10.3%) and patients with modified Rankin score >or=1 (69.2% vs 48.6%), and remained more frequent in stroke patients after adjustment for potential confounders. Within the group of patients with stroke, the prevalence of fatigue increased with initial stroke severity (87% NIHSS >or=4 vs 48% NIHSS <or=3; P=0.0087); however, stroke patients with initial NIHSS of 0 were still more fatigued than patients with TIA (57% vs 29%; P=0.015). CONCLUSIONS: The prevalence of fatigue after minor stroke is higher than after TIA, suggesting that it is not simply a consequence of the stress of a recent acute cerebral event, comorbidity, medication, or other potential confounders. The high levels of fatigue in stroke patients without neurological impairment suggest it has a central origin rather than being the result of increased physical effort required after stroke

Longitudinal evaluation, acceptability and long-term retention of knowledge on a horizontally integrated organic and functional systems course

Undergraduate medical education is moving from traditional disciplinary basic science courses into more integrated curricula. Integration models based on organ systems originated in the 1950s, but few longitudinal studies have evaluated their effectiveness. This article outlines the development and implementation of the Organic and Functional Systems (OFS) courses at the University of Minho in Portugal, using evidence collected over 10 years. It describes the organization of content, student academic performance and acceptability of the courses, the evaluation of preparedness for future courses and the retention of knowledge on basic sciences. Students consistently rated the OFS courses highly. Physician tutors in subsequent clinical attachments considered that students were appropriately prepared. Performance in the International Foundations of Medicine examination of a self-selected sample of students revealed similar performances in basic science items after the last OFS course and 4 years later, at the moment of graduation. In conclusion, the organizational and pedagogical approaches of the OFS courses achieve high acceptability by students and result in positive outcomes in terms of preparedness for subsequent training and long-term retention of basic science knowledge

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

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