Outcome measures in post-stroke arm rehabilitation trials: do existing measures capture outcomes that are important to stroke survivors, carers, and clinicians?

Objective: We sought to (1) identify the outcome measures currently used across stroke arm rehabilitation randomized trials, (2) identify and compare outcomes important to stroke survivors, carers and clinicians and (3) describe where existing research outcome measures capture outcomes that matter the most to stroke survivors, carers and clinicians and where there may be discrepancies. Methods: First, we systematically identified and extracted data on outcome measures used in trials within a Cochrane overview of arm rehabilitation interventions. Second, we conducted 16 focus groups with stroke survivors, carers and clinicians using nominal group technique, supplemented with eight semi-structured interviews, to identify these stakeholders’ most important outcomes following post-stroke arm impairment. Finally, we described the constructs of each outcome measure and indicated where stakeholders’ important outcomes were captured by each measure. Results: We extracted 144 outcome measures from 243 post-stroke arm rehabilitation trials. The Fugl-Meyer Assessment Upper Extremity section (used in 79/243 trials; 33%), Action Research Arm Test (56/243; 23%), and modified Ashworth Scale (53/243; 22%) were most frequently used. Stroke survivors (n = 43), carers (n = 10) and clinicians (n = 58) identified 66 unique, important outcomes related to arm impairment following stroke. Between one and three outcomes considered important by the stakeholders were captured by the three most commonly used assessments in research. Conclusion: Post-stroke arm rehabilitation research would benefit from a reduction in the number of outcome measures currently used, and better alignment between what is measured and what is important to stroke survivors, carers and clinicians

Five-Year Outcomes of the SuperB Trial:A Multicenter Randomized Controlled Trial Comparing Heparin-Bonded Endograft to Surgical Femoropopliteal Bypass

Objective: This study aims to compare the 5-year outcomes of endoluminal bypass (EB) using heparin-bonded self-expanding covered stents versus bypass surgery for extensive femoropopliteal disease, including technical and clinical outcomes and health status. Background: The surgical femoropopliteal bypass was the gold standard to treat peripheral arterial disease (PAD) for decades; however, endovascular treatment modalities are now recommended for most femoropopliteal lesions. One-year data of a randomized controlled trial comparing EB with surgical bypass (SB) have shown a faster recovery, less morbidity, and comparable patency rates between the two techniques. To date, long-term randomized controlled data regarding both techniques are lacking. Methods: Five-year results of a multicenter randomized controlled trial comparing EB with SB in patients with femoropopliteal artery disease were evaluated based on intention-to-treat and per-protocol analyses. Results: At 5-year follow-up, primary, primary-assisted, and secondary patency rates were 36.2%, 52.4%, and 68.1% for EB and 49.4%, 72.2%, and 77.8% for SB, respectively (p=0.608). Freedom from target lesion revascularization (fTLR) was 34.1% for EB and 57.6% for SB (p=0.365). In both groups, the ankle-brachial index, Rutherford classification, and walking distance significantly improved compared with baseline without differences between groups at follow-up. Freedom from major amputation rate was 92.6% in the EB group and 96.2% in the SB group (p=0.361). The 36-Item Short-Form Health Survey showed no significant differences between groups. Conclusion: Treatment of extensive femoropopliteal disease with self-expanding covered stents provides comparable clinical-related and health-related questionnaire outcomes when compared with SB through 5 years of follow-up. However, the EB is related to a higher number of reinterventions. Clinical Impact: This present study is the first to report five-year outcomes comparing an endoluminal (EB) using heparin-bonded self-expanding covered stents with surgical bypass (SB) for long and complex femoropopliteal disease. Although the advantages of treatment with EB are mostly seen in the early period after treatment, the outcomes support the use of EB for this indication and seems to be a valid and safe alternative for bypass surgery. Future trials comparing various endovascular strategies may provide further guidance for the development of an evidence-based treatment algorithm.</p

