The utility of the auditory brainstem response in children with atypical saccadic eye movements

Full version unavailable due to 3rd party copyright restrictionsLesions in the brainstem result in widespread damage to a number of sensorimotor systems including oculomotor and auditory neural circuits. Although these systems are spatially separate and highly specialised, they are also co-located. This thesis, investigates whether lesions in the oculomotor system will also cause co-morbid dysfunction in the auditory pathways. Specifically, we investigated the usefulness of the Auditory Brainstem Response (ABR) in two oculomotor conditions: slow saccades in Gaucher disease (GD) and opsoclonus in Dancing Eye Syndrome (DES). We present four empirical studies. In our first study we systematically investigated the ABR in GD. We found that multimodal testing can better delineate underlying neurological deficits in neuronopathic GD (nGD) and distinguish between phenotypes. In the second study we examined the ABR's utility as a longitudinal, objective marker of disease burden and in a randomised clinical control trial. ABRs continued to deteriorate regardless of treatment. In our third study we assessed audiological function in DES. We found that at least 43% of DES patients have hyperacusis. We also found subtle abnormalities in the auditory brainstem, as shown by the ABR. Our final study explored the onset-offset response in the ABR and assessed its utility as a clinical marker. Overall, this thesis provides new evidence that auditory pathways are also affected in diseases which are traditionally assumed to be ‘oculomotor’ in nature. We believe that there is sufficient evidence to warrant the inclusion of audiological testing, such as the ABR, as part of the standard assessment of newly diagnosed GD patients and that they undergo these tests prior to commencing treatment. These tests may also have a wider application as longitudinal outcome measures for use in clinical trials or as markers of neurological burden in GD and we believe may be useful in other metabolic diseases; we found that current therapies for GD have low efficacy. Understanding the underlying neurological deficits in these debilitating illnesses can only help to improve treatments and the long-term outlook for these patients

Improving the sustainability of hospital-based interventions: a study protocol for a systematic review

Introduction Sustaining effective interventions in hospital environments is essential to improving health outcomes, and reducing research waste. Current evidence suggests many interventions are not sustained beyond their initial delivery. The reason for this failure remains unclear. Increasingly research is employing theoretical frameworks and models to identify critical factors that influence the implementation of interventions. However, little is known about the value of these frameworks on sustainability. The aim of this review is to examine the evidence regarding the use of theoretical frameworks to maximise effective intervention sustainability in hospital-based settings in order to better understand their role in supporting long-term intervention use. Methods and analysis Systematic review. We will systematically search the following databases: Medline, AMED, CINAHL, Embase and Cochrane Library (CENTRAL, CDSR, DARE, HTA). We will also hand search relevant journals and will check the bibliographies of all included studies. Language and date limitations will be applied. We will include empirical studies that have used a theoretical framework (or model) and have explicitly reported the sustainability of an intervention (or programme). One reviewer will remove obviously irrelevant titles. The remaining abstracts and full-text articles will be screened by two independent reviewers to determine their eligibility for inclusion. Disagreements will be resolved by discussion, and may involve a third reviewer if required. Key study characteristics will be extracted (study design, population demographics, setting, evidence of sustained change, use of theoretical frameworks and any barriers or facilitators data reported) by one reviewer and cross-checked by another reviewer. Descriptive data will be tabulated within evidence tables, and key findings will be brought together within a narrative synthesis. Ethics and dissemination Formal ethical approval is not required as no primary data will be collected. Dissemination of results will be through peer-reviewed journal publications, presentation at an international conference and social media

Attention control comparisons with SLT for people with aphasia following stroke: methodological concerns raised following a systematic review

