Electrolyte disturbances: causes and management

This article details the clinical presentations of the most common electrolyte disturbances and how to treat them

How to perform accurate medicines reconciliation

How to approach medicines reconciliation in practice and some pitfalls to avoid. After reading this article you should be able to: • Define the term ‘medicines reconciliation’; • Discuss why timely medicines reconciliation is a vital aspect of patient care; • Appraise the strengths and weaknesses of different sources used to obtain a patient’s medication history; • Prioritise patients requiring medicines reconciliation when they are admitted to hospital

Exploring the Pathogenic and Drug Resistance Mechanisms of Staphylococcus aureus

We have previously identified σS, an ECF sigma factor that is important in the virulence and stress response of S. aureus. Transcriptional profiling of sigS revealed that it is differentially regulated in a variety of laboratory and clinical strains of S. aureus, suggesting that there exists a regulatory network that modulates its expression. In order to identify direct regulators of sigS expression, we performed a biotin pull down assay in tandem with mass spectrometry. We identified CymR as a direct regulator and observed that sigS expression is increased in cells lacking cymR. In addition, transposon mutagenesis was performed to identify regulators of sigS expression. We identified insertions in genes that are transcriptional regulators, and elements involved in amino acid biosynthesis and DNA replication, recombination and repair as influencing sigS expression. Finally, methyl nitro-nitrosoguanidine mutagenesis in conjunction with whole genome sequencing was employed and revealed mutations in the lactose repressor, lacR, and the membrane sensor histidine kinase, kdpD, as negatively effecting sigS expression. EMSAs revealed that LacR is an indirect regulator of sigS expression, while the response regulator KdpE is a direct repressor. These results indicate that a complex regulatory network is in place for sigS that modulates its expression. In a continuation of studies on σS regulation, we next explored interplay with the products of genes conserved within the sigS locus. We determined that this region is conserved amongst all the sequenced staphylococci, and includes four genes: SAUSA300_1721 (a conserved hypothetical protein), as well as sigS, ecfX, and ecfY. In order to investigate the relationship between EcfX and σS we performed protein pull down assays and observed that these two protein interact. Further to this, transcriptional analysis of sigS in an ecfX mutant reveal that expression of sigS is decreased, indicating that it is an activator. Architectural analysis of the sigS locus via RNAseq revealed that the majority of transcription in this region comes from ecfY, a gene that is downstream and divergent to sigS. We demonstrate that inactivation of ecfY leads to a significant increase in sigS expression, and that ecfY null strains are more resistant to DNA damaging agents such as UV, H2O2, MMS, and ethidium bromide, which we have previously demonstrated that a sigS mutant is highly sensitive to. Our studies also revealed that an ecfY null strain is better able to survive intracellularly following phagocytosis by RAW 264.7 cell and demonstrates increased survival in whole-human blood, which is again opposed to that previously observed for sigS deficient strains. Because the ecfY null strain overexpresses sigS, we investigated the regulon of this sigma factor using this mutant in conjunction with RNAseq analysis. We identified that genes putatively under the control of σS are involved in DNA damage and repair, virulence, amino acid starvation and nucleic acid biosynthesis. Collectively, our results indicate that σS is regulated via a unique mechanism: positively through an apparent need for an activator protein (EcfX) and negatively via RNA-RNA interaction (the 3’ UTR of ecfY). We suggest that the evidence presented here greatly adds not only to our understanding of the regulatory circuits extant within S. aureus, but also to alternative sigma factor biology in general. Finally, we evaluated the efficacy of a novel library of quinazoline-based compounds against a highly drug resistant strain of S. aureus. We performed structure activity and structure property relationship assays in order to identify lead compounds. These methods lead to the identification of N2,N4-disubstituted quinazoline-2,4-diamines that had low minimum inhibitory concentrations, along with favorable physiochemical properties. Evaluation of their biological activity demonstrated limited potential for resistance of to our quinazoline based compounds, low toxicity to human epithelial cells, and strong efficacy in vivo. Taken together, our findings support the use of quinazoline derivatives as potential new antimicrobials against multidrug resistant S. aureus

