On-demand computerised decision support in paediatric emergency medication administration

Medication errors are common and contribute significantly to avoidable morbidity and mortality. These errors are more common in paediatrics than in adult medicine and yet more common in emergencies than in non-urgent scenarios. Emergency medication use in paediatrics is a complex process, often performed by a multidisciplinary team. This practise spans paediatric emergency weight estimation, medication ordering and the preparation, labelling and finally administration of drugs to critically ill children. Discrepancies during any one of these stages may be the cause of a medication error. This thesis describes the feasibility testing and iterative development of On-Demand Computerised Decision Support (ODCDSS), a digital medication safety system designed to support emergency doctors and nurses at all stages of medication use during paediatric resuscitation. This thesis decouples paediatric weight estimation and medication administration, with each being examined separately. First, opportunities to incorporate digitally-supported weight estimation methods into a comprehensive decision support system are explored. This includes efforts to improve well-established but inaccurate methods such as age-based weight estimation, and an exploration into whether emerging technologies such as three- dimensional imaging could bring greater accuracy than current methods. To validate the design rationale behind ODCDSS, simulated resuscitations are examined using a human factors approach. Human Reliability Analysis (HRA) is 2 used to show both that the incidence of medication error is dangerously high and that many errors are clinically significant, as well to identify the individual process steps that contribute to these errors. This thesis is the first to describe the design and development of ODCDSS. The effectiveness of this experimental prototype was tested in a simulated crossover study which determined that using ODCDSS significantly reduced the odds of a clinically significant medication error occurring. The use of ODCDSS, however, was not error free, and HRA was re-applied to determine precisely where the prototype system required design refinement.Open Acces

Indication documentation and indication-based prescribing within electronic prescribing systems: a systematic review and narrative synthesis

BACKGROUND: Despite recommendations, documentation of indication on prescriptions and inpatient medication orders is not routinely practised. There has been a recent systematic review of indication documentation for antimicrobials, but not for interventions relating to indication documentation for medication more broadly. Our aims were to 1) identify, describe and synthesise the literature relating to effectiveness of interventions aimed at improving indication documentation and/or indication-based prescribing in both primary and secondary healthcare; 2) synthesise participant perspectives to identify barriers and facilitators to these interventions; and 3) make recommendations for both practice and research. METHODS: A systematic literature search was conducted using Medline, Embase and CINAHL using two search concepts: electronic prescribing systems, and indication documentation and/or indication-based prescribing. Qualitative, quantitative and mixed-methods studies were included; outcome measures and results were extracted to produce a narrative synthesis. Quality appraisal by two independent reviewers was undertaken using the Mixed Methods Appraisal Tool. RESULTS: We identified 21 studies evaluating interventions to aid indication documentation. Indication documentation was either via free-text, selection from a list, or by use of pre-defined indication-based order sentences for individual medications. For a number of outcomes, there was a mostly positive impact, including appropriateness of the medication order (6 of 8 studies), rates of prescribing error (2/2) and some less commonly reported clinical (2/4) and workflow-related outcomes (2/3). There was a less favourable impact on accuracy of indication documentation and rates of medication use, highlighting some unintended consequences that may occur when implementing new interventions. Participant insights from prescribers and other healthcare professionals complemented quantitative study results, highlighting both facilitators and barriers to indication documentation and the associated interventions. For example, barriers included long drop-down lists and the need to use workarounds to navigate approval systems due to time or knowledge constraints. Facilitating factors included the perceived benefits of indication documentation on communication among the healthcare team and with the patient. CONCLUSION: Indication documentation has the potential to improve appropriate prescribing and reduce prescribing errors. However, further benefits to the prescriber, multidisciplinary team and patient may only be realised by developing methods of indication documentation that integrate more efficiently with prescriber workflows. PROSPERO REGISTRATION NUMBER: CRD42021278495

Light Directs Zebrafish period2 Expression via Conserved D and E Boxes

A highly conserved promoter module in a vertebrate clock gene confers light-regulated gene expression

Topological insulator quantum dot with tunable barriers

Thin (6-7 quintuple layer) topological insulator Bi2Se3 quantum dot devices are demonstrated using ultrathin (2~4 quintuple layer) Bi2Se3 regions to realize semiconducting barriers which may be tuned from Ohmic to tunneling conduction via gate voltage. Transport spectroscopy shows Coulomb blockade with large charging energy >5 meV, with additional features implying excited states

A Zebrafish Model for a Rare Genetic Disease Reveals a Conserved Role for FBXL3 in the Circadian Clock System

The circadian clock, which drives a wide range of bodily rhythms in synchrony with the day–night cycle, is based on a molecular oscillator that ticks with a period of approximately 24 h. Timed proteasomal degradation of clock components is central to the fine-tuning of the oscillator’s period. FBXL3 is a protein that functions as a substrate-recognition factor in the E3 ubiquitin ligase complex, and was originally shown in mice to mediate degradation of CRY proteins and thus contribute to the mammalian circadian clock mechanism. By exome sequencing, we have identified a FBXL3 mutation in patients with syndromic developmental delay accompanied by morphological abnormalities and intellectual disability, albeit with a normal sleep pattern. We have investigated the function of FBXL3 in the zebrafish, an excellent model to study both vertebrate development and circadian clock function and, like humans, a diurnal species. Loss of fbxl3a function in zebrafish led to disruption of circadian rhythms of promoter activity and mRNA expression as well as locomotor activity and sleep–wake cycles. However, unlike humans, no morphological effects were evident. These findings point to an evolutionary conserved role for FBXL3 in the circadian clock system across vertebrates and to the acquisition of developmental roles in humans

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

A multi-centre, randomised controlled trial of cognitive therapy to prevent harmful compliance with command hallucinations

<p>Abstract</p> <p>Background</p> <p>Command hallucinations are among the most distressing, high risk and treatment resistant symptoms for people with psychosis; however, currently, there are no evidence-based treatment options available for this group. A cognitive therapy grounded in the principles of the Social Rank Theory, is being evaluated in terms of its effectiveness in reducing harmful compliance with command hallucinations.</p> <p>Methods/Design</p> <p>This is a single blind, intention-to-treat, multi-centre, randomized controlled trial comparing Cognitive Therapy for Command Hallucinations + Treatment as Usual with Treatment as Usual alone. Eligible participants have to fulfil the following inclusion criteria: i) ≥16 years; ii) ICD-10 diagnosis of schizophrenia or related disorder; iii) command hallucinations for at least 6 months leading to risk of harm to self or others. Following the completion of baseline assessments, eligible participants will be randomly allocated to either the Cognitive Therapy for Command Hallucinations + Treatment as Usual group or the Treatment as Usual group. Outcome will be assessed at 9 and 18 months post randomization with assessors blind to treatment allocation. The primary outcome is compliance behaviour and secondary outcomes include beliefs about voices' power, distress, psychotic symptoms together with a health economic evaluation. Qualitative interviews with services users will explore the acceptability of Cognitive Therapy for Command Hallucinations.</p> <p>Discussion</p> <p>Cognitive behaviour therapy is recommended for people with psychosis; however, its focus and evaluation has primarily revolved around the reduction of psychotic symptoms. In this trial, however, the focus of the cognitive behavioural intervention is on individuals' appraisals, behaviour and affect and not necessarily symptoms; this is also reflected in the outcome measures used. If successful, the results will mark a significant breakthrough in the evidence base for service users and clinicians and will provide a treatment option for this group where none currently exist. The trial will open the way for further breakthrough work with the 'high risk' population of individuals with psychosis, which we would intend to pursue.</p> <p>Trial registration</p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRCTN62304114">ISRCTN62304114</a></p