Submitted in partial compliance with the requirements for the Master’s Degree in Technology: Chiropractic, Durban University of Technology, 2014. / Background: Practitioners are required to practice evidence-based medicine. The availability of large volumes of information make this practice style difficult for the practitioner. However, a systematic review allows literature to be organised, rated and allows current, abbreviated research resources for practitioner in clinical practice. Objectives: The effectiveness of the Gonstead Chiropractic Technique (GCT) was evaluated to present current evidence available for various conditions for which the GCT is utilised in clinical practice. Thus, the aim of the study was to systematically review, collate and evaluate the research evidence in the literature to determine the effectiveness of the GCT. Method: A literature search was conducted, based on key terms including: Gonstead and manual, Gonstead and technique, and Gonstead and manipulative/manipulation. Databases searched were: CINAHL Plus, Google Scholar, MEDLINE, Metalib, Pubmed, Science Direct, Springerlink and Summons. The articles were screened according to inclusion and exclusion criteria, after which secondary hand and reference searches were done. Thereafter the articles were reviewed by six independent reviewers. Appropriate scales were used to rate the methodological rigour of each article (e.g. PEDro). The results were analysed and ranked, before these outcomes were classified and contextualised in the clinical conditions on which the included studies were based. Results: A total of 477 citations were identified; after screening 26 English articles remained. Two articles were added through the secondary hand-search. Limited to no evidence existed for the effectiveness of GCT for neck pain / headache / face pain and limited evidence existed for gynaecological issues, scoliosis, neurological disorders, fractures, blood pressure and physiological presentations. Consensus was evident for gynaecological issues, neurological disorders, fractures (with the exception of the undiagnosed fracture) and physiological presentations, whereas the neck pain / headache / face pain and scoliosis were conflicting. Conclusion: Limited evidence shows a need for future studies with stringent methodological rigour, so as to investigate the appropriateness / inappropriateness of the use of the GCT. The lack of evidence for GCT may compromise appropriate informed consent and treatment. Therefore practitioners are encouraged to use appropriate and validated tools to measure the patient’s clinical progress

The objective of the work presented in this thesis was to explore the role of potential alternatives to platelet transfusions and specifically to investigate whether desmopressin could be used for treatment of thrombocytopenia or platelet dysfunction. Patients with thrombocytopenia or platelet dysfunction are often treated with platelet transfusions to treat or prevent bleeding. However the evidence for the efficacy of platelet transfusion is limited and there is some evidence of harm. I have focused on thrombocytopenic patients with haematological malignancies or critically ill patients, who are amongst the groups most commonly treated with platelet transfusions. The aims of this research were to determine: 1. If levels of Von Willebrand factor (VWF) or other measures of haemostasis are predictive of bleeding in severe thrombocytopenia; 2. Whether VWF compensates for thrombocytopenia in vitro; 3. The evidence for the efficacy of desmopressin in all patients undergoing surgery or invasive procedures; 4. The evidence for desmopressin for platelet dysfunction or thrombocytopenia; 5. If it is feasible to use desmopressin to treat critically ill thrombocytopenic patients in a clinical trial. To identify derangements of haemostasis that may signify candidates for alternatives to platelet transfusions, I analysed blood samples from an observational trial of fifty patients with haematological malignancies and profound thrombocytopenia due to intensive chemotherapy. I used a panel of tests to investigate measures of primary haemostasis, thrombin generation, cross-linked fibrin formation and fibrinolysis. Using multivariable logistic regression, I found no consistent correlation between any measures of haemostasis and the risk of clinically significant bleeding. VWF antigen levels were the best predictor of clinically significant bleeding on the same day (odds ratio 0.31, 95% confidence interval 0.10 to 0.98, p=0.047) but were not predictive of severe bleeding over the 24 hours after the test (odds ratio 0.48, 95% confidence interval 0.10 to 2.34, p=0.36). In a separate set of experiments, I