Objective: Attention control comparisons in trials of stroke rehabilitation require care to minimize the risk of comparison choice bias. We compared the similarities and differences in SLT and social support control interventions for people with aphasia. Data sources: Trial data from the 2016 Cochrane systematic review of SLT for aphasia after stroke. Methods: Direct and indirect comparisons between SLT, social support and no therapy controls. We double-data extracted intervention details using the template for intervention description and replication. Standardized mean differences and risk ratios (95% confidence intervals (CIs)) were calculated. Results: Seven trials compared SLT with social support (n  =  447). Interventions were matched in format, frequency, intensity, duration and dose. Procedures and materials were often shared across interventions. Social support providers received specialist training and support. Targeted language rehabilitation was only described in therapy interventions. Higher drop-out (P  =  0.005, odds ratio (OR) 0.51, 95% CI 0.32–0.81) and non-adherence to social support interventions (P  <  0.00001, OR 0.18, 95% CI 0.09–0.37) indicated an imbalance in completion rates increasing the risk of control comparison bias. Conclusion: Distinctions between social support and therapy interventions were eroded. Theoretically based language rehabilitation was the remaining difference in therapy interventions. Social support is an important adjunct to formal language rehabilitation. Therapists should continue to enable those close to the person with aphasia to provide tailored communication support, functional language stimulation and opportunities to apply rehabilitation gains. Systematic group differences in completion rates is a design-related risk of bias in outcomes observed

User involvement in a Cochrane systematic review:using structured methods to enhance the clinical relevance, usefulness and usability of a systematic review update

Background: This paper describes the structured methods used to involve patients, carers and health professionals in an update of a Cochrane systematic review relating to physiotherapy after stroke and explores the perceived impact of involvement.Methods: We sought funding and ethical approval for our user involvement. We recruited a stakeholder group comprising stroke survivors, carers, physiotherapists and educators and held three pre-planned meetings during the course of updating a Cochrane systematic review. Within these meetings, we used formal group consensus methods, based on nominal group techniques, to reach consensus decisions on key issues relating to the structure and methods of the review.Results: The stakeholder group comprised 13 people, including stroke survivors, carers and physiotherapists with a range of different experience, and either 12 or 13 participated in each meeting. At meeting 1, there was consensus that methods of categorising interventions that were used in the original Cochrane review were no longer appropriate or clinically relevant (11/13 participants disagreed or strongly disagreed with previous categories) and that international trials (which had not fitted into the original method of categorisation) ought to be included within the review (12/12 participants agreed or strongly agreed these should be included). At meeting 2, the group members reached consensus over 27 clearly defined treatment components, which were to be used to categorise interventions within the review (12/12 agreed or strongly agreed), and at meeting 3, they agreed on the key messages emerging from the completed review. All participants strongly agreed that the views of the group impacted on the review update, that the review benefited from the involvement of the stakeholder group, and that they believed other Cochrane reviews would benefit from the involvement of similar stakeholder groups.Conclusions: We involved a stakeholder group in the update of a Cochrane systematic review, using clearly described structured methods to reach consensus decisions. The involvement of stakeholders impacted substantially on the review, with the inclusion of international studies, and changes to classification of treatments, comparisons and subgroup comparisons explored within the meta-analysis. We argue that the structured approach which we adopted has implications for other systematic reviews.</p

Barriers and facilitators to the implementation of the advanced nurse practitioner role in primary care settings: a scoping review

Background: Workload and workforce issues in primary care are key drivers for the growing international trend to expand nursing roles. Advanced nurse practitioners are increasingly being appointed to take on activities and roles traditionally carried out by doctors. Successful implementation of any new role within multidisciplinary teams is complex and time-consuming, therefore it is important to understand the factors that may hinder or support implementation of the advanced nurse practitioner role in primary care settings. Objectives: To identify, appraise and synthesise the barriers and facilitators that impact implementation of advanced practitioner roles in primary care settings. Methods: A scoping review conducted using the Arksey and O’Malley (2005) framework and reported in accordance with PRISMA-ScR. Eight databases (Cochrane Library, Health Business Elite, Kings Fund Library, HMIC, Medline, CINAHL, SCOPUS and Web of Science) were searched to identify studies published in English between 2002 and 2017. Study selection and methodological assessment were conducted by two independent reviewers. A pre-piloted extraction form was used to extract the following data: study characteristics, context, participants and information describing the advanced nurse practitioner role. Deductive coding for barriers and facilitators was undertaken using a modified Yorkshire Contributory Framework. We used inductive coding for barriers or facilitators that could not be classified using pre-defined codes. Disagreements were addressed through discussion. Descriptive data was tabulated within evidence tables, and key findings for barriers and facilitators were brought together within a narrative synthesis based on the volume of evidence. Findings: Systematic searching identified 5976 potential records, 2852 abstracts were screened, and 122 full texts were retrieved. Fifty-four studies (reported across 76 publications) met the selection criteria. Half of the studies (n=27) were conducted in North America (n=27), and 25/54 employed a qualitative design. The advanced nurse practitioner role was diverse, working across the lifespan and with different patient groups. However, there was little agreement about the level of autonomy, or what constituted everyday activities. Team factors were the most frequently reported barrier and facilitator. Individual factors, lines of responsibility and ‘other’ factors (i.e. funding), were also frequently reported barriers. Facilitators included individual factors, supervision and leadership and ‘other’ factors (i.e. funding, planning for role integration). Conclusion: Building collaborative relationships with other healthcare professionals and negotiating the role are critical to the success of the implementation of the advanced nurse practitioner role. Team consensus about the role and how it integrates into the wider team is also essential

