Repressive Gene Regulation Synchronizes Development with Cellular Metabolism.

Metabolic conditions affect the developmental tempo of animals. Developmental gene regulatory networks (GRNs) must therefore synchronize their dynamics with a variable timescale. We find that layered repression of genes couples GRN output with variable metabolism. When repressors of transcription or mRNA and protein stability are lost, fewer errors in Drosophila development occur when metabolism is lowered. We demonstrate the universality of this phenomenon by eliminating the entire microRNA family of repressors and find that development to maturity can be largely rescued when metabolism is reduced. Using a mathematical model that replicates GRN dynamics, we find that lowering metabolism suppresses the emergence of developmental errors by curtailing the influence of auxiliary repressors on GRN output. We experimentally show that gene expression dynamics are less affected by loss of repressors when metabolism is reduced. Thus, layered repression provides robustness through error suppression and may provide an evolutionary route to a shorter reproductive cycle.

Novice nurses' readiness to practice in an ICU: A qualitative study.

BACKGROUND: Novice nurses (newly qualified within the first 3-year period of professional practice after registration) must first face the reality and complexity of caring for high-acuity patients in the critical care setting, which can be an unfamiliar and demanding environment. The successful transition from education to professional practice of novice nurses hired for intensive care must be supported. AIM: To explore Polish novice nurses' readiness to practice in an intensive care unit (ICU). Our study objectives included investigating pre-registration preparation for work in an ICU, identifying the most needed competencies to work in an ICU, and analysing organizational aspects of the professional orientation period. STUDY DESIGN: A qualitative phenomenology design was applied. METHODS: We conducted qualitative content analysis based on individual semi-structured in-depth interviews. Study recruitment was performed using a purposeful and network sampling strategy. The final number of participants was 17 Polish novice nurses. RESULTS: The majority of responders replied that they were not prepared to work in an ICU after graduation. Professional orientation was planned-generally for a period of 3 months; however, in most places it was shortened. The respondents identified the five competencies most needed to work in an ICU: communication, teamwork, professional self-confidence, and knowledge and its practical use. Their enhancement could be achieved through simulations during both pre-registration and professional training. CONCLUSION: Analysis of the novice nurses' orientation period revealed many difficulties that indicated a lack of readiness to practice in an ICU after graduation. Identifying novice nurses' strengths and weaknesses regarding clinical competence is important to guide the design of orientation programmes in ICU settings and nursing education programmes. RELEVANCE TO CLINICAL PRACTICE: Readiness for ICU work may be improved by enriching education with simulations that enable training in the practical use of knowledge and critical care procedures. A supportive work environment is crucial during professional orientation.

Evidence in support of hyperkalaemia management strategies: A systematic literature review.

BACKGROUND: Hyperkalaemia is a potentially life-threatening condition that can be managed with pharmacological and non-pharmacological approaches. With the recent development of new hyperkalaemia treatments, new information on safe and effective management of hyperkalaemia has emerged. OBJECTIVES: This systematic literature review (SLR) aimed to identify all relevant comparative and non-comparative clinical data on management of hyperkalaemia in adults. Our secondary aim was to assess the feasibility of quantitatively comparing randomised controlled trial (RCT) data on the novel treatment sodium zirconium cyclosilicate (ZS) and established pharmacological treatments for the non-emergency management of hyperkalaemia, such as the cation-exchangers sodium/calcium polystyrene sulphonate (SPS/CPS). METHODS: MEDLINE, Embase and the Cochrane Library were searched on 3rd April 2017, with additional hand-searches of key congresses and previous SLRs. Articles were screened by two independent reviewers. Eligible records reported interventional or observational studies of pharmacological or non-pharmacological management of hyperkalaemia in adults. RESULTS: Database searches identified 2,073 unique records. Two hundred and one publications were included, reporting 30 RCTs, 29 interventional non-RCTs and 43 observational studies. Interventions investigated in RCTs included ZS (3), SPS/CPS (3), patiromer (4) and combinations of temporising agents (6 RCTs). A robust and meaningful indirect treatment comparison between ZS and long-established cation-binding agents (SPS/CPS) was infeasible because of heterogeneity between studies (including time points and dosing) and small sample size in SPS/CPS studies. CONCLUSIONS: Despite hyperkalaemia being associated with several chronic diseases, there is a paucity of high-quality randomised evidence on long-established treatment options (SPS and CPS) and a limited evidence base for hyperkalaemia management with these agents.

Victoria Cowling.

