<b>Background:</b> The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach offers a transparent framework for rating the certainty of evidence in systematic reviews. Concerns, however, have been raised that use of GRADE beyond biomedical interventions frequently downgrades the 'best evidence possible' for many complex interventions. This DPhil thesis aims to (1) further investigate the challenges of using GRADE in systematic reviews of complex interventions, (2) explore how the GRADE approach can be advanced to address these challenges, and (3) inform the write-up and dissemination of a new GRADE guidance for complex interventions. <b>Methods:</b> To address the broad aims of this thesis a range of methodological approaches were employed, primarily drawing on the best-practice techniques for developing research reporting guidelines (see Chapter 2). First, a systematic literature review method was used to establish whether an adequate system already exists for rating the certainty of evidence for complex interventions and informing the need for a new guidance (Chapter 3). Further consultation with experts, including semi-structured interviews with review authors and GRADE methodologists, provided a nuanced understanding of the challenges of applying GRADE in reviews of complex interventions and suggestions for advancing the guidance on GRADE (Chapter 4). Agreement around these suggestions was explored in a Delphi-based online expert panel (Chapter 5), and the content of the new GRADE guidance for complex interventions was discussed indepth in a three-day expert meeting held in Oxford in May 2017 (Chapter 6). <b>Results:</b> The systematic literature review identified a few systems attempting to modify GRADE for public health interventions; however, there was little reporting of rigorous procedures in the development and dissemination of these systems. Qualitative interviews captured differences in views on GRADE use between review authors and GRADE methodologists. Specifically, GRADE methodologists found it critical to consider GRADE from the beginning of the review process and exercise judgment in GRADE ratings. Review authors, on the other hand, often thought of GRADE as an 'annoying add-on' at the end of the review process and felt challenged by the need to be more interpretative with evidence and sift through many publications on GRADE. Suggestions were made to enhance the GRADE guidance. No significant disagreement was found in the online expert panel on any domain of evidence, and the expert meeting provided further insights into the content of the new GRADE guidance for complex interventions. Participants agreed that the new guidance should specify the meaning of the construct of 'certainty of evidence' for complex interventions, consider revisions of the initial categorisation of evidence based on study design, and better assess the coherence of the causal pathway of complex interventions. <b>Conclusion:</b> This thesis work consolidates up-to-date methodological knowledge on reviewing complex interventions by providing critical examination of the existing approaches and new insights. In transparent reporting of the research phases, it informs development of a new GRADE guidance on rating the certainty of evidence in systematic reviews of complex interventions.