Exploring eye care pathways, patient priorities and economics in Pakistan: a scoping review and expert consultation study with thematic analysis

PURPOSE: As the prevalence of eye diseases increases, demand for effective, accessible and equitable eye care grows worldwide. This is especially true in lower and middle‐income countries, which have variable levels of infrastructure and economic resources to meet this increased demand. In the present study we aimed to review the literature on eye care in Pakistan comprehensively, with a particular focus on eye care pathways, patient priorities and economics. METHODS: A systematic scoping review was performed to identify literature relating to eye care in Pakistan. Searches of relevant electronic databases and grey literature were carried out. The results were analysed through a mixed methods approach encompassing descriptive numerical summary and thematic analysis. To consolidate results and define priority areas for future study, expert consultation exercises with key stakeholders were conducted using qualitative semi‐structured interviews. RESULTS: One hundred and thirty‐two papers (published and unpublished) were included in the final review. The majority (n = 93) of studies utilised a quantitative design. Seven interlinked themes were identified: eye care pathways, burden of eye disease, public views on eye‐related issues, workforce, barriers to uptake of eye care services, quality of eye care services and economic impact of blindness. Research priorities included investigating the eye care workforce, the quality and efficiency of current eye care services, eye care services available in rural Pakistan and the costs and benefits related to eye care provision and sustaining eye care programmes. CONCLUSIONS: To the best of our knowledge, this is the first review to synthesise evidence from papers across the field relating to eye care in Pakistan. As such, this work provides new insights into the achievements of the national eye health programme, challenges in eye care in Pakistan and priority areas for future research

Speech and language therapy for aphasia following stroke

Background  Aphasia is an acquired language impairment following brain damage that affects some or all language modalities: expression and understanding of speech, reading, and writing. Approximately one third of people who have a stroke experience aphasia.  Objectives  To assess the effects of speech and language therapy (SLT) for aphasia following stroke.  Search methods  We searched the Cochrane Stroke Group Trials Register (last searched 9 September 2015), CENTRAL (2015, Issue 5) and other Cochrane Library Databases (CDSR, DARE, HTA, to 22 September 2015), MEDLINE (1946 to September 2015), EMBASE (1980 to September 2015), CINAHL (1982 to September 2015), AMED (1985 to September 2015), LLBA (1973 to September 2015), and SpeechBITE (2008 to September 2015). We also searched major trials registers for ongoing trials including ClinicalTrials.gov (to 21 September 2015), the Stroke Trials Registry (to 21 September 2015), Current Controlled Trials (to 22 September 2015), and WHO ICTRP (to 22 September 2015). In an effort to identify further published, unpublished, and ongoing trials we also handsearched theInternational Journal of Language and Communication Disorders(1969 to 2005) and reference lists of relevant articles, and we contacted academic institutions and other researchers. There were no language restrictions.  Selection criteria  Randomised controlled trials (RCTs) comparing SLT (a formal intervention that aims to improve language and communication abilities, activity and participation) versus no SLT; social support or stimulation (an intervention that provides social support and communication stimulation but does not include targeted therapeutic interventions); or another SLT intervention (differing in duration, intensity, frequency, intervention methodology or theoretical approach).  Data collection and analysis  We independently extracted the data and assessed the quality of included trials. We sought missing data from investigators.  Main results  We included 57 RCTs (74 randomised comparisons) involving 3002 participants in this review (some appearing in more than one comparison). Twenty-seven randomised comparisons (1620 participants) assessed SLT versus no SLT; SLT resulted in clinically and statistically significant benefits to patients' functional communication (standardised mean difference (SMD) 0.28, 95% confidence interval (CI) 0.06 to 0.49, P = 0.01), reading, writing, and expressive language, but (based on smaller numbers) benefits were not evident at follow-up. Nine randomised comparisons (447 participants) assessed SLT with social support and stimulation; meta-analyses found no evidence of a difference in functional communication, but more participants withdrew from social support interventions than SLT. Thirty-eight randomised comparisons (1242 participants) assessed two approaches to SLT. Functional communication was significantly better in people with aphasia that received therapy at a high intensity, high dose, or over a long duration compared to those that received therapy at a lower intensity, lower dose, or over a shorter period of time. The benefits of a high intensity or a high dose of SLT were confounded by a significantly higher dropout rate in these intervention groups. Generally, trials randomised small numbers of participants across a range of characteristics (age, time since stroke, and severity profiles), interventions, and outcomes.  Authors' conclusions  Our review provides evidence of the effectiveness of SLT for people with aphasia following stroke in terms of improved functional communication, reading, writing, and expressive language compared with no therapy. There is some indication that therapy at high intensity, high dose or over a longer period may be beneficial. HIgh-intensity and high dose interventions may not be acceptable to all.REF Eligible with Permitted Exceptio