Tracer concentration profiles measured in central London as part of the REPARTEE campaign

There have been relatively few tracer experiments carried out that have looked at vertical plume spread in urban areas. In this paper we present results from two tracer (cyclic perfluorocarbon) experiments carried out in 2006 and 2007 in central London centred on the BT Tower as part of the REPARTEE (Regent’s Park and Tower Environmental Experiment) campaign. The height of the tower gives a unique opportunity to study vertical dispersion profiles and transport times in central London. Vertical gradients are contrasted with the relevant Pasquill stability classes. Estimation of lateral advection and vertical mixing times are made and compared with previous measurements. Data are then compared with a simple operational dispersion model and contrasted with data taken in central London as part of the DAPPLE campaign. This correlates dosage with non-dimensionalised distance from source. Such analyses illustrate the feasibility of the use of these empirical correlations over these prescribed distances in central London

Extending periodic eddy covariance latent heat fluxes through tree sap-flow measurements to estimate long-term total evaporation in a peat swamp forest

A combination of measurement and modelling was used to find a pragmatic solution to estimate the annual total evaporation from the rare and indigenous Nkazana Peat Swamp Forest (PSF) on the east coast of Southern Africa to improve the water balance estimates within the area. Actual total evaporation (ETa) was measured during three window periods (between 7 and 9 days each) using an eddy covariance (EC) system on a telescopic mast above the forest canopy. Sap flows of an understory tree and an emergent tree were measured using a low-maintenance heat pulse velocity system for an entire hydrological year (October 2009 to September 2010). An empirical model was derived, describing the relationship between ETa from the Nkazana PSF and sap-flow measurements. These overlapped during two of the window periods (R2 = 0.92 and 0.90), providing hourly estimates of ETa from the Nkazana PSF for a year, totalling 1125 mm (while rainfall was 650 mm). In building the empirical model, it was found that to include the understory tree sap flow provided no benefit to the model performance. In addition, the relationship between the emergent tree sap flow with ETa between the two field campaigns was consistent and could be represented by a single empirical model (R2 = 0.90; RMSE = 0.08 mm h−1). During the window periods of EC measurement, no single meteorological variable was found to describe the Nkazana PSF ETa satisfactorily. However, in terms of evaporation models, the hourly FAO Penman–Monteith reference evaporation (ETo) best described ETa during the August 2009 (R2 = 0.75), November 2009 (R2 = 0.85) and March 2010 (R2 = 0.76) field campaigns, compared to the Priestley–Taylor potential evaporation (ETp) model (R2 = 0.54, 0.74 and 0.62 during the respective field campaigns). From the extended record of ETa (derived in this study from sap flow) and ETo, a monthly crop factor (Kc) was derived for the Nkazana PSF, providing a method of estimating long-term swamp forest water-use from meteorological data. The monthly Kc indicated two distinct periods. From February to May, it was between 1.2 and 1.4 compared with June to January, when the crop factor was 0.8 to 1.0. The derived monthly Kc values were verified as accurate (to one significant digit) using historical data measured at the same site, also using EC, from a previous study. The measurements provided insights into the microclimate within a subtropical peat swamp forest and the contrasting sap flow of emergent and understory trees. They showed that expensive, high-maintenance equipment can be used during manageable window periods in conjunction with low-maintenance systems, dedicated to individual trees, to derive a model to estimate long-term ETa over remote heterogeneous forests. In addition, the contrast in annual ETa and rainfall emphasised the reliance of the Nkazana PSF on groundwater

The adolescent HIV executive function and drumming (AHEAD) study, a feasibility trial of a group drumming intervention amongst adolescents with HIV

