Reconstruction of cell surface densities of ion pumps, exchangers, and channels from mRNA expression, conductance kinetics, whole-cell calcium, and current-clamp voltage recordings, with an application to human uterine smooth muscle cells

Uterine smooth muscle cells remain quiescent throughout most of gestation, only generating spontaneous action potentials immediately prior to, and during, labor. This study presents a method that combines transcriptomics with biophysical recordings to characterise the conductance repertoire of these cells, the ‘conductance repertoire’ being the total complement of ion channels and transporters expressed by an electrically active cell. Transcriptomic analysis provides a set of potential electrogenic entities, of which the conductance repertoire is a subset. Each entity within the conductance repertoire was modeled independently and its gating parameter values were fixed using the available biophysical data. The only remaining free parameters were the surface densities for each entity. We characterise the space of combinations of surface densities (density vectors) consistent with experimentally observed membrane potential and calcium waveforms. This yields insights on the functional redundancy of the system as well as its behavioral versatility. Our approach couples high-throughput transcriptomic data with physiological behaviors in health and disease, and provides a formal method to link genotype to phenotype in excitable systems. We accurately predict current densities and chart functional redundancy. For example, we find that to evoke the observed voltage waveform, the BK channel is functionally redundant whereas hERG is essential. Furthermore, our analysis suggests that activation of calcium-activated chloride conductances by intracellular calcium release is the key factor underlying spontaneous depolarisations

Mathematical modeling of ovine footrot in the UK: the effect of Dichelobacter nodosus and Fusobacterium necrophorum on the disease dynamics

Dichelobacter nodosus is a virulent, invasive, anaerobic bacterium that is believed to be the causative agent of ovine footrot, an infectious bacterial disease of sheep that causes lameness. Another anaerobe, Fusobacterium necrophorum, has been intimately linked with the disease occurrence and severity. Here we examine data from a longitudinal study of footrot on one UK farm, including quantitative PCR (qPCR) estimates of bacterial load of D. nodosus and F. necrophorum. The data is at foot level; all feet were monitored for five weeks assessing disease severity (healthy, interdigital dermatitis (ID), or severe footrot (SFR)) and bacterial load (number of bacteria/swab). We investigate the role of D. nodosus and F. necrophorum in the progress of the disease using a continuous-time Markov model with 12 different states characterising the foot. The transition rates between the adjacent states are the (34) model parameters, these are determined using Metropolis Hasting MCMC. Our aim is to determine the predictive relationship between past and future D. nodosus and F. necrophorum load and disease states. We demonstrate a high level of predictive accuracy at the population level for the D. nodosus model, although the dynamics of individual feet is highly stochastic. However, we note that this predictive accuracy at population level is only high in more diseased states for F. necrophorum model. This supports our hypothesis that D. nodosus load and status of the foot work in combination to give rise to severe footrot and lameness, and that D. nodosus load plays the primary role in the initiation and progression of footrot, while F. necrophorum load rather increases disease severity of SFR

The inwardly rectifying K+ channel KIR7.1 controls uterine excitability throughout pregnancy

Abnormal uterine activity in pregnancy causes a range of important clinical disorders, including preterm birth, dysfunctional labour and post-partum haemorrhage. Uterine contractile patterns are controlled by the generation of complex electrical signals at the myometrial smooth muscle plasma membrane. To identify novel targets to treat conditions associated with uterine dysfunction, we undertook a genome-wide screen of potassium channels that are enriched in myometrial smooth muscle. Computational modelling identified Kir7.1 as potentially important in regulating uterine excitability during pregnancy. We demonstrate Kir7.1 current hyper-polarizes uterine myocytes and promotes quiescence during gestation. Labour is associated with a decline, but not loss, of Kir7.1 expression. Knockdown of Kir7.1 by lentiviral expression of miRNA was sufficient to increase uterine contractile force and duration significantly. Conversely, overexpression of Kir7.1 inhibited uterine contractility. Finally, we demonstrate that the Kir7.1 inhibitor VU590 as well as novel derivative compounds induces profound, long-lasting contractions in mouse and human myometrium; the activity of these inhibitors exceeds that of other uterotonic drugs. We conclude Kir7.1 regulates the transition from quiescence to contractions in the pregnant uterus and may be a target for therapies to control uterine contractility