Victoria Cowling received her BA from the University of Cambridge. She completed her PhD with Julian Downward and Gerard Evan at Cancer Research UK in London, and then moved to the US for a postdoctoral position at Princeton University and Dartmouth College with Michael Cole. Since 2008, she has been running a lab at Dundee University. She is an MRC Senior Research Fellow, a Lister Institute Research Fellow and an EMBO Young Investigator and, in 2015, she was the first recipient of the Women in Cell Biology medal, awarded by the British Society for Cell Biology.

Paul Conduit.

Paul Conduit was a research assistant in John Kilmartin's lab at the MRC/LMB in Cambridge, UK, before beginning his PhD in 2006 with Jordan Raff. In 2010 he moved with Jordan from the Gurdon Institute in Cambridge to the University of Oxford, where he continued his work as a postdoctoral fellow. Paul is now a Sir Henry Dale Wellcome Fellow at the University of Cambridge and has been a group leader at the Department of Zoology since April 2015. His lab studies microtubule nucleation from both centrosomes and from other microtubule-organising centres in the cell.

Targeted screening in the UK: A narrow concept with broad application.

A recent report on screening in the UK proposed that the responsibility for recommendations on population and targeted screening programmes should be held by one new integrated advisory body. There is no wide international consensus on the definition of targeted screening. Our review identified and compared the defining components of screening terms: targeted, population, selective, and cascade screening, and case finding. Definitions of targeted screening and population screening were clearly demarcated by the eligible population; targeted and selective screening were found to be conceptually interchangeable; cascade screening, whilst conceptually similar to targeted screening across several components, was only used within the context of genetic diseases. There was little consensus between different definitions of case finding. These comparisons contributed to an updated definition of targeted screening. Considerable overlap between definition components across terms implies that a broad range of disease areas may fall into the remit of the new advisory body.

Prevalence of Epidermal Growth Factor Receptor Exon 20 Insertion Mutations in Non-small-Cell Lung Cancer in Europe: A Pragmatic Literature Review and Meta-analysis.

BACKGROUND: Information on the epidemiology of uncommon EGFR mutations including exon 20 insertions amongst non-small-cell lung cancer (NSCLC) is lacking. OBJECTIVE: The objective of this pragmatic literature review (PLR) and meta-analysis was to generate robust prevalence and incidence estimates based on ranges of exon 20 insertion mutations reported in the literature. MATERIALS AND METHODS: Searches of MEDLINE, Embase, congresses and reference lists for articles published from 2013 in key European countries of interest (Belgium, France, Germany, Italy, The Netherlands, Spain, Sweden, Switzerland, United Kingdom) were performed. Articles were reviewed against pre-specified criteria and their quality was appraised using a published checklist. Prevalence estimates were synthesised by random-effects meta-analyses. RESULTS: Eighty unique studies of moderate-to-high quality were included in the PLR. The meta-analysed prevalence for EGFR mutations was 12.5% (95% confidence interval [CI]: 11.0, 14.1) in any stage NSCLC and 14.8% (12.8, 17.1) in advanced/metastatic NSCLC. The prevalence of exon 20 insertions was 0.7% (0.4, 1.1) in any stage NSCLC and 6.1% (4.0, 9.4) in any stage EGFR-positive NSCLC. Mutation status was primarily measured using direct sequencing or a combination of methods. One study reporting exon 20 insertions in advanced/metastatic disease was identified, which reported a prevalence of 0.5% in overall NSCLC and 4.0% in EGFR-positive NSCLC. CONCLUSIONS: EGFR exon 20 insertion mutations are rare in NSCLC. There is a high unmet need in patients with exon 20 insertions, including effective therapies. Prospective cohort studies are needed to better clinically characterise these patients.

Correction: SIRT2 Ablation Has No Effect on Tubulin Acetylation in Brain, Cholesterol Biosynthesis or the Progression of Huntington's Disease Phenotypes In Vivo.

[This corrects the article DOI: 10.1371/journal.pone.0034805.].

Burden of Chronic Kidney Disease by KDIGO Categories of Glomerular Filtration Rate and Albuminuria: A Systematic Review.