evaluated thrombus formation under flow in thrombocytopenia. This technique was sensitive to the platelet count . Addition of exogenous VWF to thrombocytopenic blood resulted in improvement in thrombus formation, suggesting that agents that affect or influence VWF pathways might have a role. Desmopressin can be used to increase VWF levels, so leading on from my laboratory experiments; I used systematic reviews and meta-analyses to assess whether desmopressin could be used in unselected patients to reduce bleeding peri-operatively. I identified 62 randomised controlled trials. Overall there was no evidence of benefit for administering desmopressin to unselected patients. However further analysis of eleven randomised controlled trials that focused on patients with platelet dysfunction found that desmopressin resulted in transfusion of fewer units of red cells (equivalent to a 25% reduction compared to control), less blood loss (equivalent to a 23% reduction compared to control) and a lower risk of requiring a re-operation due to bleeding (Peto odds ratio 0.39, 95% confidence interval 0.18 to 0.84). There was no evidence for an increase in thrombotic events. There was no randomised controlled trial evidence for perioperative desmopressin for patients with thrombocytopenia. These specific research gaps were addressed by designing new clinical trials. I have commenced a randomised controlled feasibility trial of desmopressin versus placebo for critically ill patients with thrombocytopenia undergoing invasive procedures. This trial is ongoing and is the first randomised trial evaluating peri-procedural desmopressin in thrombocytopenia. The programme of work arising from this research has the potential to benefit a large number of patients by preventing bleeding and reducing exposure to allogeneic blood components such as platelets. The results presented in this thesis are exploratory but are an important step on a path towards larger trials using desmopressin as an alternative, or adjunct to platelet transfusion.

Orientador: Vania dos Santos Nunes Nogueira / Resumo: Objetivo: esta revisão sistemática da literatura e metanálise comparou a taxa da mortalidade na acromegalia com a taxa esperada na população geral dos estudos publicados antes de 2009 versus estudos publicados após. Métodos: foram criadas três estratégias de busca gerais e adaptáveis às bases de dados eletrônicas na área da saúde: Embase (1980–2015), Pubmed (1966–2016) e Biblioteca Virtual da Saúde (1982–2016). Foram incluídos estudos observacionais em que a mortalidade na acromegalia foi comparada à da população geral, por meio do número de mortes observadas nessa doença em comparação à taxa de mortalidade esperada para população geral (O/E). A partir do O/E, recalculamos todos os Standardized Mortality Ratio (SMR) e os seus respectivos intervalos de confiança (IC) que foram plotados em uma metanálise. Resultados: foram identificadas 1005 referências, dois revisores independentemente leram os títulos e resumos desses artigos. Dos 27 estudos potencialmente elegíveis, 23 foram incluídos e quatro foram excluídos por não preencherem os critérios de elegibilidade. A mortalidade geral na acromegalia foi significativamente superior a da população geral (SMR: 1,66, IC 1,44 - 1,93, p < 0,00001, I2 84%). Separando os artigos publicados a partir de 2009, a mortalidade na acromegalia não foi significativamente diferente 1,29 (IC 0,95-1,76, p=0,10, I2 86%). Nas análises por subgrupo de acordo com o status da doença, sete estudos consideraram como curados os pacientes que apresentaram a n... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Objective: This systematic literature review and meta-analysis compared the mortality rate in acromegaly with the expected rate in the general population of studies published before 2009 versus studies published after. Methods: three general and adaptive search strategies were created from the electronic databases in the health area: Embase (1980-2015), Pubmed (1966-2016) and Virtual Health Library. Observational studies were included in which the mortality in acromegaly was compared to the general population, the number of deaths observed compared to the expected mortality rate in the general population (O/E). From O/E, we recalculated all the Standardized Mortality Ratio (SMR) and their respective confidence intervals (CI) that were plotted in a meta-analysis. Results: 1005 references were identified and two reviewers independently read the titles and abstracts of these articles. Of the 27 potentially eligible studies, 23 were included and four were excluded because they did not meet the eligibility criteria. Overall mortality in acromegaly was significantly higher than the general population (SMR: 1.66, CI 1.44 - 1.93, p <0.00001, I² 84%). Analyzing articles published as of 2009, the mortality in acromegaly was not significantly different, SMR 1.29 (CI 0.95-1.76, p = 0.10, I² 86%). In subgroup analyzes according to disease status, seven studies considered patients with IGF-1 normalization associated with random GH <2.5 ng / mL as cured. In these individuals, the SMR was 0.... (Complete abstract click electronic access below) / Mestre