Development of a method to characterise the expression profile of electrogenic transmembrane proteins in excitable cells

Computational and mathematical models have become increasingly important and have contributed to significant advances in our understanding of complex biological systems. We developed a mathematical model to characterise the expression profile of transmembrane electrogenic proteins of excitable cells. The cell of interest is the myometrium smooth muscle cell, which is the principal unit of electrical activity in the uterus. These cells remain quiescent throughout most of gestation, whereas just prior to and during labour they are able to generate spontaneous action potentials. A more detailed and comprehensive characterisation of these cells, in comparison to previous models, would furnish an appropriate tool for the development of therapeutics to manage preterm birth and other perinatal problems associated with uterine contractility, such as postpartum haemorrhage. The "conductome" can be defined as the totality of ion channels and ion transporters expressed by an electrically active cell, i.e., a list specifying the cell surface density and oligomeric composition of each of these species. Gene expression techniques can accurately survey the complete set of all mRNA species encoding electrogenic proteins (e.g., subunits of channels). The conductome is constrained by this transcriptome, but the link between the two is complicated by the facts that (i) presence of an mRNA species does not necessarily imply the presence at the transmembrane proteomics level; and (ii) subunits can combine in various ways to give rise to conducting channels with different properties. Every individual potential oligomeric channel complex was represented as a mathematical model on the basis of biophysical data taken from the literature; these data were obtained mainly using heterologous expression systems. We investigate the possibility of combining the behavioural information of the action potential with the detailed molecular data of the transcriptome. The general problem is that electrical behaviour does not necessarily lead to a unique solution. The question addressed here is to what extent the additional information provided by transcriptomics helps to constrain the solution space. We develop and apply a method to characterise the functional redundancy of electrically active cells. We use mRNA sequencing to determine which electrogenic species the cell is capable of expressing, combined with a least-squares parameter estimation procedure to determine the conductome from electrophysiological data. Moreover, we estimate the parameters associated with the gating kinetics from published data, so that the only remaining free parameters are the surface densities of the species on the list defined by the transcriptomics analysis

Adoption by clinicians of electronic order communications in NHS secondary care:a descriptive account

Background: Due to the rapid advancement in information technology, changes to communication modalities are increasingly implemented in healthcare. One such modality is Computerised Provider Order Entry (CPOE) systems which replace paper, verbal or telephone orders with electronic booking of requests. We aimed to understand the uptake, and user acceptability, of CPOE in a large National Health Service hospital system. Methods: This retrospective single-centre study investigates the longitudinal uptake of communications through the Prescribing, Information and Communication System (PICS). The development and configuration of PICS are led by the doctors, nurses and allied health professionals that use it and requests for CPOE driven by clinical need have been described. Records of every request (imaging, specialty review, procedure, laboratory) made through PICS were collected between October 2008 and July 2019 and resulting counts were presented. An estimate of the proportion of completed requests made through the system has been provided for three example requests. User surveys were completed. Results: In the first 6 months of implementation, a total of 832 new request types (imaging types and specialty referrals) were added to the system. Subsequently, an average of 6.6 new request types were added monthly. In total, 8 035 132 orders were requested through PICS. In three example request types (imaging, endoscopy and full blood count), increases in the proportion of requests being made via PICS were seen. User feedback at 6 months reported improved communications using the electronic system. Conclusion: CPOE was popular, rapidly adopted and diversified across specialties encompassing wide-ranging requests

Computational physiology of uterine smooth muscle.

Pregnancy can be accompanied by serious health risks to mother and child, such as pre-eclampsia, premature birth and postpartum haemorrhage. Understanding of the normal physiology of uterine function is essential to an improved management of such risks. Here we focus on the physiology of the smooth muscle fibres which make up the bulk of the uterine wall and which generate the forceful contractions that accompany parturition. We survey computational methods that integrate mathematical modelling with data analysis and thereby aid the discovery of new therapeutic targets that, according to clinical needs, can be manipulated to either stop contractions or cause the uterine wall muscle to become active

Does acute kidney injury alerting improve patient outcomes?