Implementation strategies for the use of clinical practice guidelines are an integral component in bridging the gap between the best research evidence and clinical practice. However, despite some remarkable investments in health research regarding clinical practice guidelines implementation strategies, it is not yet known which of these are the most effective for intensive care units. The purpose of this research study was to systematically identify and /or search, appraise, extract and synthesize the best available evidence for clinical practice guidelines implementation strategies in intensive care units, in order to develop a draft guideline for clinical practice guidelines implementation strategies in the intensive care units. A systematic review design was used to systematically identify and /or search, appraise, extract and synthesize the best available evidence from the eligible included Level 2 studies (randomized controlled trials and quasi-experimental studies). Level 2 studies were applicable because they present robust evidence in the research results regarding effectiveness of clinical practice guideline implementation strategies. Furthermore, although other systematic reviews conducted in this area before, they included studies of In addition, no systematic review was identified that reviewed Level 2 studies and developed a guideline for clinical practice guideline implementation strategies in the intensive care units. Hence, including only Level 2 studies was distinctive to this research study. Databases searched included: CINAHL with full text, Google Scholar, Academic search complete, Cochrane Register for Randomized Controlled Trials Issue 8 of 12, August 2013, and MEDLINE via PUBMED. Hand search in bound journals was also done. The search strategy identified 315 potentially relevant studies. After the process of critical appraisal, thirteen Level 2 studies were identified as relevant for the review. Of the 13 relevant studies, 10 were randomized controlled trials and three were quasi experimental studies. After the critical appraisal ten RCTs were included in the systematic review. Three studies (quasi-experimental) were excluded on the basis of methodological quality after the critical appraisal and agreement by the two independent reviewers. The Joanna Briggs Institute Critical Appraisal MASTARI Instrument for Randomized Controlled trials/ Experimental studies, and The Joanna Briggs Institute data extraction tools were used to critically appraise, and extract data from the ten included randomized controlled trials. The two reviewers who performed the critical appraisal were qualified critical care professional nurses and experts in research methodology. These reviewers conducted the critical appraisal independently to ensure the objectivity of the process. Appropriate ethical considerations were maintained throughout the process of the research study. The results indicated that 80 percent of the included studies were conducted in adult intensive care units while 20 percent were conducted in the neonatal intensive care units. Furthermore, 60 percent of the studies were conducted in the United States of America, 10 percent in France, a further 10 percent in Taiwan, another 10 percent in England and yet another 10 percfent was conducted in Australia and Newzealand. The included studies utilized more than one (multifaceted) implementation strategies to implement clinical practice guidelines in the intensive care units. The first most utilized were: printed educational materials; Information/ educational sessions/meetings; audit and feedback and champion/local opinion leaders; seconded by educational outreach visits; and computer or internet usage. Third most used were active/passive reminders; systems support; academic detailing/ one-on-one sessions teleconferences/videoconferences and workshops/in services. Fourth most used were ollaboration/interdisciplinary teams; slide shows, teleconferences/videoconferences and discussions. Fifth most used were practical training; monitoring visits and grand rounds. However all the strategies were of equal importance. Conclusively, the included studies utilized multifaceted implementation strategies. However, no study indicated the use of a guideline for the implementation strategies in the process of clinical practice guidelines implementation. The systematic review developed a draft guideline for clinical practice guideline implementation strategies in the intensive care units. The guideline will enhance effective implementation of clinical practice guidelines in such a complex environment.

As our understanding of the platelet’s systemic role continues to expand beyond hemostasis and thrombosis, interrogation of the platelet’s ability to affect diverse biological processes is required. Studies of the platelet’s non-traditional roles have focused on developing our understanding of the platelet’s relation to specific disease phenotypes as well as elucidation of platelet characteristics, content, and function. The generic content, traditional function and heterogeneity of platelets have long been accepted; more ambiguous and controversial has been how these factors are interrelated. Investigation of platelet content revealed the presence of biologically functional RNA in anucleated platelets, the correlation of platelet RNA to distinct phenotypes, and the ability of platelets to transfer RNA to other vascular cells; however how these processes occur is unclear. To further interrogate platelet RNA processes, we utilized sorting and RNA sequencing to develop platelet subpopulation transcriptome profiles. We found that platelet heterogeneity extends to the platelet transcriptome: distinct RNA profiles exist dependent on platelet size. We hypothesized that this RNA heterogeneity is the result of RNA transfer between platelets and vascular cells. Using in vitro and in vivo modeling, we were able to show the novel ability of platelets to take up RNA from vascular cells, correlating to the unique functional profile associated with small platelet transcriptomes. These findings reveal a role for platelet RNA transfer in platelet RNA heterogeneity, with potential correlation to platelet functional diversity previously proposed. The ability of the platelet to bidirectionally transfer RNA within circulation has implications for vascular health and beyond.

Noninvasive brain-computer interfaces (BCIs) use scalp-recorded electrical activity from the brain to control an application. Over the past 20 years, research demonstrating that BCIs can provide communication and control to individuals with severe motor impairment has increased almost exponentially. Although considerable effort has been dedicated to offline analysis for improving signal detection and translation, far less effort has been made to conduct online studies with target populations. Thus, there remains a great need for both long-term and translational BCI studies that include individuals with disabilities in their own homes. Completing these studies is the only sure means to answer questions about BCI utility and reliability. Here we suggest an algorithm for candidate selection for electroencephalographic (EEG)-based BCI home studies. This algorithm takes into account BCI end-users and their environment and should assist in study design and substantially improve subject retention rates, thereby improving the overall efficacy of BCI home studies. It is the result of a workshop at the Fifth International BCI Meeting that allowed us to leverage the expertise of multiple research laboratories and people from multiple backgrounds in BCI research.