Orientador: Marcos da Cunha Lopes Virmond / Resumo: Introdução: Indivíduos que estão em estreita associação ou proximidade com pacientes com hanseníase têm maior chance de adquirir a doença. A eficácia da quimioprofilaxia na prevenção da hanseníase nos contatos dos pacientes afetados para um ótimo controle da doença ainda não é clara. Métodos: pesquisas eletrônicas de Medline, EMBASE, CENTRAL e LILACS até outubro de 2017 foram realizadas para identificar estudos elegíveis. As listas de referência de estudos potencialmente elegíveis foram revisadas. Incluímos ensaios clínicos randomizados (RCTs) que compararam a quimioprofilaxia com placebo para a prevenção da infecção da hanseníase em contatos de pacientes afetados. O par de revisores examinou de forma independente artigos elegíveis, extraiu dados e avaliou o risco de viés. A abordagem GRADE foi utilizada para avaliar a certeza geral da evidência. Resultados: seis ECRs, incluindo 52.483 participantes, se mostraram elegíveis. Os resultados sugeriram uma redução estatisticamente significativa na hanseníase clínica em contatos até dois anos (Rácio de Risco (RR) 0,32, Intervalo Confidencial (IC) 0,11 0,62; p <0,0007; I2 = 70%, p = 0,07; evidência de qualidade) e de dois a cinco anos de seguimento (RR 0,51, IC 95% 0,29, 0,89; p = 0,02; I2 = 80%, p <0,0005; evidência de baixa qualidade) com o uso de 6 quimioprofilaxia em comparação com placebo. No entanto, os resultados sugeriram uma redução não significativa na hanseníase clínica nos contatos ao longo de cinco anos (RR 0,77, IC 95%... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Background: Individuals who are in close association or proximity with leprosy patients have a greater chance of acquiring the disease. The effectiveness of chemoprophylaxis in preventing leprosy in contacts of affected patients for optimal disease control remains unclear. Methods: Electronic searches of Medline, EMBASE, CENTRAL, and LILACS up to October 2017 were conducted to identify eligible studies. Reference lists of potentially eligible studies were reviewed. We included randomized controlled trials (RCTs) comparing chemoprophylaxis with placebo for the prevention of leprosy infection in contacts of affected patients. Pair of reviewers independently screened eligible articles, extracted data, and assessed risk of bias. The GRADE approach was used to rate overall certainty of the evidence. Results: Six RCTs including 52,483 participants proved eligible. Results suggested a statistically significantly reduction in clinical leprosy in contacts both up to two years (Risk Ratio (RR) 0.32, 95% Confidential Interval (CI) 0.17, 0.62; p < 0.0007; I 2 =70%, p=0.07; low-quality evidence) and from two to five years of follow-up (RR 0.51, 95% CI 0.29, 0.89; p=0.02; I 2 =80%, p < 0.0005; low-quality evidence) with the use of chemoprophylaxis in comparison to placebo. However, results suggested a non-significant reduction in clinical leprosy in contacts over five years (RR 0.77, 95% CI 0.46, 1.28; p =0.31; I 2 =48%, p=0.16; low-quality evidence). Conclusions: Low-quality evidence show... (Complete abstract click electronic access below) / Mestre

Orientador: Vânia dos Santos Nunes-Nogueira / Resumo: Introdução: Existem quatro medicações disponíveis como tratamento complementar da doença de Cushing: pasireotida, cabergolina, cetoconazol e mifepristone. Contudo, não existe um consenso sobre qual medicação é mais efetiva e segura para o controle dessa neoplasia. Objetivo: comparar a segurança e a efetividade destas quatro medicações no controle de indivíduos com doença de Cushing não curados pela cirurgia, recidivados ou que não puderam realizar esse procedimento. Metodologia: para isso foi realizada uma revisão sistemática de acordo com a metodologia da colaboração Cochrane, no qual seriam incluídos estudos randomizados das comparações destas medicações entre si e fossem avaliados como desfechos primários a remissão do hipercortisolismo por meio da normalização do cortisol livre urinário (CLU), melhora na qualidade de vida, frequência de eventos adversos, melhora das comorbidades e sintomas associadas a essa doença. Foram realizadas três estratégias de busca adaptadas as bases eletrônicas de saúde: EMBASE, PubMed e CENTRAL-Cochrane. Os estudos foram selecionados por dois revisores independentes e os dados extraídos a partir de um formulário padronizado. Resultados: Foram incluídos dez estudos randomizados, um comparando cabergolina versus cetoconazol, e nove avaliando doses diferentes do pasireotida, sendo que oito se referiam ao mesmo protocolo de estudo. A normalização do CLU em seis meses de tratamento foi inferior na cabergolina em relação ao cetoconazol (33% versus 62... (Resumo completo, clicar acesso eletrônico abaixo) / Mestre