Intestinal fatty-acid binding protein and gut permeability responses to exercise

Purpose Intestinal cell damage due to physiological stressors (e.g. heat, oxidative, hypoperfusion/ischaemic) may contribute to increased intestinal permeability. The aim of this study was to assess changes in plasma intestinal fatty acid-binding protein (I-FABP) in response to exercise (with bovine colostrum supplementation, Col, positive control) and compare this to intestinal barrier integrity/permeability (5 h urinary lactulose/rhamnose ratio, L/R). Methods In a double-blind, placebo-controlled, crossover design, 18 males completed two experimental arms (14 days of 20 g/day supplementation with Col or placebo, Plac). For each arm participants performed two baseline (resting) intestinal permeability assessments (L/R) pre-supplementation and one post-exercise following supplementation. Blood samples were collected pre- and post-exercise to determine I-FABP concentration. Results Two-way repeated measures ANOVA revealed an arm?×?time interaction for L/R and I-FABP (P?<?0.001). Post hoc analyses showed urinary L/R increased post-exercise in Plac (273% of pre, P?<?0.001) and Col (148% of pre, P?<?0.001) with post-exercise values significantly lower with Col (P?<?0.001). Plasma I-FABP increased post-exercise in Plac (191% of pre-exercise, P?=?0.002) but not in the Col arm (107%, P?=?0.862) with post-exercise values significantly lower with Col (P?=?0.013). Correlations between the increase in I-FABP and L/R were evident for visit one (P?=?0.044) but not visit two (P?=?0.200) although overall plots/patterns do appear similar for each. Conclusion These findings suggest that exercise-induced intestinal cellular damage/injury is partly implicated in changes in permeability but other factors must also contribute

Sensory Innervation of Human Bone: An Immunohistochemical Study to Further Understand Bone Pain

Skeletal diseases and their surgical treatment induce severe pain. The innervation density of bone potentially explains the severe pain reported. Animal studies concluded that sensory myelinated A∂-fibers and unmyelinated C-fibers are mainly responsible for conducting bone pain, and that the innervation density of these nerve fibers was highest in periosteum. However, literature regarding sensory innervation of human bone is scarce. This observational study aimed to quantify sensory nerve fiber density in periosteum, cortical bone, and bone marrow of axial and appendicular human bones using immunohistochemistry and confocal microscopy. Multivariate Poisson regression analysis demonstrated that the total number of sensory and sympathetic nerve fibers was highest in periosteum, followed by bone marrow, and cortical bone for all bones studied. Bone from thoracic vertebral bodies contained most sensory nerve fibers, followed by the upper extremity, lower extremity, and parietal neurocranium. The number of nerve fibers declined with age and did not differ between male and female specimens. Sensory nerve fibers were organized as a branched network throughout the periosteum. The current results provide an explanation for the severe pain accompanying skeletal disease, fracture, or surgery. Further, the results could provide more insight into mechanisms that generate and maintain skeletal pain and might aid in developing new treatment strategies. PERSPECTIVE: This article presents the innervation of human bone and assesses the effect of age, gender, bone compartment and type of bone on innervation density. The presented data provide an explanation for the severity of bone pain arising from skeletal diseases and their surgical treatment

Study design and methods of the BoTULS trial: a randomised controlled trial to evaluate the clinical effect and cost effectiveness of treating upper limb spasticity due to stroke with botulinum toxin type A

Background Following a stroke, 55–75% of patients experience upper limb problems in the longer term. Upper limb spasticity may cause pain, deformity and reduced function, affecting mood and independence. Botulinum toxin is used increasingly to treat focal spasticity, but its impact on upper limb function after stroke is unclear. The aim of this study is to evaluate the clinical and cost effectiveness of botulinum toxin type A plus an upper limb therapy programme in the treatment of post stroke upper limb spasticity. Methods Trial design : A multi-centre open label parallel group randomised controlled trial and economic evaluation. Participants : Adults with upper limb spasticity at the shoulder, elbow, wrist or hand and reduced upper limb function due to stroke more than 1 month previously. Interventions : Botulinum toxin type A plus upper limb therapy (intervention group) or upper limb therapy alone (control group). Outcomes : Outcome assessments are undertaken at 1, 3 and 12 months. The primary outcome is upper limb function one month after study entry measured by the Action Research Arm Test (ARAT). Secondary outcomes include: spasticity (Modified Ashworth Scale); grip strength; dexterity (Nine Hole Peg Test); disability (Barthel Activities of Daily Living Index); quality of life (Stroke Impact Scale, Euroqol EQ-5D) and attainment of patient-selected goals (Canadian Occupational Performance Measure). Health and social services resource use, adverse events, use of other antispasticity treatments and patient views on the treatment will be compared. Participants are clinically reassessed at 3, 6 and 9 months to determine the need for repeat botulinum toxin type A and/or therapy. Randomisation : A web based central independent randomisation service. Blinding : Outcome assessments are undertaken by an assessor who is blinded to the randomisation group. Sample size : 332 participants provide 80% power to detect a 15% difference in treatment successes between intervention and control groups. Treatment success is defined as improvement of 3 points for those with a baseline ARAT of 0–3 and 6 points for those with ARAT of 4–56

