Identification of MYCN non-amplified neuroblastoma subgroups points towards molecular signatures for precision prognosis and therapy stratification.

BACKGROUND: Despite the extensive study of MYCN-amplified neuroblastomas, there is a significant unmet clinical need in MYCN non-amplified cases. In particular, the extent of heterogeneity within the MYCN non-amplified population is unknown. METHODS: A total of 1566 samples from 16 datasets were identified in Gene Expression Omnibus (GEO) and ArrayExpress. Characterisation of the subtypes was analysed by ConsensusClusterPlus. Independent predictors for subgrouping were constructed from the single sample predictor based on the multiclassPairs package. Findings were verified using immunohistochemistry and CIBERSORTx analysis. RESULTS: We demonstrate that MYCN non-amplified neuroblastomas are heterogeneous and can be classified into 3 subgroups based on their transcriptional signatures. Within these groups, subgroup_2 has the worst prognosis and this group shows a 'MYCN' signature that is potentially induced by the overexpression of Aurora Kinase A (AURKA); whilst subgroup_3 is characterised by an 'inflamed' gene signature. The clinical implications of this subtype classification are significant, as each subtype demonstrates a unique prognosis and vulnerability to investigational therapies. A total of 420 genes were identified as independent subgroup predictors with average balanced accuracy of 0.93 and 0.84 for train and test datasets, respectively. CONCLUSION: We propose that transcriptional subtyping may enhance precision prognosis and therapy stratification for patients with MYCN non-amplified neuroblastomas.

Safety and Efficacy of Ethanol for Catheter Salvage and Central Line-Associated Bloodstream Infection Prophylaxis in Polyurethane Catheters in the PICU.

OBJECTIVES: Ethanol lock therapy (ELT) is a potential method of central catheter salvage following central line-associated bloodstream infection (CLABSI) although there is potential risk of catheter damage in polyurethane catheters. Further, there is limited efficacy data across the spectrum of common pediatric catheters, and published ELT protocols describe dwell times that are not feasible for critically ill children. We sought to evaluate the safety and efficacy of ELT in polyurethane catheters using brief (30 min to 2 hr) dwell times in our PICU. DESIGN: Investigational pilot study using historical control data. SETTING: PICU in quaternary care, free-standing children's hospital. INTERVENTIONS: ELT in polyurethane central venous catheters for catheter salvage. RESULTS: ELT with brief dwell times was used in 25 patients, 22 of whom were bacteremic. Ultimately 11 patients, comprising 14 catheters, were diagnosed with a primary CLABSI. The catheter salvage rate in primary CLABSI patients receiving ELT was 92% (13/14) and significantly higher than the salvage rate in patients receiving antibiotics alone (non-ELT) (62%, 39/64; mean difference 0.32, 95% CI [0.14-0.50], p = 0.03). The rate of catheter fracture in all patients receiving ELT was 8% (2/25) while the rate of fracture in the non-ELT group was 13% (8/64; mean difference -0.05, 95% CI [-0.18 to 0.09], p = 0.72). The rate of tissue plasminogen activator (tPA) use in the ELT group was 8% (2/25), whereas the rate of tPA use in the non-ELT group was significantly higher at 42% (26/64; mean difference -0.34, 95% CI [-0.49 to -0.17], p = 0.002). CONCLUSIONS: The use of ELT for catheter salvage and prophylaxis in the PICU is safe in a variety of polyurethane catheters. Dwell times ranging from 30 minutes to 2 hours were effective in sterilizing the catheters while allowing other therapies to continue. This approach may decrease the need for frequent line changes in a medically fragile pediatric population.

A Survey of PICU Clinician Practices and Perceptions regarding Respiratory Cultures in the Evaluation of Ventilator-Associated Infections in the BrighT STAR Collaborative.

