Improving stroke pathways using an adhesive ambulatory ECG patch: reducing time for patients to ECGs and subsequent results.

Three south-London hospital trusts undertook a feasibility study, comparing data from 93 patients who received the 14-day adhesive ambulatory electrocardiography (ECG) patch Zio XT with retrospective data from 125 patients referred for 24-hour Holter for cryptogenic stroke and transient ischaemic attack following negative 12-lead ECG. As the ECG patch was fitted the same day as the clinical decision for ambulatory ECG monitoring was made, median time to the patient having the monitor fitted was significantly reduced in all three hospital trusts compared with 24-hour Holter being ordered and fitted. Hospital visits reduced by a median of two for patients receiving Zio XT. This project supports that it is feasible to use a patch as part of routine clinical care with a positive impact on care pathways.

Prognosis in dysphagic patients who are eating and drinking with acknowledged risk: results from the evaluation of the FORWARD project.

BACKGROUND: patients with a permanently unsafe swallow may choose to eat and drink with acknowledged risk (EDAR). Informed decision-making and advance care planning depend on prognosis, but no data have yet been published on outcomes after EDAR decisions. METHODS: the study was undertaken in 555 hospital inpatients' (mean [SD] age: 83 {12}) EDAR supported by the Feeding via the Oral Route with Acknowledged Risk of Deterioration care bundle between January 2015 and November 2019. Data were collected prospectively on clinical characteristics, dates of discharge, readmissions and death (where relevant). Kaplan-Meier survival functions and readmission risks per surviving patient per month were calculated. RESULTS: mortality is 56% in the first 3 months after discharge but then mortality risk sharply decreases. The 3-month survival in EDAR patients was more likely in those <75 years of age, those with Parkinson's disease or a structural oral lesion as the dominating cause of dysphagia and those with mental capacity regarding EDAR decisions. Readmission risk in the 3 months post-discharge is 21% but reduces to 12% thereafter (P < 0.001). Thirty-eight percent of readmissions are secondary to EDAR-linked conditions such as chest infections and reduced oral intake. CONCLUSION: there is a high mortality and readmission risk after an EDAR decision but much of this is frontloaded into the first 3 months, with a relatively favourable prognosis thereafter. This may be an appropriate time-point to reassess the plan for eating and drinking such that it continues to reflect the most appropriate balance of risk, comfort and nutrition.

Approaches to Eating and Drinking with Acknowledged Risk: A Systematic Review.

BACKGROUND: Patients with dysphagia may consider eating and drinking with acknowledged risk (EDAR) instead of artificial hydration/nutrition. Timely consideration of complex issues is required including dysphagia reversibility, risk/benefit discussions, patient wishes, their capacity and best interests. OBJECTIVE: This study aimed to establish if EDAR protocols improve care through a systematic literature review with a secondary aim to explore important factors for the development and success of a protocol. METHODS: PUBMED, MEDLINE, CINAHL and EMBASE were searched for English language articles to May 2019 with terms related to EDAR, dysphagia and end of life. Articles were agreed for inclusion by three independent reviewers. Levels of evidence were assessed using the modified Sackett scale. Study themes were identified and discussed. RESULTS: 8 articles met the inclusion criteria with varied methodology. The highest level of evidence was III (cohort study). Most were limited to patients with dementia, stroke, in older person's wards or residential homes. Three articles described a systematic approach to EDAR for in-patients, reporting reductions in days nil-by-mouth until feeding plans are made and improvements in documentation of decision making, nutrition plans and capacity assessment. Five papers explored the views and knowledge of staff, patients and families/carers relating to EDAR and complex feeding decisions. Formal meta-analysis was not possible due to the level and mix of methodology. CONCLUSION: There is a paucity of evidence to determine if EDAR protocols improve care. However, support is emerging for a coordinated approach to managing EDAR. Findings suggest having a protocol is not enough; training and communication within teams is essential, together with incorporating feedback from patients and carers, and this justifies further work.

Using mobile ECG devices to increase detection of atrial fibrillation across a range of settings in south London.

The NHS Long Term Plan aims to transform how we tackle cardiovascular disease by improving the detection and treatment of high-risk conditions. One in five strokes are linked to atrial fibrillation (AF) and it is estimated that 500,000 people in the UK have undiagnosed AF. To increase detection of AF, in 2017 NHS England commissioned the Academic Health Science Networks to procure 6,000 mobile electrocardiography (ECG) devices, which were distributed to community settings across the county. The Health Innovation Network as the Academic Health Science Network for south London was responsible for the distribution of approximately 400 mobile ECG devices to a range of settings. A total of 14,835 pulse rhythm checks were performed, detecting 597 people with possible AF. This project provides insight into effectiveness of a wide range of settings in providing opportunistic testing for AF using mobile ECG devices.

FORWARD (Feeding via the Oral Route With Acknowledged Risk of Deterioration): evaluation of a novel tool to support patients eating and drinking at risk of aspiration.