Systematic reviews - appraisal and synthesis of all primary research - are increasingly being used to inform policy and practice in health care. Therefore, it is important to understand how the key questions in systematic reviews are identified and prioritised and whether they are relevant to policy makers, practitioners and members of the public. Research priority setting (RPS) is usually defined as any interpersonal activity that leads to the selection of topics and/or choices of key questions to investigate . Diverse approaches to setting research priorities are used in different countries, regions and organisations. There is no consensus in the literature on the most effective processes with which to set these priorities. However, these decisions define the quality and implications of the evidence, and syntheses of it, available to patients, public and policy makers to help them make informed decisions. My initial scoping work, was to design and conduct a survey across an influential international systematic review organisation (Cochrane Collaboration ) on how they set priorities for their reviews. We identified 13 structured approaches to setting priorities. As part of the project, we developed an evaluation framework that demonstrated whether the priority setting processes meet the values and principles of the Cochrane Collaboration. Subsequently, we developed an equity lens for research priority setting exercises to inform the design of research priority setting processes to ensure that they consider the priorities of disadvantaged groups along with advantaged groups. We used the equity lens to do a second evaluation on the priority setting processes in the Cochrane Collaboration. Both evaluation frameworks demonstrated that the Cochrane Collaboration requires better designed priority setting approaches and must be more transparent in reporting those processes. The evaluation of research priority setting exercises in the Cochrane Collaboration, along with the wider literature, demonstrates that research priority setting exercises cannot be evaluated in isolation from organisational cultures, values and context. Therefore, the next step of the project focused on a specific stakeholder group (major research funders) with significant influence on research, including support for systematic reviews. We selected 11 national research agencies in the UK, Netherlands, France, Norway, Denmark, Germany, Australia, Canada, and the USA. We devised and used a checklist based on Chalmers and Glasziou’s “avoidable research waste” framework (and evaluated the processes and policies of these agencies using this checklist). As previous evaluations had demonstrated, this second evaluation found a lack of transparency in the process of setting priorities for research and other related organisational and policy issues. Increased funding is needed for methodological research to evaluate research practices and to monitor how funding research projects is done and reported. My evaluation of funding agencies and the Cochrane Collaboration found a similar lack of transparency and accountability in the context of conflicting values among stakeholders that decreases accountability and scrutiny of researchers and their institutions. However, the projects have led to organisational and policy changes in the two key stakeholder groups (the Cochrane Collaboration and selected funding agencies). Officials of national health research funding agencies have approached me to collaborate with them to address the issues raised by my work on reducing research waste. This led to the establishment of Funders Forum - the Ensuring Value in Research (EViR) Funders’ Collaboration and Development Forum - to enable agencies in various countries to exchange their experience in addressing issues and creating work groups to address them. The Forum is chaired by individuals from three major research funders: NIHR (UK), ZonMW (Netherlands) and Patient-Centered Outcomes Research Institute (PCORI; USA). The Forum organises several meetings to establish common principles, standards and work plans to achieve the common objective around reducing research waste and adding value for research for a national research funder.