Abstract Background Electronic alerts (e-alerts) for Acute Kidney Injury (AKI) have been implemented into a variety of different Electronic Health Records (EHR) systems worldwide in order to improve recognition and encourage early appropriate management of AKI. We were interested in the impact on patient safety, specialist referral and clinical management. Methods All patients admitted to our institution with AKI were included in the study. We studied AKI progression, dialysis dependency, length of hospital stay, emergency readmission, ICU readmission, and death, before and after the introduction of electronic alerts. The impact on prescription of high risk drugs, fluid administration, and referral to renal services was also analysed. Results After the introduction of the e-alert, progression to higher AKI stage, emergency readmission to hospital and death during admission were significantly reduced. More prescriptions were stopped for drugs that adversely affect renal function in AKI and there was a significant increase in the ICU admissions and in the number of patients having dialysis, especially in earlier stages. Longer term mortality, renal referrals, and fluid alteration did not change significantly after the AKI e-alert introduction. Conclusions AKI e-alerts can improve clinical outcomes in hospitalised patients

Introduction of Systematized Nomenclature of Medicine-Clinical Terms Coding Into an Electronic Health Record and Evaluation of its Impact: Qualitative and Quantitative Study.

BACKGROUND This study describes the conversion within an existing electronic health record (EHR) from the International Classification of Diseases, Tenth Revision coding system to the SNOMED-CT (Systematized Nomenclature of Medicine-Clinical Terms) for the collection of patient histories and diagnoses. The setting is a large acute hospital that is designing and building its own EHR. Well-designed EHRs create opportunities for continuous data collection, which can be used in clinical decision support rules to drive patient safety. Collected data can be exchanged across health care systems to support patients in all health care settings. Data can be used for research to prevent diseases and protect future populations. OBJECTIVE The aim of this study was to migrate a current EHR, with all relevant patient data, to the SNOMED-CT coding system to optimize clinical use and clinical decision support, facilitate data sharing across organizational boundaries for national programs, and enable remodeling of medical pathways. METHODS The study used qualitative and quantitative data to understand the successes and gaps in the project, clinician attitudes toward the new tool, and the future use of the tool. RESULTS The new coding system (tool) was well received and immediately widely used in all specialties. This resulted in increased, accurate, and clinically relevant data collection. Clinicians appreciated the increased depth and detail of the new coding, welcomed the potential for both data sharing and research, and provided extensive feedback for further development. CONCLUSIONS Successful implementation of the new system aligned the University Hospitals Birmingham NHS Foundation Trust with national strategy and can be used as a blueprint for similar projects in other health care settings

Effectiveness of clinical decision support in controlling inappropriate red blood cell and platelet transfusions, speciality specific responses and behavioural change

Abstract Background Electronic clinical decision support (CDS) within Electronic Health Records has been used to improve patient safety, including reducing unnecessary blood product transfusions. We assessed the effectiveness of CDS in controlling inappropriate red blood cell (RBC) and platelet transfusion in a large acute hospital and how speciality specific behaviours changed in response. Methods We used segmented linear regression of interrupted time series models to analyse the instantaneous and long term effect of introducing blood product electronic warnings to prescribers. We studied the impact on transfusions for patients in critical care (CC), haematology/oncology (HO) and elsewhere. Results In non-CC or HO, there was significant and sustained decrease in the numbers of RBC transfusions after introduction of alerts. In CC the alerts reduced transfusions but this was not sustained, and in HO there was no impact on RBC transfusion. For platelet transfusions outside of CC and HO, the introduction of alerts stopped a rising trend of administration of platelets above recommended targets. In CC, alerts reduced platelet transfusions, but in HO alerts had little impact on clinician prescribing. Conclusion The findings suggest that CDS can result in immediate change in user behaviour which is more obvious outside specialist settings of CC and HO. It is important that this is then sustained. In CC and HO, blood transfusion practices differ. CDS thus needs to take specific circumstances into account. In this case there are acceptable reasons to transfuse outside of these crude targets and CDS should take these into account