OBJECTIVES: To characterize respiratory culture practices for mechanically ventilated patients, and to identify drivers of culture use and potential barriers to changing practices across PICUs. DESIGN: Cross-sectional survey conducted May 2021-January 2022. SETTING: Sixteen academic pediatric hospitals across the United States participating in the BrighT STAR Collaborative. SUBJECTS: Pediatric critical care medicine physicians, advanced practice providers, respiratory therapists, and nurses. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We summarized the proportion of positive responses for each question within a hospital and calculated the median proportion and IQR across hospitals. We correlated responses with culture rates and compared responses by role. Sixteen invited institutions participated (100%). Five hundred sixty-eight of 1,301 (44%) e-mailed individuals completed the survey (median hospital response rate 60%). Saline lavage was common, but no PICUs had a standardized approach. There was the highest variability in perceived likelihood (median, IQR) to obtain cultures for isolated fever (49%, 38-61%), isolated laboratory changes (49%, 38-57%), fever and laboratory changes without respiratory symptoms (68%, 54-79%), isolated change in secretion characteristics (67%, 54-78%), and isolated increased secretions (55%, 40-65%). Respiratory cultures were likely to be obtained as a "pan culture" (75%, 70-86%). There was a significant correlation between higher culture rates and likelihood to obtain cultures for isolated fever, persistent fever, isolated hypotension, fever, and laboratory changes without respiratory symptoms, and "pan cultures." Respondents across hospitals would find clinical decision support (CDS) helpful (79%) and thought that CDS would help align ICU and/or consulting teams (82%). Anticipated barriers to change included reluctance to change (70%), opinion of consultants (64%), and concern for missing a diagnosis of ventilator-associated infections (62%). CONCLUSIONS: Respiratory culture collection and ordering practices were inconsistent, revealing opportunities for diagnostic stewardship. CDS would be generally well received; however, anticipated conceptual and psychologic barriers to change must be considered.

Ultrasound in Cardiopulmonary Arrest and Resuscitation: Constructing Comprehensive Implementation Frameworks in High-Risk Settings.

OBJECTIVES: Information obtained from point-of-care ultrasound during cardiopulmonary arrest and resuscitation (POCUS-CA) can be used to identify underlying pathophysiology and provide life-sustaining interventions. However, integration of POCUS-CA into resuscitation care is inconsistent. We used expert consensus building methodology to help identify discrete barriers to clinical integration. We subsequently applied implementation science frameworks to generate generalizable strategies to overcome these barriers. MEASURES AND MAIN RESULTS: Two multidisciplinary expert working groups used KJ Reverse-Merlin consensus building method to identify and characterize barriers contributing to failed POCUS-CA utilization in a hypothetical future state. Identified barriers were organized into affinity groups. The Center for Implementation Research (CFIR) framework and Expert Recommendations for Implementing Change (CFIR-ERIC) tool were used to identify strategies to guide POCUS-US implementation. RESULTS: Sixteen multidisciplinary resuscitation content experts participated in the working groups and identified individual barriers, consolidated into 19 unique affinity groups that mapped 12 separate CFIR constructs, representing all 5 CFIR domains. The CFIR-ERIC tool identified the following strategies as most impactful to address barriers described in the affinity groups: identify and prepare champions, conduct local needs assessment, conduct local consensus discussions, and conduct educational meetings. CONCLUSIONS: KJ Reverse-Merlin consensus building identified multiple barriers to implementing POCUS-CA. Implementation science methodologies identified and prioritized strategies to overcome barriers and guide POCUS-CA implementation across diverse clinical settings.

Readmission after discharge from a medium secure service between 1999 and 2017: A retrospective cohort study.

BACKGROUND: Previous research into outcomes after treatment in medium secure psychiatric hospitals has mostly relied on pre-millennium data. AIMS: To examine patient and inpatient service-related factors associated with readmission within 2 years following discharge to the community or open conditions from conditions of medium security. METHODS: A retrospective cohort study of 137 patients discharged either to the community or to open conditions from one 64-bed South Wales Regional Medium Secure Hospital Unit between July 1999 and November 2017 was completed using data from healthcare records to document demographics, diagnosis and nature of index offences together with researcher-completed ratings of inpatient progress using the Dangerousness Understanding Recovery and Urgency Manual (DUNDRUM) Programme Completion and DUNDRUM Recovery scales. Binary logistic regression analyses were used to identify independent associations between inpatient progress according to these measures and readmission. RESULTS: Forty-three patients (31%) were readmitted within 2 years of discharge and 23 (17%) in breach of legal conditions on discharge. Most readmitted patients (n = 29, 67%) returned directly to medium secure care. There were significant binary level associations between readmission and severity of the index offences (lower), number of adverse childhood experiences (higher), history of drug misuse (more likely) and number of previous psychiatric admissions (higher). Binary logistic regression confirmed that these relationships were not independent. No inpatient service-related variables, according to DUNDRUM scale scores, showed an independent association with readmission within 2 years post-discharge. CONCLUSIONS: The proportion of medium security hospital patients who were readmitted within 2 years of discharge aligns with estimates found in earlier national research using the same follow-up period. Since levels of inpatient progress bore little if any relationship to longer term outcomes, our findings highlight the need for investigating factors in the discharge environment that are linked to readmission. It is possible that readmission may indicate effective monitoring and responsive care to the changing needs of patients, but a better understanding of this is essential.