Orientador: Vania dos Santos Nunes Nogueira / Resumo: Além das complicações agudas relacionadas à hiperglicemia, os pacientes com Diabetes Mellitus terão ao decorrer da vida várias complicações crônicas que juntas contribuirão para uma maior morbidade e mortalidade nesses indivíduos. A Polineuropatia Diabética Periférica (PND) é uma dessas complicações, que além dos sintomas de parestesia e hiperestesia, bem como vários tipos de dor espontânea, pode levar a diminuição do equilíbrio postural e aumento do risco de quedas. Objetivo: realizar uma revisão sistemática para avaliar a eficácia do exercício físico pré-programado e supervisionado no tratamento complementar da PND. Métodos: foram criadas estratégias de busca gerais e adaptáveis às bases de dados eletrônicas na área da saúde EMBASE, MEDLINE, CENTRAL (Registro de Ensaios Controlados da Colaboração Cochrane), LILACS e PEDro. Nós incluímos estudos randomizados, nos quais os pacientes com PND foram alocados a participar ou não de um programa pré-determinado e supervisionado de atividade física. Os desfechos primários foram: número de quedas, melhora do risco de cair (aferida pelo Teste de Alcance Funcional (TAF), Teste Get Up and Go (TUG), Escala de Equilíbrio de Berg (EEB), estabilometria, apoio unipodal) e melhora do medo de cair (mensurada pelo Fall Efficacy Scale International – FES-I). Os desfechos homogêneos e com a mesma unidade de medida em pelo menos dois estudos foram plotados em uma metanálise, utilizando-se o software Review Manager 5.3. A qualida... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: In addition to acute complications related to hyperglycemia, patients with Diabetes Mellitus develop several chronic complications throughout life that together contribute to greater morbidity and mortality in these individuals. Peripheral Diabetic Polyneuropathy (PND) is one of these complications, which, in addition to symptoms of paresthesia and hyperesthesia, and several types of spontaneous pain, can lead to a decrease in postural balance and an increased risk of falls. Objective: We performed a systematic review to evaluate the effectiveness of pre-programmed and supervised physical activity in the complementary treatment of PND. Methods: General and adaptive search strategies were created for electronic databases in the health area; Embase, Medline, CENTRAL-Cochrane, Lilacs, and PEDro. We included randomized trials in which patients with PND were allocated to participate or not in a pre-determined and supervised program of physical activity. The primary outcomes were: number of falls, improvement in the risk of falls (measured by the Functional Reach Test (FRT), Get Up and Go Test (TUG), Berg Balance Scale (BBS), stabilometry, and one leg stance test) and improvement in fear of falling (measured by the Fall Efficacy Scale International – FES-I). The homogeneous outcomes, with the same unit of measurement in at least two studies were plotted in a meta-analysis, using the software Review Manager 5.3. The quality of evidence was generated in accordance w... (Complete abstract click electronic access below) / Doutor

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Added 1 bitstream(s) on 2015-08-11T03:26:20Z : No. of bitstreams: 5 Publico-165a.pdf: 463473 bytes, checksum: cae240c8ee591f50351d96ca3258bfba (MD5) Publico-165b.pdf: 155628 bytes, checksum: 1115706461101400dcec7e30309c015b (MD5) Publico-165c.pdf: 1838976 bytes, checksum: 98bc6262f927468869ae5e34cde1918a (MD5) Publico-165d.pdf: 1269518 bytes, checksum: f1bbb32c8edea554dfa6517033d47653 (MD5) Publico-165e.pdf: 1520227 bytes, checksum: 275186328f675001df3bba84180ce117 (MD5) / Contexto: A síndrome das pernas inquietas (SPI) é uma desordem caracterizada por uma angustiante necessidade de movê-las e, às vezes, mover também outras partes do corpo, geralmente acompanhada de desconforto ou dor. O tratamento desta síndrome com agonistas dopaminérgicos tem sido reconhecido como terapêutica de primeira linha, porque parece eficaz com base em princípios fisiopatológicos; vários grupos farmacológicos compreendem seu tratamento. Objetivos: Avaliar se intervenções farmacológicas são eficazes e seguras para o tratamento da SPI. Método: Revisão Sistemática Cochrane de estudos randomizados ou quasirandomizados sobre agentes farmacológicos utilizados no tratamento da SPI. Foram avaliados