No / Ester Garne and Joan Morris are correct that the Born in Bradford birth cohort data for congenital anomalies do not include pregnancies that terminated before 28 weeks: the data we report refer to liveborn and stillborn infants only. We reported a protective effect of education on anomaly rates but we did not propose any theory to account for the finding because we had no further data that related to this observation.

Thesis (MPhil)--University of Stellenbosch, 2001. / ENGLISH ABSTRACT: Background: Scientists seem to have an 'international corporate culture' of mistrusting the media. Attitudes of South African scientists to the media and their experiences of reporting findings to the public and media have not been documented. The South African Medical Research Council (MRC) is a statutory research body with an excellent research record - but awareness of the MRC among the South African public is almost non-existent. The MRC needs to publicise and increase knowledge of its goals and research findings by promoting scientists' engagement with the public and other stakeholders. Objective: A postal survey was carried out among MRC scientists to obtain a 'baseline' indication of attitudes and experiences regarding communication to the public and media. Results would inform development and implementation of strategies to fast-track a turnaround in culture at the MRC towards promotion of science communication. Method: A questionnaire with prompted responses was sent to 253 MRC scientists. One hundred were returned (39.5%), representing an impressive assemblage of the MRC's research leaders. Findings: Although 48.9% of the scientists had each published over 30 articles in peerreviewed journals, 38.9% had never had these articles mentioned in the lay media. Yet the scientists regard 'the public' and 'policy makers' as the most important groups they should communicate with, and most think the public glean their knowledge of scientific research and its implications from the lay media. The scientists might not trust the media to provide accurate scientific information, but they feel that the general public do. The vast majority (92.8%) strongly agree or tend to agree that they have a duty to communicate their research and its implications to the public, and 70.8% would like to spend more time on this. However, the scientists also agree that the day-to-day requirements of their jobs leave them with too little time to communicate the implications of their research to others (47.5%) or even to get on with research (36.4%). Most of the scientists had never had contact with the media, or only every few years. When the source or subject ofa news story, 65.4% had been either 'very satisfied' or 'somewhat satisfied' with the coverage. Many of their comments reflected unrealistic expectations which can only be addressed by training in what the media are all about. Most (86.9%) had never had any training in dealing with the media, but 80.8% would be interested in such training. Conclusions: It is clear that the scientists generally want to communicate and see the potential benefits. For the MRC to become a communicating organisation it must spell out to its scientists the importance and value placed on their communication activities. Science communication and development of links with community and media should be seen as part and parcel of scientific research, and given due recognition and support. Policies must be agreed and communicated with the scientists about recognising, encouraging and rewarding such efforts. The MRC also needs a clear media strategy giving