INTRODUCTION: The Kidney Disease: Improving Global Outcomes (KDIGO) 2012 guidelines recommend classifying patients by glomerular filtration rate (GFR) and albuminuria to predict chronic kidney disease (CKD) prognosis. The aim of this systematic review was to explore the epidemiological burden of CKD stratified by the KDIGO 2012 categories. METHODS: MEDLINE® and Embase were searched for observational studies of patients with CKD with results stratified according to the KDIGO 2012 classification. Investigated outcomes were prevalence, incidence, and risk factors and complications of CKD, including mortality. RESULTS: The review included ten observational studies with 3033 to 46,949 participants, conducted in the USA, China, France, Italy and Spain. The most frequently reported outcome was the prevalence of CKD (GFR categories G3-5), ranging from 2% to 17%. Most participants were normoalbuminuric, with 0.4-3.2% macroalbuminuric, and most fell within the KDIGO 2012 low-risk or moderate-risk groups, with 0.9-5.6% in the high-risk and 0.3-4.8% in the very high-risk groups. Although scarce, data on the prevalence of comorbidities in CKD according to the KDIGO classification suggest that they increase with albuminuria severity. CONCLUSIONS: Patients with CKD frequently have complications, but only a small proportion have severely increased albuminuria or fall within the KDIGO high-risk or very high-risk groups. These groups, however, are associated with the highest burden of disease, as comorbidities are more prevalent with increasing albuminuria severity. New studies framed by the KDIGO 2012 classification are needed to address key gaps in the understanding of CKD burden and outcomes.

Assessment of Problem-Solving Skills and Inhibitory Control in Mice Using Water Escape Detour Test.

Despite the importance of emotional intelligence, its biological mechanism is still not well understood. For this reason, we have developed a rodent detour task which requires an animal to reach a highly desired object placed directly behind a transparent barrier that blocks the direct route to the target. This apparently simple task is highly dependent on the emotional control that is necessary to inhibit prepotent and counterproductive responses driven by the sight of a desired object. The water escape detour task designed for mice enables testing the ability to solve emotionally challenging problems, as well as identification of an impairment termed perseveration. Such a maladaptive reaction to a challenging situation is characterized by difficulty in terminating an unsuccessful response, leading to persistent repetition of inappropriate behavior. This issue is important because perseveration is associated with schizophrenia, drug abuse, and aging. © 2020 Wiley Periodicals LLC. Basic Protocol: Water escape detour task Support Protocol 1: Preparation of escape platform Support Protocol 2: Preparation of the transparent barrier Alternate Protocol: Water escape detour task for testing acute effects.

Velamentous cord insertion: results from a rapid review of incidence, risk factors, adverse outcomes and screening.

BACKGROUND: Velamentous cord insertion (VCI) is an umbilical cord attachment to the membranes surrounding the placenta instead of the central mass. VCI is strongly associated with vasa praevia (VP), where umbilical vessels lie in close proximity to the internal cervical os. VP leaves the vessels vulnerable to rupture, which can lead to fatal fetal exsanguination. Screening for VP using second-trimester transabdominal sonography (TAS) to detect VCI has been proposed. We conducted a rapid review investigating the quality, quantity and direction of evidence available on the epidemiology, screening test accuracy and post-screening management pathways for VCI. METHODS: MEDLINE, Embase and the Cochrane Library were searched on 5 July 2016 and again on 11 October 2019, using general search terms for VP and VCI. Only peer-reviewed articles reporting on the epidemiology of VCI, the accuracy of the screening test and/or downstream management pathways for VCI pregnancies were included. Quality and risk of bias of each included study were assessed using pre-specified tools. RESULTS: Forty-one relevant publications were identified; all but one were based on non-UK pregnancy cohorts, and most included relatively few VCI cases. The estimated incidence of VCI was 0.4-11% in singleton pregnancies, with higher incidence in twin pregnancies (1.6-40%). VCI incidence was also increased among pregnancies with one or more other risk factors, including in vitro fertilisation pregnancies or nulliparity. VCI incidence among women without any known risk factors was unclear. VCI was associated with adverse perinatal outcomes, most notably pre-term birth and emergency caesarean section in singleton pregnancies, and perinatal mortality in twins; however, associations varied across studies and the increased risk was typically low or moderate compared with pregnancies without VCI. In studies on limited numbers of cases, screening for VCI using TAS had good overall accuracy, driven by high specificity. No studies on post-screening management of VCI were identified. CONCLUSIONS: Literature on VCI epidemiology and outcomes is limited and low-quality. The accuracy of second-trimester TAS and the benefits and harms of screening cannot be determined without prospective studies in large cohorts. Modelling studies may indicate the feasibility and value of studying the epidemiology of VCI and the potential impact of detecting VCI as part of a population screening programme for VP.

Case report: a rapid review approach used by the UK National Screening Committee to inform recommendations on general population screening for vasa praevia.