Wristband accelerometers to motivate arm exercise after stroke (WAVES): study protocol for a pilot randomized controlled trial

BACKGROUND: Loss of upper limb function affects up to 85 % of acute stroke patients. Recovery of upper limb function requires regular intensive practise of specific upper limb tasks. To enhance intensity of practice interventions are being developed to encourage patients to undertake self-directed exercise practice. Most interventions do not translate well into everyday activities and stroke patients continue to find it difficult remembering integration of upper limb movements into daily activities. A wrist-worn device has been developed that monitors and provides ‘live’ upper limb activity feedback to remind patients to use their stroke arm in daily activities (The CueS wristband). The aim of this trial is to assess the feasibility of a multi-centre, observer blind, pilot randomised controlled trial of the CueS wristband in clinical stroke services. METHODS/DESIGN: This pilot randomised controlled feasibility trial aims to recruit 60 participants over 15 months from North East England. Participants will be within 3 months of stroke which has caused new reduced upper limb function and will still be receiving therapy. Each participant will be randomised to an intervention or control group. Intervention participants will wear a CueS wristband (between 8 am and 8 pm) providing “live” feedback towards pre-set movement goals through a simple visual display and vibration prompts whilst undertaking a 4-week upper limb therapy programme (reviewed twice weekly by an occupational/physiotherapist). Control participants will also complete the 4-week upper limb therapy programme but will wear a ‘sham’ CueS wristband that monitors upper limb activity but provides no feedback. Outcomes will determine study feasibility in terms of recruitment, retention, adverse events, adherence and collection of descriptive clinical and accelerometer motor performance data at baseline, 4 weeks and 8 weeks. DISCUSSION: The WAVES study will address an important gap in the evidence base by reporting the feasibility of undertaking an evaluation of emerging and affordable technology to encourage impaired upper limb activity after stroke. The study will establish whether the study protocol can be supported by clinical stroke services, thereby informing the design of a future multi-centre randomised controlled trial of clinical and cost-effectiveness. TRIAL REGISTRATION: ISRCTN:82306027. Registered 12 July 2016. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13063-016-1628-2) contains supplementary material, which is available to authorized users

Rapid Low-Cost Microarray-Based Genotyping for Genetic Screening in Primary Immunodeficiency

Background: Genetic tests for primary immunodeficiency disorders (PIDs) are expensive, time-consuming, and not easily accessible in developing countries. Therefore, we studied the feasibility of a customized single nucleotide variant (SNV) microarray that we developed to detect disease-causing variants and copy number variation (CNV) in patients with PIDs for only 40 Euros. Methods: Probes were custom-designed to genotype 9,415 variants of 277 PID-related genes, and were added to the genome-wide Illumina Global Screening Array (GSA). Data analysis of GSA was performed using Illumina GenomeStudio 2.0, Biodiscovery Nexus 10.0, and R-3.4.4 software. Validation of genotype calling was performed by comparing the GSA with whole-genome sequencing (WGS) data of 56 non-PID controls. DNA samples of 95 clinically diagnosed PID patients, of which 60 patients (63%) had a genetically established diagnosis (by Next-Generation Sequencing (NGS) PID panels or Sanger sequencing), w

Effects of food on physical and sleep complaints in children with ADHD: a randomised controlled pilot study