guidelines on specific situations, as well as on the Ingelfinger rule. / AFRIKAANSE OPSOMMING: Agtergrond: Dit kom voor asofwetenskaplikes 'n 'internasionale gedragskode' het om die media te wantrou. Gesindhede van Suid-Afrikaanse wetenskaplikes teenoor die media en hulle ondervinding van die bekendmaking van hulle bevindinge aan die publiek en die media is nog nooit opgeteken nie. Die Suid-Afrikaanse Mediese Navorsingsraad (MNR) is 'n statutêre navorsingsliggaam met 'n uitstekende navorsingsgeskiedenis - maar die Suid-Afrikaanse publiek is haas onbewus van sy bestaan. Die MNR moet sy doelwitte en navorsingsbevindinge openbaar maak deur wetenskaplikes se kontak met die publiek en ander belangegroepe te bevorder. Doelwit: 'n Posopname is onder die MNR se wetenskaplikes gedoen om 'n 'basislyn' aanduiding van hulle gesindhede teenoor en ondervinding van kommunikasie met die publiek en media te verkry. Die resultate hiervan sal die ontwikkeling and implimentering van strategie om 'n vinnige handomkeer in gebruike by die MNR ten einde die bevordering van wetenskapskommunikasie te weeg te bring, stuur. Metode: 'n Vraelys met voorgestelde antwoorde is aan 253 MNR wetenskaplikes gestuur. Eenhonderd is teruggestuur (39.5%), wat 'n indrukwekkende groep van die MNR se navorsingsleiers verteenwoordig. Bevindinge: AlhoeweI48.9% van die wetenskaplikes elk al meer as 30 artikels in portuurevalueerde joernale publiseer het, het 38.9% nog nooit enige dekking in verband met hierdie artikels in die lekemedia ontvang nie. Desondanks beskou die wetenskaplikes' die publiek' en 'beleidmakers' as die mees belangrike groepe waarmee hulle moet kommunikeer. Die meeste dink ook die publiek verkry hul kennis van wetenskaplike navorsing en die gevolge daarvan vanuit die lekemedia. Die wetenskaplikes mag nie die media vertrou om akkurate wetenskaplike inligting weer te gee nie, maar hulle dink die algemene publiek vertrou wel die media. Die oorgrote meerderheid (92.8%) stem sterk saam of stem saam dat hulle 'n verpligting het om hulle navorsing en die implikasies daarvan met die publiek te deel, en 70.8% sou graag meer tyd hieraan wou afstaan. Die wetenskaplikes stem egter ook saam dat die dag tot-dag eise van hulle beroep te min tyd oorlaat om die implikasies van hulle navorsing aan ander te kommunikeer (47.5%) of om selfs hulle navorsing te doen (36.4%). Die meeste van die wetenskaplikes het nog nooit enige kontak met die media gehad nie, of dan wel slegs met tussenposes vanjare. Wanneer hulle die bron ofonderwerp van 'n nuusstorie was, was 65.4% óf 'baie tevrede' óf 'effens tevrede' met die dekking. Baie van hul kommentaar dui op onrealistiese verwagtinge wat slegs aangespreek kan word deur opleiding oor die 'hoe' en 'wat' van die media. Die meeste (86.9%) het nog nooit enige opleiding gehad om met die media te werk nie, maar 80.8% sou belangstel in sulke opleiding. Gevolgtrekkings: Dit is duidelik dat die wetenskaplikes oor die algemeen wil kommunikeer en ook die moontlike voordele daarvan insien. Om 'n kommunikerende organisasie te word, moet die MNR die belang en waarde wat geheg word aan wetenskaplikes se kommunikasieaktiwiteite, aan hulle uitspel. Wetenskaplike kommunikasie en die vorming van netwerke met die gemeenskap en die media moet gesien word as 'n deel van wetenskaplike navorsing en moet paslike erkenning en ondersteuning geniet. Beleid rakende die herkenning, aanmoediging en beloning van sulke pogings moet vasgestel en oorgedra word aan die wetenskaplikes. Die MNR het ook 'n duidelike mediastrategie nodig wat riglyne oor spesifieke situasies en die Ingelfinger reël gee.

