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Background Despite widespread use, the optimal implementation and clinical impact of FilmArray Meningitis Encephalitis Panel (MEP; Table 1) multiplex PCR testing of cerebrospinal fluid (CSF) in children with suspected (CNS) infections is unknown. Table 1: FilmArray Meningitis Encephalitis Panel Test Characteristics Methods A pre-post quasi-experimental cohort study to investigate the impact of implementing MEP using a rapid CSF diagnostic stewardship program was conducted at Children’s Hospital Colorado (CHCO). MEP was implemented with EMR indication selection to guide testing to children meeting approved use criteria: i. infants < 2mo, ii. immunocompromised, iii. encephalitis, iv. > 5 WBCs in CSF. Positive results were communicated with antimicrobial stewardship real-time decision support (Fig 1). All cases with CSF obtained by lumbar puncture (LP) sent to the CHCO microbiology laboratory meeting any of the 4 criteria above were included with pre-implementation controls (2015-2016) compared to post-implementation cases (2017-2018). Primary outcome was time-to-optimal antimicrobials (time from LP to 1st dose of antimicrobials targeted to identified pathogen, or cessation when no treatable pathogen identified). Figure 1: Rapid Cerebrospinal Fluid Diagnostic Stewardship Program Intervention Design Results Post-implementation (n=1127) and pre-implementation (n=1124) group characteristics are in Table 2. Following implementation, MEP was sent in 72% of cases, largely replacing pathogen-specific singleplex CSF testing (Table 3). Time-to-optimal antimicrobials decreased by 10 hours (p< 0.0001; Fig 2). There were no differences in time-to-effective antimicrobials, hospital admissions, antimicrobial starts or length of stay. Time-to-positive CSF results was faster (4.8 vs. 9.6 hrs, p< 0.0001), IV antimicrobial duration was shorter (24 vs 36 hrs, p=0.004) with infectious neurologic diagnoses more frequently identified (15% vs. 10%, p=0.03). Overall, 3% had bacterial and 9% viral CNS infection identified. Enterovirus (n=128) was most common, then HSV (n=28) and parechovirus (n=17) with similar detection rates between groups Conclusion Implementation of MEP with a rapid CNS diagnostic stewardship program improved antimicrobial use with faster results shortening empiric therapy. Routine MEP testing in high-yield cases rapidly detects common viral causes and rules out bacterial targets to enable antimicrobial optimization Disclosures Samuel R. Dominguez, MD, PhD, BioFire Diagnostics (Consultant, Research Grant or Support)DiaSorin Molecular (Consultant)Pfizer (Grant/Research Support) Samuel R. Dominguez, MD, PhD, BioFire (Individual(s) Involved: Self): Consultant, Research Grant or Support; DiaSorin Molecular (Individual(s) Involved: Self): Consultant; Pfizer (Individual(s) Involved: Self): Grant/Research Support

Hazard identification is a critical task that needs to be carried out for safe process design and operation. HAZOP studies are widely used for identifying hazard and operability problems. However, HAZOP studies are time consuming, labour intensive and expensive. Automated HAZOP identification systems that emulate the HAZOP technique have been developed to overcome this bottleneck. This work considers batch processes, where a batch plant moves through a number of different stages during operation, rather than each equipment item remaining in a “steady state”, as is normal for continuously operating plants. In batch plants deviations which can lead to hazards can arise both from deviations from operating procedures and process variable deviations. Therefore, the effect of operator actions needs to be considered. Much of the research on automated HAZOP identification, based on signed-directed graphs, has concentrated on continuous plants. However, this technique is inappropriate for batch processes. The signed-directed graph approach used in continuous plant HAZOP emulators is found to be unsuitable for batch plants. The main problem is that it does not keep state related information as the HAZOP analysis moves from one operating instruction to the next. Preliminary research at Loughborough University has demonstrated the feasibility of applying stated-based qualitative simulation in this domain. The research described in this thesis builds on an existing proof of concept system. The project develops a prototype automated batch HAZOP identification system, called CHECKOP. CHECKOP takes a plant description and a set of operating instructions as input and produces a HAZOP report automatically. Object- oriented technologies are utilised to model the state changes required for automated batch HAZOP analysis. To produce a product in a batch process, a plant operator follows a series of operating instructions. For an operating procedure to be analysed by a computerised system, such as an automated HAZOP system, it must be formally represented. CHECKOP verifies if an operating procedure achieves its desired results and does not also lead to any additional, unexpected effects. Deviations may be applied to the operating instructions to simulate batch HAZOP. CHECKOP simulates the change of plant state as each operating instruction is executed. Potential hazards which result from the operating instructions are tested for. CHECKOP infers the consequences if a certain instruction in the procedure is not executed, or if the instruction is carried out too early or too late, etc. The original, existing proof of concept system was unstructured. CHECKOP defines a formal template representation for the operating instructions. A modelling structure is derived to describe the state and connectivity of plant items. A state-based simulation engine simulates the effect of the operating instructions upon the plant model. CHECKOP contains a rule- based system to test for potential hazards or operability issues.