BACKGROUND: care of patients with a permanently unsafe swallow who are inappropriate for tube feeding is challenging. Eating and drinking with acknowledged risk (EDAR) may be an appropriate strategy but without clear decision making and communication patients may spend unnecessarily long 'nil by mouth' (NBM), they or their family may experience significant anxieties and advance care plans may not be made. METHODS: the FORWARD (Feeding via the Oral Route With Acknowledged Risk of Deterioration) care bundle was sequentially co-designed and embedded across different in-patient clinical services using 'plan-do-study-act' methodology to systematise best practice. Care before and after FORWARD's implementation was evaluated using a time-series analysis of 305 'EDAR patients' (19 in 6 months pre-FORWARD; 42 in a 12-month 'pilot'; 244 patients in the subsequent 27 months). RESULTS: median (IQR) days patients were NBM without an alternative feeding route reduced significantly from 2 (1-4) pre-FORWARD to 0 (0-2) in the 'pilot' and 0 (0) post-'pilot' (P < 0.05). G-chart analysis demonstrated sustained performance across time and different clinical settings. Implementation of FORWARD significantly improved documentation of capacity assessment (42%→98%), discussions with next of kin (47%→98%) and onward communication of feeding plans (67%→81%). In wards where FORWARD was introduced, rate of aspiration pneumonia (a 'balancing measure' sensitive to harm associated with EDAR) increased at half the rate of dysphagia (0.8%/year versus 1.6%/year). CONCLUSION: the FORWARD care bundle supported complex decision-making around EDAR in patients with persistent dysphagia. The benefits of FORWARD were shown to be sustained over time and in a wide in-patient context.

Development of an integrated multimodal optical imaging system with real-time image analysis for the evaluation of oral premalignant lesions.

Oral premalignant lesions (OPLs), such as leukoplakia, are at risk of malignant transformation to oral cancer. Clinicians can elect to biopsy OPLs and assess them for dysplasia, a marker of increased risk. However, it is challenging to decide which OPLs need a biopsy and to select a biopsy site. We developed a multimodal optical imaging system (MMIS) that fully integrates the acquisition, display, and analysis of macroscopic white-light (WL), autofluorescence (AF), and high-resolution microendoscopy (HRME) images to noninvasively evaluate OPLs. WL and AF images identify suspicious regions with high sensitivity, which are explored at higher resolution with the HRME to improve specificity. Key features include a heat map that delineates suspicious regions according to AF images, and real-time image analysis algorithms that predict pathologic diagnosis at imaged sites. Representative examples from ongoing studies of the MMIS demonstrate its ability to identify high-grade dysplasia in OPLs that are not clinically suspicious, and to avoid unnecessary biopsies of benign OPLs that are clinically suspicious. The MMIS successfully integrates optical imaging approaches (WL, AF, and HRME) at multiple scales for the noninvasive evaluation of OPLs.

Cellular reprogramming dynamics follow a simple 1D reaction coordinate.

Cellular reprogramming, the conversion of one cell type to another, induces global changes in gene expression involving thousands of genes, and understanding how cells globally alter their gene expression profile during reprogramming is an ongoing problem. Here we reanalyze time-course data on cellular reprogramming from differentiated cell types to induced pluripotent stem cells (iPSCs) and show that gene expression dynamics during reprogramming follow a simple 1D reaction coordinate. This reaction coordinate is independent of both the time it takes to reach the iPSC state as well as the details of the experimental protocol used. Using Monte-Carlo simulations, we show that such a reaction coordinate emerges from epigenetic landscape models where cellular reprogramming is viewed as a 'barrier-crossing' process between cell fates. Overall, our analysis and model suggest that gene expression dynamics during reprogramming follow a canonical trajectory consistent with the idea of an 'optimal path' in gene expression space for reprogramming.

Thyroid Progenitors Are Robustly Derived from Embryonic Stem Cells through Transient, Developmental Stage-Specific Overexpression of Nkx2-1.

The clinical importance of anterior foregut endoderm (AFE) derivatives, such as thyrocytes, has led to intense research efforts for their derivation through directed differentiation of pluripotent stem cells (PSCs). Here, we identify transient overexpression of the transcription factor (TF) NKX2-1 as a powerful inductive signal for the robust derivation of thyrocyte-like cells from mouse PSC-derived AFE. This effect is highly developmental stage specific and dependent on FOXA2 expression levels and precise modulation of BMP and FGF signaling. The majority of the resulting cells express thyroid TFs (Nkx2-1, Pax8, Foxe1, Hhex) and thyroid hormone synthesis-related genes (Tg, Tpo, Nis, Iyd) at levels similar to adult mouse thyroid and give rise to functional follicle-like epithelial structures in Matrigel culture. Our findings demonstrate that NKX2-1 overexpression converts AFE to thyroid epithelium in a developmental time-sensitive manner and suggest a general methodology for manipulation of cell-fate decisions of developmental intermediates.

Improving the care of patients feeding at risk using a novel care bundle.