Attention deficit/hyperactivity disorder (ADHD), a common behavioural disorder in children, may be associated with comorbid physical and sleep complaints. Dietary intervention studies have shown convincing evidence of efficacy in reducing ADHD symptoms in children. In this pilot study, we investigated the effects of an elimination diet on physical and sleep complaints in children with ADHD. A group of 27 children (3.8–8.5 years old), who all met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for ADHD, were assigned randomly to either a diet group (15/27) or a control group (12/27). The diet group followed a 5-week elimination diet; the control group adhered to their normal diet. Parents of both groups had to keep an extended diary and had to monitor the behaviour and the physical and sleep complaints of their child conscientiously. The primary endpoint was the clinical response, i.e. a decrease of physical and sleep complaints, at the end of the trial, based on parent ratings on a Physical Complaints Questionnaire. The number of physical and sleep complaints was significantly decreased in the diet group compared to the control group (p < 0.001), with a reduction in the diet group of 77% (p < 0.001, effect size = 2.0) and in the control group of 17% (p = 0.08, effect size = 0.2). Specific complaints that were significantly reduced were in three domains: headaches or bellyaches, unusual thirst or unusual perspiration, and sleep complaints. The reduction of complaints seemed to occur independently of the behavioural changes (p = 0.1). However, the power of this comparison was low. A positive correlation existed between the reduction of physical and behavioural symptoms (p < 0.01). The reduction did not differ between children with or without an atopic constitution (p = 0.7). An elimination diet may be an effective instrument to reduce physical complaints in children with ADHD, but more research is needed to determine the effects of food on (functional) somatic symptoms in children with and without ADHD. This trial was registered as an International Standard Randomised Controlled Trial, ISRCTN47247160

The PINE study: rationale and design of a randomised comparison of epidural injection of local anaesthetics and steroids versus care-as-usual to prevent postherpetic neuralgia in the elderly [ISRCTN32866390]

BACKGROUND: Postherpetic neuralgia (PHN) is by far the most common complication of herpes zoster (HZ) and one of the most intractable pain disorders. Since PHN is seen most often in the elderly, the number of patients with this disorder is expected to increase in our ageing society. PHN may last for months to years and has a high impact on the quality of life. The results of PHN treatment are rather disappointing. Epidural injection of local anaesthetics and steroids in the acute phase of HZ is a promising therapy for the prevention of PHN. Since randomised trials on the effectiveness of this intervention are lacking, the PINE (Prevention by epidural Injection of postherpetic Neuralgia in the Elderly) study was set up. The PINE study compares the effectiveness and cost-effectiveness of a single epidural injection of local anaesthetics and steroids during the acute phase of HZ with that of care-as-usual (i.e. antivirals and analgesics) in preventing PHN in elderly patients. METHODS / DESIGN: The PINE study is an open, multicenter clinical trial in which 550 elderly (age ≥ 50 yr.) patients who consult their general practitioner in the acute phase of HZ (rash < 7 days) are randomised to one of the treatment groups. The primary clinical endpoint is the presence of HZ-related pain one month after the onset of the rash. Secondary endpoints include duration and severity of pain, re-interventions aiming to treat the existing pain, side effects, quality of life, and cost-effectiveness. CONCLUSION: The PINE study is aimed to quantify the (cost-) effectiveness of a single epidural injection during the acute phase of HZ on the prevention of PHN

Bioinformatic meta-analysis reveals novel differentially expressed genes and pathways in sarcoidosis

IntroductionSarcoidosis is a multi-system inflammatory disease of unknown origin with heterogeneous clinical manifestations varying from a single organ non-caseating granuloma site to chronic systemic inflammation and fibrosis. Gene expression studies have suggested several genes and pathways implicated in the pathogenesis of sarcoidosis, however, due to differences in study design and variable statistical approaches, results were frequently not reproducible or concordant. Therefore, meta-analysis of sarcoidosis gene-expression datasets is of great importance to robustly establish differentially expressed genes and signalling pathways.MethodsWe performed meta-analysis on 22 published gene-expression studies on sarcoidosis. Datasets were analysed systematically using same statistical cut-offs. Differentially expressed genes were identified by pooling of p-values using Edgington’s method and analysed for pathways using Ingenuity Pathway Analysis software.ResultsA consistent and significant signature of novel and well-known genes was identified, those collectively implicated both type I and type II interferon mediated signalling pathways in sarcoidosis. In silico functional analysis showed consistent downregulation of eukaryotic initiation factor 2 signalling, whereas cytokines like interferons and transcription factor STAT1 were upregulated. Furthermore, we analysed affected tissues to detect differentially expressed genes likely to be involved in granuloma biology. This revealed that matrix metallopeptidase 12 was exclusively upregulated in affected tissues, suggesting a crucial role in disease pathogenesis.DiscussionOur analysis provides a concise gene signature in sarcoidosis and expands our knowledge about the pathogenesis. Our results are of importance to improve current diagnostic approaches and monitoring strategies as well as in the development of targeted therapeutics