Implementation Science Research in Pediatric Critical Care Medicine.

OBJECTIVES: Delay or failure to consistently adopt evidence-based or consensus-based best practices into routine clinical care is common, including for patients in the PICU. PICU patients can fail to receive potentially beneficial diagnostic or therapeutic interventions, worsening the burden of illness and injury during critical illness. Implementation science (IS) has emerged to systematically address this problem, but its use of in the PICU has been limited to date. We therefore present a conceptual and methodologic overview of IS for the pediatric intensivist. DESIGN: The members of Excellence in Pediatric Implementation Science (ECLIPSE; part of the Pediatric Acute Lung Injury and Sepsis Investigators Network) represent multi-institutional expertise in the use of IS in the PICU. This narrative review reflects the collective knowledge and perspective of the ECLIPSE group about why IS can benefit PICU patients, how to distinguish IS from quality improvement (QI), and how to evaluate an IS article. RESULTS: IS requires a shift in one's thinking, away from questions and outcomes that define traditional clinical or translational research, including QI. Instead, in the IS rather than the QI literature, the terminology, definitions, and language differs by specifically focusing on relative importance of generalizable knowledge, as well as aspects of study design, scale, and timeframe over which the investigations occur. CONCLUSIONS: Research in pediatric critical care practice must acknowledge the limitations and potential for patient harm that may result from a failure to implement evidence-based or professionals' consensus-based practices. IS represents an innovative, pragmatic, and increasingly popular approach that our field must readily embrace in order to improve our ability to care for critically ill children.

Retrospective Assessment of Patient and Catheter Characteristics Associated With Malpositioned Central Venous Catheters in Pediatric Patients.

OBJECTIVES: The primary objective was to determine the prevalence and characteristics associated with malpositioned temporary, nontunneled central venous catheters (CVCs) placed via the internal jugular (IJ) and subclavian (SC) veins in pediatric patients. DESIGN: Single-center retrospective cohort study. SETTING: Quaternary academic PICU. PATIENTS: Children greater than 1 month to less than 18 years who had a CVC placed between January 2014 and December 2018. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the CVC tip position located on the first postprocedural radiograph. CVC tip was defined as follows: "recommended" (tip location between the carina and two vertebral bodies inferior to the carina), "high" (tip location between one and four vertebral bodies superior to the carina), "low" (tip position three or more vertebral bodies inferior to the carina), and "other" (tip grossly malpositioned). Seven hundred eighty-one CVCs were included: 481 (61.6%) were in "recommended" position, 157 (20.1%) were "high," 131 (16.8%) were "low," and 12 (1.5%) were "other." Multiple multinomial regression (referenced to "recommended" position) showed that left-sided catheters (adjusted odds ratio [aOR], 2.00, 95% CI 1.17-3.40) were associated with "high" CVC tip positions, whereas weight greater than or equal to 40 kg had decreased odds of having a "high" CVC tip compared with the reference (aOR, 0.45; 95% CI, 0.24-0.83). Further, weight category 20-40 kg (aOR, 2.42; 95% CI, 1.38-4.23) and females (aOR, 1.51; 95% CI, 1.01-2.26) were associated with "low" CVC tip positions. There was no difference in rates of central line-associated blood stream infection, venous thromboembolism, or tissue plasminogen activator usage or dose between the CVCs with tips outside and those within the recommended location. CONCLUSIONS: The prevalence of IJ and SC CVC tips outside of the recommended location was high. Left-sided catheters, patient weight, and sex were associated with malposition. Malpositioned catheters were not associated with increased harm.

Differentially Expressed Genes and Signaling Pathways Potentially Involved in Primary Resistance to Chemo-Immunotherapy in Advanced-Stage Gastric Cancer Patients.