Research on New Procedures Using a Method That Has Not Yet Been Used in Clinical Practice on a Living Human Abstract Uterus transplantation, use of hypothermia in acute myocardial infarction or gastric peroral endoscopic pyloromyotomy, these are the topics of three Czech on going researches of novel medical methods, to which this thesis is devoted. The aim of this thesis is to elaborate on the whole issue of new methods by presenting the Czech legislative framework and current clinical practice and to assess the overall situation in this area. In one of the chapters, attention is also paid to the potential legal ground for the possibility of compensating patients for injury, ie civil liability, most likely occurring as a liability for the non lege artis procedure or as a specific type of strict no-fault liability.

Cancer metastasis directly accounts for an estimated 90% of all cancer related deaths and is correlated with the presence of malignant cells in systemic circulation. This observed relationship has prompted efforts to develop a fluid biopsy, with the goal of detecting these rare cells in patient peripheral blood as surrogate markers for metastatic disease as a partial replacement or supplement to tissue biopsies. Numerous platforms have been designed, yet these have generally failed to support a reliable fluid biopsy due to poor performance parameters such as low throughput, low purity of enriched antigen positive cells, and insufficiently low detection thresholds to detect poor expressed surface markers of target cell populations. This work describes the development of a rapid cell sorting technology called Antigen Specific Lysis (ASL) based on photo-crosslinked polymer encapsulation to isolate tumor cells in suspension. In the first study, we characterize the chemical and structural properties of the surface-initiated polymer films formed directly on mammalian cell surfaces. Coated populations are shown to remain highly viable after coating formation. Biomolecular transport is examined though film coatings on cellular substrates using fluorescent, time-resolved confocal microscopy and diffusivity estimates are generated for these materials. In the next study, a lysis-based cell isolation platform is described in which marker positive cells can be specifically coated in a heterogeneous cell suspension. Anionic surfactants lyse virtually 100% of uncoated cells while fully encapsulated cells remain protected, and are then easily collected by centrifugation. We report that purified cells are released from polymeric coatings to yield viable and functional populations. We monitor cell response throughout the isolation process by multiple techniques, and report viability >80% after the sorting process. Lastly, we examine the response of process yield on the level of photoinitiator loading on target populations. Streptavidin-fluorochrome loading was quantitatively assessed on a panel of markers, both epithelial and mesenchymal, on representative model breast and lung cancer cells. We report that ASL is fundamentally capable of achieving 50-60% yield which is promising for fluid biopsy applications. Finally, both EpCAM and metastatic targeting strategies are then compared to covalently biotinylated samples to inform future robust targeting strategies.

Background Selective reporting of outcomes within a published study based on their nature or direction can result in systematic differences between reported and unreported data. Direct evidence of outcome reporting bias is limited to case reports. Objective To study empirically the nature of outcome reporting bias in randomised controlled trials (RCTs). Methods Three cohorts of RCTs were identified: PubMed-indexed RCTs published in December 2000; trial protocols approved by a Danish ethics committee from 1994-95; and trial protocols funded by a government agency in Canada from 1990-98. Data on reported and unreported outcomes were recorded from all trial publications and a survey of authors. An outcome was considered incompletely reported if insufficient data were presented for meta-analysis. Odds ratios relating the completeness of outcome reporting to statistical significance were calculated for each trial, and then pooled using a random effects meta-analysis. Protocols and publications were also reviewed for discrepancies in primary outcome reporting. Results 519 trials with 10,557 outcomes, 102 trials with 3613 outcomes, and 48 trials with 1390 outcomes were identified for the PubMed, ethics committee, and funding agency cohorts respectively. 22%-35% of outcomes per parallel group study were, on average, incompletely reported for meta-analysis. Fully reported outcomes had a two- to three-fold higher odds of being statistically significant compared to incompletely reported outcomes. The most common reasons given for omitting outcomes included a lack of clinical importance, lack of statistical significance, and space constraints. Major discrepancies between primary outcomes in protocols and publications were found in one half of trials. Discussion and conclusions The reporting of trial outcomes is frequently inadequate for meta-analysis; is biased to favour statistical significance; and is inconsistent with pre-specified protocol outcomes. Unacknowledged modifications to outcomes specified in trial protocols constitute scientific misconduct. Meta-analyses may therefore produce inflated and unreliable estimates of treatment effect.

Medical Academia Conflict of Interest Policy and Potential Impact on Research Funding by Michael K. Maahs MPA, Troy University, 1993 BA, Ripon College, 1990 Dissertation Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Public Policy and Administration Walden University July 2015 The partnership between medical academia and the pharmaceutical industry has been scrutinized for issues associated with research bias. As a result of this scrutiny, the Institute of Medicine (IOM) issued policy recommendations in 2009 directing academia to adopt comprehensive conflict of interest (COI) policies. During the same time, a slowdown of funded research into academia occurred, and it is not clear whether the IOM recommendations contributed to this problem. The purpose of this case study was to determine the extent to which compliance with the IOM policy resulted in a reduction in funded research. The Advocacy Coalition Framework (ACF) was the theoretical lens used for study. COI policy statements (n = 15) were analyzed from American Association of Medical Colleges member schools that engage in medical research. In addition, in-depth interviews were conducted with 4 medical academic researchers. Data were inductively coded and organized around key themes. Key findings indicated that medical academia is compliant with IOM recommendations and COI policies did not appear to have a direct effect on research placement by industry. Interestingly, a possible explanation for reductions in industry funding relate to inefficient institutional review board processes. Additionally, the ACF construct was validated via an observed complex and slowly evolving COI policy process. The positive social change implications of this study include recommendations to academia to continue to monitor and report on COI and explore efficiency improvements related to IRB oversight in order to support important pharmaceutical research that ultimately improves the health and wellbeing of people.