os seguintes desfechos para cada fármaco: alívio dos sintomas medido pela escala de gravidade para a síndrome das pernas inquietas (IRLSSG Rating Scale), eventos adversos, parâmetros polissonográficos, melhora subjetiva, qualidade de vida, impressão clínica global, impressão global do paciente, escala de sonolência de Epworth MSLT: Múltiplos Testes de Latência do Sono; PLMI: índice dos Movimentos Periódicos dos Membros. A autora desta tese avaliou os estudos recuperados nas buscas, utilizando critérios que envolviam os métodos randômicos, de cegamento e sigilo de alocação. As divergências foram resolvidas em reunião de consenso. Resultados: As buscas manual e eletrônica encontraram 1.026 estudos. Foram incluídos 94 ensaios clínicos que atendiam aos critérios de inclusão (estudos randomizados ou quasi-randomizados). A análise dos dados considerados em conjunto permitiu concluir que as intervenções farmacológicas foram efetivas para os agonistas dopaminérgicos. Dentre as drogas de segunda linha, apenas a clonidina mostrou-se efetiva. A qualidade dos estudos foi adequada para os ensaios clínicos envolvendo os agonistas dopaminérgicos, parcialmente adequada para levodopa e anticonvulsivantes e pouco adequada para os demais fármacos estudados. Conclusões: Há evidências de que os agonistas dopaminérgicos são eficazes e seguros para o tratamento da SPI a curto prazo, mas não há evidência científica de que os demais fármacos são efetivos nesta doença. / Background: The restless legs syndrome (RLS) is a disorder characterized by a distressing need to move the legs and sometimes other parts of the body. Usually accompanied by a marked sense of discomfort or pain in the leg or other body part affected. The treatment of restless legs syndrome with dopamine agonists has been recognized as the main first-line treatment because it seems to be effective based on pathophysiologic principles. Although, several pharmacological drugs are envolved in the treatment of RLS. Objectives: To assess whether pharmacological interventions are effective and safe for the treatment of RLS. Methods: Systematic Cochrane Review of randomized studies or quasi-randomized on pharmacological agents used to treat RLS. The following outcomes were assessed for each drug: relief of symptoms measured by the restless legs syndrome ranting scale (IRLSSG Rating Scale), adverse events, polysomnographic parameters, subjective improvement, quality of life and clinical global impression, overall impression of the patient , the scale of Epiworth MSLT: Multiple Sleep Latency Test; PLM periodic limb movments and others. The authors evaluated the studies retrieved in searches using criteria involving the method of randomization, blinding and the method of allocation concelment. Disagreements were resolved by consensus. Results: The electronic and manual search found 1,026 studies. Were included 94 studies that met the clinical criteria for inclusion (randomized studies or quasi-randomized). The analysis of data, taken together, indicated that the pharmacological interventions were effective for dopamine agonists. Among the second-line drugs, only clonidine was shown to be effective. The quality of studies was suitable for clinical trials involving the dopamine agonists, partially adequated to levodopa and anticonvulsants, and unsuited for the other drugs studied. Conclusions: There is evidence that dopamine agonists are effective and safe for the treatment of RLS in the short term, there is no scientific evidence that all drugs are effective in this disease. / TEDE / BV UNIFESP: Teses e dissertações

Background: Pain is frequently reported by people with multiple sclerosis (MS). It has been associated with decreased quality of life, psychiatric morbidity, interference with day to day activities, and frequent healthcare attendance. It has been reported by people with multiple sclerosis to be one of their most important symptoms, and available treatments are limited in their effectiveness. Despite this, our understanding of the epidemiology and mechanisms of pain in people with MS are limited. Our understanding of the interactions of central nervous system mechanisms and pain states overall is growing. However, the application of this knowledge to MS is incomplete. Previous studies have shown that the descending pain modulatory system (DPMS) is an endogenous