Feeding with acknowledged risk is appropriate for patients unsuitable for tube feeding who have an unsafe swallow that is unlikely to improve. However, without excellent multidisciplinary decision making and communication, patients may spend unnecessarily long 'nil by mouth' (NBM) and advance feeding/care plans may not be made or communicated. The FORWARD bundle (Feeding via the Oral Route With Acknowledged Risk of Deterioration) was sequentially co-designed and embedded across different services using 'plan-do-study-act' methodology to systematise best practice. Care before and after FORWARD was evaluated using a time-series analysis of 80 patients who had been risk-fed. Time NBM without tube feeding improved from 2 to 0 days (p=0.02) with significantly better documentation of capacity assessments and discussions with next of kin. There were sustained trends to improved rates of best interest discussions and communication of feeding plans to downstream care providers. The significance and applicability of these findings is discussed.

Emergence of a stage-dependent human liver disease signature with directed differentiation of alpha-1 antitrypsin-deficient iPS cells.

Induced pluripotent stem cells (iPSCs) provide an inexhaustible source of cells for modeling disease and testing drugs. Here we develop a bioinformatic approach to detect differences between the genomic programs of iPSCs derived from diseased versus normal human cohorts as they emerge during in vitro directed differentiation. Using iPSCs generated from a cohort carrying mutations (PiZZ) in the gene responsible for alpha-1 antitrypsin (AAT) deficiency, we find that the global transcriptomes of PiZZ iPSCs diverge from normal controls upon differentiation to hepatic cells. Expression of 135 genes distinguishes PiZZ iPSC-hepatic cells, providing potential clues to liver disease pathogenesis. The disease-specific cells display intracellular accumulation of mutant AAT protein, resulting in increased autophagic flux. Furthermore, we detect beneficial responses to the drug carbamazepine, which further augments autophagic flux, but adverse responses to known hepatotoxic drugs. Our findings support the utility of iPSCs as tools for drug development or prediction of toxicity.

Thermodynamics of statistical inference by cells.

The deep connection between thermodynamics, computation, and information is now well established both theoretically and experimentally. Here, we extend these ideas to show that thermodynamics also places fundamental constraints on statistical estimation and learning. To do so, we investigate the constraints placed by (nonequilibrium) thermodynamics on the ability of biochemical signaling networks to estimate the concentration of an external signal. We show that accuracy is limited by energy consumption, suggesting that there are fundamental thermodynamic constraints on statistical inference.

Epigenetic landscapes explain partially reprogrammed cells and identify key reprogramming genes.

A common metaphor for describing development is a rugged "epigenetic landscape" where cell fates are represented as attracting valleys resulting from a complex regulatory network. Here, we introduce a framework for explicitly constructing epigenetic landscapes that combines genomic data with techniques from spin-glass physics. Each cell fate is a dynamic attractor, yet cells can change fate in response to external signals. Our model suggests that partially reprogrammed cells are a natural consequence of high-dimensional landscapes, and predicts that partially reprogrammed cells should be hybrids that co-express genes from multiple cell fates. We verify this prediction by reanalyzing existing datasets. Our model reproduces known reprogramming protocols and identifies candidate transcription factors for reprogramming to novel cell fates, suggesting epigenetic landscapes are a powerful paradigm for understanding cellular identity.

Metabolic resource allocation in individual microbes determines ecosystem interactions and spatial dynamics.

The interspecies exchange of metabolites plays a key role in the spatiotemporal dynamics of microbial communities. This raises the question of whether ecosystem-level behavior of structured communities can be predicted using genome-scale metabolic models for multiple organisms. We developed a modeling framework that integrates dynamic flux balance analysis with diffusion on a lattice and applied it to engineered communities. First, we predicted and experimentally confirmed the species ratio to which a two-species mutualistic consortium converges and the equilibrium composition of a newly engineered three-member community. We next identified a specific spatial arrangement of colonies, which gives rise to what we term the "eclipse dilemma": does a competitor placed between a colony and its cross-feeding partner benefit or hurt growth of the original colony? Our experimentally validated finding that the net outcome is beneficial highlights the complex nature of metabolic interactions in microbial communities while at the same time demonstrating their predictability.

Intrinsic noise of microRNA-regulated genes and the ceRNA hypothesis.

MicroRNAs are small noncoding RNAs that regulate genes post-transciptionally by binding and degrading target eukaryotic mRNAs. We use a quantitative model to study gene regulation by inhibitory microRNAs and compare it to gene regulation by prokaryotic small non-coding RNAs (sRNAs). Our model uses a combination of analytic techniques as well as computational simulations to calculate the mean-expression and noise profiles of genes regulated by both microRNAs and sRNAs. We find that despite very different molecular machinery and modes of action (catalytic vs stoichiometric), the mean expression levels and noise profiles of microRNA-regulated genes are almost identical to genes regulated by prokaryotic sRNAs. This behavior is extremely robust and persists across a wide range of biologically relevant parameters. We extend our model to study crosstalk between multiple mRNAs that are regulated by a single microRNA and show that noise is a sensitive measure of microRNA-mediated interaction between mRNAs. We conclude by discussing possible experimental strategies for uncovering the microRNA-mRNA interactions and testing the competing endogenous RNA (ceRNA) hypothesis.