Application of compositional models for glycan HILIC data

Glycoconjugates constitute a major class of biomolecules which include glycoproteins, glycosphingolipids and proteoglycans. The enzymatic process in which glycans (sugar chains) are linked to proteins or lipids is called glycosylation. Glycosylation is involved in many biological processes, both physiological and pathological, inlcuding host-pathogen interactions, tumour invasion, cell trafficking and signalling. Changes in glycan structure are thought be be at least partly responsible for the development of inflammation, infection, arteriosclerosis, immune defects and autoimmunity. Such changes have been observed in human diseases such as diabetes mellitus, rheumatoid arthritis and Alzheimer’s Disease. Aberrant patterns of glycosylation are also a universal feature of cancer cells. The field of glycobiology thus shows great potential for the discovery of glycan biomarkers for disease diagnosis and prognosis. Here we focus specifically on N-glycans, that is, glycans attached to protein molecules via a nitrogen atom. This class of glycans is the best characterized. High-throughput HILIC analysis is a well-established technique for the separation and quantification of N-linked glycans released from glycoproteins. HILIC analysis quantifies theN-glycan structures in serum via a chromatogram, which is subsequently standardized and integrated. The generated data for each sample is a set of relative HILIC peak areas and as a result, the data is compositional. To-date, most statistical analyses of these glycan data fail to account for their compositional nature. We compare and contrast three compositional data models for the glycan HILIC data: the Dirichlet, Nested Dirichlet and Logistic Normal models, with the intention of providing tools for the statistical analysis of compositional data analysis in the glycobiology field. We use these three models for classification of disease/control cases in ovarian and lung cancer diagnosis applications. We discuss and compare these models in terms of their classification performance and goodness-of-fit

Neutron reflectometry to investigate the delivery of lipids and DNA to interfaces (Review)

The application of scattering methods in the study of biological and biomedical problems is a field of research that is currently experiencing fast growth. In particular, neutron reflectometry (NR) is a technique that is becoming progressively more widespread, as indicated by the current commissioning of several new reflectometers worldwide. NR is valuable for the characterization of biomolecules at interfaces due to its capability to provide quantitative structural and compositional information on relevant molecular length scales. Recent years have seen an increasing number of applications of NR to problems related to drug and gene delivery. We start our review by summarizing the experimental methodology of the technique with reference to the description of biological liquid interfaces. Various methods for the interpretation of data are then discussed, including a new approach based on the lattice mean-field theory to help characterize stimulus-responsive surfaces relevant to drug delivery function. Recent progress in the subject area is reviewed in terms of NR studies relevant to the delivery of lipids and DNA to surfaces. Lastly, we discuss two case studies to exemplify practical features of NR that are exploited in combination with complementary techniques. The first case concerns the interactions of lipid-based cubic phase nanoparticles with model membranes (a drug delivery application), and the second case concerns DNA compaction at surfaces and in the bulk solution (a gene delivery application). (C) 2008 American Vacuum Society. [DOI: 10.1116/1.2976448