network of cortical and subcortical brain structures which act to limit, or accentuate, an individual’s perception of pain, via descending brainstem pathways. Associated clinical measures include depression, anxiety, and cognitive flexibility. Our understanding of the function or dysfunction of this system in MS is limited. We do not know if the MS disease process may adversely affect the structure or function of the DPMS. Hypothesis: In people with neuropathic limb pain in relapsing remitting MS (RRMS), compared to people with RRMS who do not have pain, there will be disruption of the endogenous descending pain modulatory system. This will manifest as impaired descending inhibition of pain. Aims and Methods Establishing the background using systematic reviews: The first aim of this thesis was to establish the prevalence, natural history and associations of pain (and pain syndromes) occurring in people with MS. The second aim was to explore existing knowledge of how the MS disease process may contribute to pain states, using a systematic review of neuroimaging studies. Prospective clinical study: A case-control study of 47 people with RRMS was then carried out. 31 of these had neuropathic pain in the limbs, and 16 did not have pain. Using targeted assessments, function of the descending pain modulatory system was assessed in the following ways: First: Detailed clinical, behavioural and neuropsychological assessment, focussing on cognitive, behavioural and affective features known to be closely related to the DPMS. Second: MRI imaging of brain structure, focussing on the volume and location of MS lesions, as well as the volume of key grey-matter structures involved in the DPMS. Third: Resting state functional MRI imaging of the brain, focussing on functional connectivity between the rostral anterior cingulate cortex and two other key DPMS structures (dorsolateral prefrontal cortex, and periaqueductal gray). Results: Systematic reviews: Meta-analysis of existing prospective studies confirmed that pain is very common in MS, affecting about 63% of people with MS on average (95%CI between 55 and 70%). Many different types of pain contribute to this overall estimate. No significant associations with disease course or stage emerged. Several neuroimaging studies have assessed people with MS-associated pain using MRI. These studies were often small, and with associated methodological issues. It is likely that location of MS lesions is implicated in aetiology of pain syndromes in some cases, though our overall knowledge is limited. Prospective study: In a prospective study, people with and without pain were matched for age and gender. Furthermore, groups were balanced for a range of other variables. The pain group more frequently received gabapentinoid medications. The presence of pain was significantly associated with increased scores for depression, fatigue and catastrophising, as well as with specific impairments at neuropsychological assessment, including cognitive flexibility. Many of these impairments are directly relevant to existing models of the DPMS. Overall volume of MS lesions was not different in people with pain, though lesions were more likely to occur in the brainstem. Some alterations of grey-matter volumes in people with pain which mirrored studies of pain disorders outside MS were found, but these did not involve structures key to the DPMS. Affected structures included trigeminothalamic nucleus (relative volume increase in pain group), posterior cingulate cortex and parahippocampal gyrus (volume decrease in pain group). Functional connectivity of the rostral anterior cingulate cortex to the periaqueductal grey matter, a key structure in the descending modulation of pain, was stronger in the group without pain. Conversely, functional connectivity to the dorsolateral prefrontal cortex, repeatedly implicated in the DPMS and thought to be involved in cognitive evaluation and flexibility, was stronger in the pain group. MS lesion volume appeared to account for some of this difference in a multivariate analysis. Limitations: Key limitations of this work include cross-sectional design, small sample size, and number of statistical comparisons carried out. Conclusions: Systematic reviews examined the prevalence, natural history and associations of pain in MS, as well as examining existing neuroimaging