Recently, the combination of chemotherapy plus nivolumab (chemo-immunotherapy) has become the standard of care for advanced-stage gastric cancer (GC) patients. However, despite its efficacy, up to 40% of patients do not respond to these treatments. Our study sought to identify variations in gene expression associated with primary resistance to chemo-immunotherapy. Diagnostic endoscopic biopsies were retrospectively obtained from advanced GC patients previously categorized as responders (R) or non-responders (NR). Thirty-four tumor biopsies (R: n = 16, NR: n = 18) were analyzed by 3' massive analysis of cDNA ends (3'MACE). We found >30 differentially expressed genes between R and NRs. Subsequent pathway enrichment analyses demonstrated that angiogenesis and the Wnt-ß-catenin signaling pathway were enriched in NRs. Concomitantly, we performed next generation sequencing (NGS) analyses in a subset of four NR patients that confirmed alterations in genes that belonged to the Wnt/ß-catenin and the phosphoinositide 3-kinase (PI3K) pathways. We speculate that angiogenesis, the Wnt, and the PI3K pathways might offer actionable targets. We also discuss therapeutic alternatives for chemo-immunotherapy-resistant advanced-stage GC patients.

A case-control study of a combination of single nucleotide polymorphisms and clinical parameters to predict clinically relevant toxicity associated with fluoropyrimidine and platinum-based chemotherapy in gastric cancer.

BACKGROUND: Fluoropyrimidine plus platinum chemotherapy remains the standard first line treatment for gastric cancer (GC). Guidelines exist for the clinical interpretation of four DPYD genotypes related to severe fluoropyrimidine toxicity within European populations. However, the frequency of these single nucleotide polymorphisms (SNPs) in the Latin American population is low (< 0.7%). No guidelines have been development for platinum. Herein, we present association between clinical factors and common SNPs in the development of grade 3-4 toxicity. METHODS: Retrospectively, 224 clinical records of GC patient were screened, of which 93 patients were incorporated into the study. Eleven SNPs with minor allelic frequency above 5% in GSTP1, ERCC2, ERCC1, TP53, UMPS, SHMT1, MTHFR, ABCC2 and DPYD were assessed. Association between patient clinical characteristics and toxicity was estimated using logistic regression models and classification algorithms. RESULTS: Reported grade ≤ 2 and 3-4 toxicities were 64.6% (61/93) and 34.4% (32/93) respectively. Selected DPYD SNPs were associated with higher toxicity (rs1801265; OR = 4.20; 95% CI = 1.70-10.95, p = 0.002), while others displayed a trend towards lower toxicity (rs1801159; OR = 0.45; 95% CI = 0.19-1.08; p = 0.071). Combination of paired SNPs demonstrated significant associations in DPYD (rs1801265), UMPS (rs1801019), ABCC2 (rs717620) and SHMT1 (rs1979277). Using multivariate logistic regression that combined age, sex, peri-operative chemotherapy, 5-FU regimen, the binary combination of the SNPs DPYD (rs1801265) + ABCC2 (rs717620), and DPYD (rs1801159) displayed the best predictive performance. A nomogram was constructed to assess the risk of developing overall toxicity. CONCLUSION: Pending further validation, this model could predict chemotherapy associated toxicity and improve GC patient quality of life.

Consensus Recommendations for Blood Culture Use in Critically Ill Children Using a Modified Delphi Approach.

OBJECTIVES: Blood cultures are fundamental in evaluating for sepsis, but excessive cultures can lead to false-positive results and unnecessary antibiotics. Our objective was to create consensus recommendations focusing on when to safely avoid blood cultures in PICU patients. DESIGN: A panel of 29 multidisciplinary experts engaged in a two-part modified Delphi process. Round 1 consisted of a literature summary and an electronic survey sent to invited participants. In the survey, participants rated a series of recommendations about when to avoid blood cultures on five-point Likert scale. Consensus was achieved for the recommendation(s) if 75% of respondents chose a score of 4 or 5, and these were included in the final recommendations. Any recommendations that did not meet these a priori criteria for consensus were discussed during the in-person expert panel review (Round 2). Round 2 was facilitated by an independent expert in consensus methodology. After a review of the survey results, comments from round 1, and group discussion, the panelists voted on these recommendations in real-time. SETTING: Experts' institutions; in-person discussion in Baltimore, MD. SUBJECTS: Experts in pediatric critical care, infectious diseases, nephrology, oncology, and laboratory medicine. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the 27 original recommendations, 18 met criteria for achieving consensus in Round 1; some were modified for clarity or condensed from multiple into single recommendations during Round 2. The remaining nine recommendations were discussed and modified until consensus was achieved during Round 2, which had 26 real-time voting participants. The final document contains 19 recommendations. CONCLUSIONS: Using a modified Delphi process, we created consensus recommendations on when to avoid blood cultures and prevent overuse in the PICU. These recommendations are a critical step in disseminating diagnostic stewardship on a wider scale in critically ill children.