AHEAD feasibility trial assessed the feasibility and acceptability of an 8-session group drummingprogramme aiming to improve executive function, depression and anxiety symptoms, andperceived social support in adolescents living with HIV in a rural low-income South Africansetting. Sixty-eight 12- to 19-year-old adolescents participated. They were individuallyrandomised. The intervention arm (n= 34) received weekly hour-long group drumming sessions.Controls (n= 34) received no intervention. Feasibility and acceptability were assessed usingrates of: enrolment; retention; attendance; logistical problems; adolescent-reportedacceptability. Secondary measures included:five Oxford Cognitive Screen-Executive Function(OCS-EF) tasks; two Rapid Assessment of Cognitive and Emotional Regulation (RACER) tasks; theSelf-Reporting Questionnaire-20 (SRQ-20) measuring depression and anxiety symptoms; theMultidimensional Scale of Perceived Social Support (MSPSS). All feasibility criteria were withingreen progression limits. Enrolment, retention, and acceptability were high. There was a positive effect on adolescent depressed mood with a signal for a working memory effect. There were no significant effects on executive function or socio-emotional scales. Qualitative findings suggested socio-emotional benefits including group belonging; decreased internalised stigma; improved mood; and decreased anxiety. Group drumming is a feasible and acceptable intervention among adolescents living with HIV in rural South Africa. A full-scale trial is recommendedAfrica-Oxford Initiative (AfiOx-32), the Society for Education, Music and Psychology Research (SEMPRE) Gerry Farrell scholarship, the Murray Speight grant, the Rhodes Trust, and the Medical Research Council United Kingdom.https://www.tandfonline.com/loi/caic20Musi

Blood pressure monitoring in high-risk pregnancy to improve the detection and monitoring of hypertension (the BUMP 1 and 2 trials): protocol for two linked randomised controlled trials.

INTRODUCTION: Self-monitoring of blood pressure (BP) in pregnancy could improve the detection and management of pregnancy hypertension, while also empowering and engaging women in their own care. Two linked trials aim to evaluate whether BP self-monitoring in pregnancy improves the detection of raised BP during higher risk pregnancies (BUMP 1) and whether self-monitoring reduces systolic BP during hypertensive pregnancy (BUMP 2). METHODS AND ANALYSES: Both are multicentre, non-masked, parallel group, randomised controlled trials. Participants will be randomised to self-monitoring with telemonitoring or usual care. BUMP 1 will recruit a minimum of 2262 pregnant women at higher risk of pregnancy hypertension and BUMP 2 will recruit a minimum of 512 pregnant women with either gestational or chronic hypertension. The BUMP 1 primary outcome is the time to the first recording of raised BP by a healthcare professional. The BUMP 2 primary outcome is mean systolic BP between baseline and delivery recorded by healthcare professionals. Other outcomes will include maternal and perinatal outcomes, quality of life and adverse events. An economic evaluation of BP self-monitoring in addition to usual care compared with usual care alone will be assessed across both study populations within trial and with modelling to estimate long-term cost-effectiveness. A linked process evaluation will combine quantitative and qualitative data to examine how BP self-monitoring in pregnancy is implemented and accepted in both daily life and routine clinical practice. ETHICS AND DISSEMINATION: The trials have been approved by a Research Ethics Committee (17/WM/0241) and relevant research authorities. They will be published in peer-reviewed journals and presented at national and international conferences. If shown to be effective, BP self-monitoring would be applicable to a large population of pregnant women. TRIAL REGISTRATION NUMBER: NCT03334149

OPtimising Treatment for MIld Systolic hypertension in the Elderly (OPTiMISE): protocol for a randomised controlled non-inferiority trial