There is a need for remote learning and virtual learning applications such as virtual reality (VR) and tablet-based solutions which the current pandemic has demonstrated. Creating complex learning scenarios by developers is highly time-consuming and can take over a year. There is a need to provide a simple method to enable lecturers to create their own content for their laboratory tutorials. Research is currently being undertaken into developing generic models to enable the semi-automatic creation of a virtual learning application. A case study describing the creation of a virtual learning application for an electrical laboratory tutorial is presented., 6 pages, 4 figures, accepted for publication ICMR2021 18th International Conference in Manufacturing Research Virtual Conference hosted by the University of Derby, UK 7 - 10 September 2021

The lineage identity of a particular cell within a multi-cellular organism is defined by the repertoire of mRNA it expresses. Changes to the transcript repertoire can affect cell identity and stage of differentiation. Chromatin as the biologically relevant target of transcription factors has a direct impact on cell identity and differentiation, with changes to its structure central to lineage choice, cellular identity and differentiation. The requirement of chromatin remodeling in these developmental processes is evident throughout myogenesis, with changes to the cell's chromatin structure occurring during both the specification of myoblasts and the differentiation of specified myoblasts to myotubes. This thesis examines three distinct aspects of chromatin remodeling in relation to myogenesis. Firstly, the role of Snf2h in MyoD-mediated repression of target genes during myoblast proliferation was investigated. Snf2h was identified as a MyoD-interacting protein in a repressed transactivator yeast two-hybrid screen. Overexpression of either an active or inactive form of human SNF2H in myoblasts accelerated the differentiation process without affecting either growth rate or cell cycle kinetics. Furthermore, the chromatin structure surrounding the myogenin E boxes was more open in myoblasts expressing inactive human SNF2H compared to control myoblasts suggesting functional Snf2h complexes are required to repress differentiation specific genes during growth and subsequently maintain the myoblast proliferative state. From these and published results, a model describing the role of Snf2h in myogenesis is suggested. This model proposes that Snf2h activity facilitates the repression of MyoD target genes by histone deacetylases. In addition, genome-wide changes to histone H4 acetylation and histone H3-K9 dimethylation during myoblast differentiation were assessed. The patterns of genome-wide histone modifications in proliferating myoblasts were distinct from the patterns observed in myotubes, suggesting distinct mechanisms are targeting histone-modifying activity in myoblasts and myotubes. Furthermore, in our study, hyperacetylation of histone H4 and hypomethylation of histone H3 did not correlate strongly with transcriptional status. Our results support the hypothesis of the Histone Code Model, which theorizes that a combination of distinct histone modifications and not individual histone modifications defines the transcriptional competence of a particular gene. (Abstract shortened by UMI.) Doctor of Philosophy (PhD)

Since the 1970s, in UK adoption practice, there has been a shift away from placing relinquished infants towards placing children who were once considered to be ‘unadoptable’. These children included older children, placed from the foster care system. The practice of placing older children for adoption is now well established. This dissertation examines the experiences of early parenthood of parents who adopted older children, defined in this study as children aged four and over at the time of adoptive placement.\ud The data presented in this study are drawn from data collected for a larger study, the Wales Adoption Cohort Study. The study is primarily based on 14 in-depth interviews with new adoptive parents 9-months after an older child or children arrived in their home. The findings from the qualitative data are supplemented by findings from an analysis of quantitative data from a questionnaire issued to 84 new adoptive parents at two time points (four-months and sixteen-months post-placement). Using the quantitative data, the characteristics, support needs and experiences of adjustment to parenthood of parents of older- and younger-placed children are compared. \ud The qualitative data were analysed thematically, using codes organised into categories to manage and organise the data. Several key themes were developed from the data, these include the notion of adoption as a marketplace, ideas of family practices, displays of family, identity work, surveillance, and risk. The approach to analysis allowed for new insights to be made around family formation in adoptive homes. From the analysis of the interview data, this study presents the process of decision-making which caused adoptive parents to adopt older children; parents’ experiences of establishing routines and relationships with older-placed children; how parents began to explore and address issues of identity with their new children; and parents’ experiences of receiving support from, and being scrutinised by, social workers after the arrival of their child. \ud The findings from this study, when taken together, suggest that becoming a parent to an older child represents a challenging and emotionally complex transition to parenthood, as adopters of older children face immediate and non-normative parenting tasks. Adopters of older children often experience a high level of scrutiny in early parenthood, both from professionals and from their new child or children. Social workers have the potential to help or hinder adoptive parents as they negotiate this transition to parenthood, and at times, social work practice appeared to be overly scrutinising rather than being experienced as supportive by the new parents in the study. Within this dissertation, recommendations are made as to how social work practice, and policy relating to this, could shift to better support new adoptive parents of older children.