All-mail voting in Colorado increases turnout and reduces turnout inequality.

The COVID-19 crisis has generated interest in all-mail voting (AMV) as a potential policy solution for avoiding in-person elections. However, the quality of AMV implementation has varied greatly across states, leading to mixed results in previous research. We exploit the understudied 2014 implementation of AMV in Colorado to estimate the effect on turnout for all registered voters, along with age, racial, education, income and wealth, and occupational subgroups. Using large voter file data and a difference-in-differences design within individuals, we find a positive overall turnout effect of approximately 8 percentage points-translating into an additional 900,000 ballots being cast between 2014 and 2018. Effects are significantly larger among lower-propensity voting groups, such as young people, blue-collar workers, voters with less educational attainment, and voters of color. The results suggest that researchers and policymakers should look to Colorado's AMV approach as an effective model for boosting aggregate turnout and reducing voting disparities across subgroups.

Practices, Perceptions, and Attitudes in the Evaluation of Critically Ill Children for Bacteremia: A National Survey.

OBJECTIVES: Sending blood cultures in children at low risk of bacteremia can contribute to a cascade of unnecessary antibiotic exposure, adverse effects, and increased costs. We aimed to describe practice variation, clinician beliefs, and attitudes about blood culture testing in critically ill children. DESIGN: Cross-sectional electronic survey. SETTING: Fifteen PICUs enrolled in the Blood Culture Improvement Guidelines and Diagnostic Stewardship for Antibiotic Reduction in Critically Ill Children collaborative, an investigation of blood culture use in critically ill children in the United States. SUBJECTS: PICU clinicians (bedside nurses, resident physicians, fellow physicians, nurse practitioners, physician assistants, and attending physicians). INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Survey items explored typical blood culture practices, attitudes and beliefs about cultures, and potential barriers to changing culture use in a PICU setting. Fifteen of 15 sites participated, with 347 total responses, 15-45 responses per site, and an overall median response rate of 57%. We summarized median proportions and interquartile ranges of respondents who reported certain practices or beliefs: 86% (73-91%) report that cultures are ordered reflexively; 71% (61-77%) do not examine patients before ordering cultures; 90% (86-94%) obtain cultures for any new fever in PICU patients; 33% (19-61%) do not obtain peripheral cultures when an indwelling catheter is in place; and 64% (36-81%) sample multiple (vs single) lumens of central venous catheters for new fever. When asked about barriers to reducing unnecessary cultures, 80% (73-90%) noted fear of missing sepsis. Certain practices (culture source and indication) varied by clinician type. Obtaining surveillance cultures and routinely culturing all possible sources (each lumen of indwelling catheters and peripheral specimens) are positively correlated with baseline blood culture rates. CONCLUSIONS: There is variation in blood culture practices in the PICU. Fear and reflexive habits are common drivers of cultures. These practices may contribute to over-testing for bacteremia. Further investigation of how to optimize blood culture use is warranted.

How good is our diagnostic intuition? Clinician prediction of bacteremia in critically ill children.

BACKGROUND: Clinical intuition and nonanalytic reasoning play a major role in clinical hypothesis generation; however, clinicians' intuition about whether a critically ill child is bacteremic has not been explored. We endeavored to assess pediatric critical care clinicians' ability to predict bacteremia and to evaluate what affected the accuracy of those predictions. METHODS: We conducted a retrospective review of clinicians' responses to a sepsis screening tool ("Early Sepsis Detection Tool" or "ESDT") over 6 months. The ESDT was completed during the initial evaluation of a possible sepsis episode. If a culture was ordered, they were asked to predict if the culture would be positive or negative. Culture results were compared to predictions for each episode as well as vital signs and laboratory data from the preceding 24 h. RESULTS: From January to July 2017, 266 ESDTs were completed. Of the 135 blood culture episodes, 15% of cultures were positive. Clinicians correctly predicted patients with bacteremia in 82% of cases, but the positive predictive value was just 28% as there was a tendency to overestimate the presence of bacteremia. The negative predictive value was 96%. The presence of bandemia, thrombocytopenia, and abnormal CRP were associated with increased likelihood of correct positive prediction. CONCLUSIONS: Clinicians are accurate in predicting critically ill children whose blood cultures, obtained for symptoms of sepsis, will be negative. Clinicians frequently overestimate the presence of bacteremia. The combination of evidence-based practice guidelines and bedside judgment should be leveraged to optimize diagnosis of bacteremia.