Introduction: Recent evidence suggests that larger blood pressure reductions and multiple antihypertensive drugs may be harmful in older people, particularly frail individuals with polypharmacy and multi-morbidity. However, there is a lack of evidence to support de-prescribing of antihypertensives, which limits the practice of medication reduction in routine clinical care. The aim of this trial is to examine whether antihypertensive medication reduction is possible in older patients without significant changes in blood pressure control at follow-up. Methods and analysis: This trial will use a Primary Care based, open label, randomised controlled trial design. A total of 540 participants will be recruited, aged ≥80 years, with systolic blood pressure <150 mmHg and receiving ≥2 antihypertensive medications. Participants will have no compelling indication for medication continuation and will be considered to potentially benefit from medication reduction due to existing polypharmacy, co-morbidity and frailty. Following a baseline appointment, individuals will be randomised to a strategy of medication reduction (intervention) with optional self-monitoring or usual care (control). Those in the intervention group will have one antihypertensive medication stopped. The primary outcome will be to determine if a reduction in medication can achieve a proportion of participants with clinically safe blood pressure levels at 12 week follow-up (defined as a systolic blood pressure <150mmHg) which is non-inferior (within 10%) to that achieved by the usual care group. Qualitative interviews will be used to understand the barriers and facilitators to medication reduction. The study will use economic modelling to predict the long term effects of any observed changes in blood pressure and quality-of-life. Ethics and dissemination: The protocol and written information has been approved by a Research Ethics Committee, medicines regulatory authority (MHRA), and national and local health research authorities. All research outputs will be published in peer-reviewed journals and presented at national and international conferences

A certified plasmid reference material for the standardisation of BCR-ABL1 mRNA quantification by real-time quantitative PCR

Serial quantification of BCR–ABL1 mRNA is an important therapeutic indicator in chronic myeloid leukaemia, but there is a substantial variation in results reported by diff

Efficacy of self-monitored blood pressure, with or without telemonitoring, for titration of antihypertensive medication (TASMINH4): an unmasked randomised controlled trial.

BACKGROUND: Studies evaluating titration of antihypertensive medication using self-monitoring give contradictory findings and the precise place of telemonitoring over self-monitoring alone is unclear. The TASMINH4 trial aimed to assess the efficacy of self-monitored blood pressure, with or without telemonitoring, for antihypertensive titration in primary care, compared with usual care. METHODS: This study was a parallel randomised controlled trial done in 142 general practices in the UK, and included hypertensive patients older than 35 years, with blood pressure higher than 140/90 mm Hg, who were willing to self-monitor their blood pressure. Patients were randomly assigned (1:1:1) to self-monitoring blood pressure (self-montoring group), to self-monitoring blood pressure with telemonitoring (telemonitoring group), or to usual care (clinic blood pressure; usual care group). Randomisation was by a secure web-based system. Neither participants nor investigators were masked to group assignment. The primary outcome was clinic measured systolic blood pressure at 12 months from randomisation. Primary analysis was of available cases. The trial is registered with ISRCTN, number ISRCTN 83571366. FINDINGS: 1182 participants were randomly assigned to the self-monitoring group (n=395), the telemonitoring group (n=393), or the usual care group (n=394), of whom 1003 (85%) were included in the primary analysis. After 12 months, systolic blood pressure was lower in both intervention groups compared with usual care (self-monitoring, 137·0 [SD 16·7] mm Hg and telemonitoring, 136·0 [16·1] mm Hg vs usual care, 140·4 [16·5]; adjusted mean differences vs usual care: self-monitoring alone, -3·5 mm Hg [95% CI -5·8 to -1·2]; telemonitoring, -4·7 mm Hg [-7·0 to -2·4]). No difference between the self-monitoring and telemonitoring groups was recorded (adjusted mean difference -1·2 mm Hg [95% CI -3·5 to 1·2]). Results were similar in sensitivity analyses including multiple imputation. Adverse events were similar between all three groups. INTERPRETATION: Self-monitoring, with or without telemonitoring, when used by general practitioners to titrate antihypertensive medication in individuals with poorly controlled blood pressure, leads to significantly lower blood pressure than titration guided by clinic readings. With most general practitioners and many patients using self-monitoring, it could become the cornerstone of hypertension management in primary care. FUNDING: National Institute for Health Research via Programme Grant for Applied Health Research (RP-PG-1209-10051), Professorship to RJM (NIHR-RP-R2-12-015), Oxford Collaboration for Leadership in Applied Health Research and Care, and Omron Healthcare UK