BACKGROUND: The UK National Screening Committee (UK NSC) reviews evidence about existing or potential population screening programmes using rapid review products called evidence summaries. We provide a case report as an example of how rapid reviews are developed within the UK NSC's process, consider how the quality of rapid reviews should be assessed and ask whether the rapid review was an appropriate tool to inform the UK NSC's decision-making process. METHODS: We present the rapid review approach taken by the commissioner and the reviewers to develop an evidence summary for vasa praevia (VP), which the UK NSC reappraised as part of its 3-yearly cycle for conditions where screening is currently not recommended. We apply the AMSTAR 2 quality appraisal checklist for systematic reviews, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist and a published checklist of items to consider with a rapid review approach. As UK NSC evidence summaries do not include meta-analyses, any related AMSTAR 2 or PRISMA checklist items were considered inapplicable. RESULTS: The evidence summary was available within the required timelines and highlighted little change from the previous review in terms of key evidence gaps relating to the epidemiology of VP, the screening test and the management pathway. Therefore, the UK NSC concluded that there was insufficient evidence to support a change in its previous recommendation against screening. The evidence summary scored moderately against the applicable AMSTAR 2 and PRISMA checklist items. Against the published checklist of items to consider with a rapid review approach, the evidence summary performed well. CONCLUSIONS: In this case report, the use of a rapid review as part of the UK NSC's process enabled a pragmatic approach to assessing the overall volume, quality and direction of literature on key questions relating to the viability of a population screening programme for VP. Based on our assessments of this single evidence summary, systematic review quality appraisal tools may undervalue rapid reviews. The validity of the methods used in this case report, as well as the wider generalisability of our insights relating to rapid review practice, reporting and quality assessment, requires analysis of a larger sample of rapid reviews.

SIRT2 ablation has no effect on tubulin acetylation in brain, cholesterol biosynthesis or the progression of Huntington's disease phenotypes in vivo.

Huntington's disease (HD) is a devastating neurodegenerative disorder for which there are no disease-modifying treatments. The molecular pathogenesis of HD is complex and many mechanisms and cellular processes have been proposed as potential sites of therapeutic intervention. However, prior to embarking on drug development initiatives, it is essential that therapeutic targets can be validated in mammalian models of HD. Previous studies in invertebrate and cell culture HD models have suggested that inhibition of SIRT2 could have beneficial consequences on disease progression. SIRT2 is a NAD(+)-dependent deacetylase that has been proposed to deacetylate α-tubulin, histone H4 K16 and to regulate cholesterol biogenesis - a pathway which is dysregulated in HD patients and HD mouse models. We have utilized mice in which SIRT2 has been reduced or ablated to further explore the function of SIRT2 and to assess whether SIRT2 loss has a beneficial impact on disease progression in the R6/2 mouse model of HD. Surprisingly we found that reduction or loss of SIRT2 had no effect on the acetylation of α-tubulin or H4K16 or on cholesterol biosynthesis in the brains of wild type mice. Equally, genetic reduction or ablation of SIRT2 had no effect on HD progression as assessed by a battery of physiological and behavioural tests. Furthermore, we observed no change in aggregate load or levels of soluble mutant huntingtin transprotein. Intriguingly, neither the constitutive genetic loss nor acute pharmacological inhibition of SIRT2 affected the expression of cholesterol biosynthesis enzymes in the context of HD. Therefore, we conclude that SIRT2 inhibition does not modify disease progression in the R6/2 mouse model of HD and SIRT2 inhibition should not be prioritised as a therapeutic option for HD.

Hdac6 knock-out increases tubulin acetylation but does not modify disease progression in the R6/2 mouse model of Huntington's disease.

Huntington's disease (HD) is a progressive neurodegenerative disorder for which there is no effective disease modifying treatment. Following-on from studies in HD animal models, histone deacetylase (HDAC) inhibition has emerged as an attractive therapeutic option. In parallel, several reports have demonstrated a role for histone deacetylase 6 (HDAC6) in the modulation of the toxicity caused by the accumulation of misfolded proteins, including that of expanded polyglutamine in an N-terminal huntingtin fragment. An important role for HDAC6 in kinesin-1 dependent transport of brain-derived neurotrophic factor (BDNF) from the cortex to the striatum has also been demonstrated. To elucidate the role that HDAC6 plays in HD progression, we evaluated the effects of the genetic depletion of HDAC6 in the R6/2 mouse model of HD. Loss of HDAC6 resulted in a marked increase in tubulin acetylation throughout the brain. Despite this, there was no effect on the onset and progression of a wide range of behavioural, physiological, molecular and pathological HD-related phenotypes. We observed no change in the aggregate load or in the levels of soluble mutant exon 1 transprotein. HDAC6 genetic depletion did not affect the efficiency of BDNF transport from the cortex to the striatum. Therefore, we conclude that HDAC6 inhibition does not modify disease progression in R6/2 mice and HDAC6 should not be prioritized as a therapeutic target for HD.