studies which investigated how the MS disease process could contribute to pain states. A prospective study found evidence of both emotional/affective and cognitive dysfunctions relevant to the hypothesis of dysfunction in the DPMS. Higher likelihood of MS lesions in the brainstem could be relevant to DPMS function. Separately, there were structural grey-matter volume alterations reflecting those found in many pain studies outside MS. Importantly, however, these did not affect key DPMS structures. Resting state functional MRI however demonstrated altered connectivity of core DPMS structures, which may be partly mediated by MS lesion volume. Functional connectivity findings could be consistent with the hypothesis of impaired descending pain inhibition, in people with relapsing remitting MS affected by neuropathic limb pain.

Introduction: There is an increased acceptance and demand for online and mobile health (mHealth) interventions to support physical and mental health problems. However, the uptake and engagement of these interventions is relatively low and the evidence base for these interventions requires continual updating in line with technological advances. A systematic review was conducted, focusing on anxiety and depression, to explore the existing evidence base of both physical health and mental health mobile applications. The first research paper explores the acceptability of mHealth interventions for both mental health and physical health problems. The final research paper explores use and strategies when searching for mental health information online. Additionally, perceived quality, sentiment and barriers to online health information was explored. Methods: Studies were identified by searching for articles published between January 2008 and January 2016. Databases included: PsycINFO, MEDLINE, CINAHL PLUS and the Cochrane Central Register of Controlled Trials for 2016. In the research articles, 218 people completed an online survey in January 2016 exploring, online health seeking for mental health and physical health problems, and acceptability of mHealth interventions. Sentiment of online health resources was explored by extracting 432 individual tweets from Twitter. Results: The systematic review revealed twenty-seven studies for inclusion; 10 with a physical health focus and 17 with a mental health focus. Targeted depression applications have the superior evidence base; however, no firm conclusions can be made regarding interventions that targeted physical health, or those measuring anxiety. The first research paper found that face-to-face therapy would more likely meet expectations for treatment of both physical and mental health problems compared to mHealth interventions. Computerised interventions were more likely to meet expectations than mobile applications. Expectations of treatment were higher for the treatment of mental health problems than physical health problems. The second research paper found that a large proportion of the public use the internet to search for information on mental health, with half citing it as their primary source for mental health information. The online survey found that the quality of mental health information available on the internet was rated favourably, compared to mobile applications. Overall, the sentiment towards specific online mental health resources was generally positive. Conclusions: Research into online and mHealth interventions has developed considerably in recent years in line with advances in technology. These interventions have the potential to be an effective treatment of common mental health problems. The systematic review highlighted that depression applications are more established and effective than applications targeting anxiety. The first research paper suggests that mHealth interventions fall short of public expectations for treatment of health problems. The final research paper reflects that the perceived quality of online mental health information is rated favourably. However, many barriers still limit uptake. Future research could focus on continually developing and evaluating evidence based online and mHealth interventions and the outcome of this study suggests that incorporating them more widely into existing care systems, alongside face to face interventions could increase the public’s confidence in these interventions.