Deconvolution of RNA-Seq Analysis of Hyperbaric Oxygen-Treated Mice Lungs Reveals Mesenchymal Cell Subtype Changes.

Hyperbaric oxygen (HBO) is widely applied to treat several hypoxia-related diseases. Previous studies have focused on the immediate effect of HBO-exposure induced oxidative stress on the lungs, but knowledge regarding the chronic effects from repetitive HBO exposure is limited, especially at the gene expression level. We found that repetitive HBO exposure did not alter the morphology of murine lungs. However, by deconvolution of RNA-seq from those mice lungs using CIBERSORTx and the expression profile matrices of 8 mesenchymal cell subtypes obtained from bleomycin-treated mouse lungs, we identify several mesenchymal cell subtype changes. These include increases in Col13a1 matrix fibroblasts, mesenchymal progenitors and mesothelial cell populations and decreases in lipofibroblasts, endothelial and Pdgfrb high cell populations. Our data suggest that repetitive HBO exposure may affect biological processes in the lungs such as response to wounding, extracellular matrix, vasculature development and immune response.

Development and Implementation of a Bedside Peripherally Inserted Central Catheter Service in a PICU.

OBJECTIVES: To create a bedside peripherally inserted central catheter service to increase placement of bedside peripherally inserted central catheter in PICU patients. DESIGN: Two-phase observational, pre-post design. SETTING: Single-center quaternary noncardiac PICU. PATIENTS: All patients admitted to the PICU. INTERVENTIONS: From June 1, 2015, to May 31, 2017, a bedside peripherally inserted central catheter service team was created (phase I) and expanded (phase II) as part of a quality improvement initiative. A multidisciplinary team developed a PICU peripherally inserted central catheter evaluation tool to identify amenable patients and to suggest location and provider for procedure performance. Outcome, process, and balancing metrics were evaluated. MEASUREMENTS AND MAIN RESULTS: Bedside peripherally inserted central catheter service placed 130 of 493 peripherally inserted central catheter (26%) resulting in 2,447 hospital central catheter days. A shift in bedside peripherally inserted central catheter centerline proportion occurred during both phases. Median time from order to catheter placement was reduced for peripherally inserted central catheters placed by bedside peripherally inserted central catheter service compared with placement in interventional radiology (6 hr [interquartile range, 2-23 hr] vs 34 hr [interquartile range, 19-61 hr]; p < 0.001). Successful access was achieved by bedside peripherally inserted central catheter service providers in 96% of patients with central tip position in 97%. Bedside peripherally inserted central catheter service central line-associated bloodstream infection and venous thromboembolism rates were similar to rates for peripherally inserted central catheters placed in interventional radiology (all central line-associated bloodstream infection, 1.23 vs 2.18; p = 0.37 and venous thromboembolism, 1.63 vs 1.57; p = 0.91). Peripherally inserted central catheters in PICU patients had reduced in-hospital venous thromboembolism rate compared with PICU temporary catheter in PICU rate (1.59 vs 5.36; p < 0.001). CONCLUSIONS: Bedside peripherally inserted central catheter service implementation increased bedside peripherally inserted central catheter placement and employed a patient-centered and timely process. Balancing metrics including central line-associated bloodstream infection and venous thromboembolism rates were not significantly different between peripherally inserted central catheters placed by bedside peripherally inserted central catheter service and those placed in interventional radiology.

Syndecan 4 interacts genetically with Vangl2 to regulate neural tube closure and planar cell polarity.

Syndecan 4 (Sdc4) is a cell-surface heparan sulfate proteoglycan (HSPG) that regulates gastrulation, neural tube closure and directed neural crest migration in Xenopus development. To determine whether Sdc4 participates in Wnt/PCP signaling during mouse development, we evaluated a possible interaction between a null mutation of Sdc4 and the loop-tail allele of Vangl2. Sdc4 is expressed in multiple tissues, but particularly in the non-neural ectoderm, hindgut and otic vesicles. Sdc4;Vangl2(Lp) compound mutant mice have defective spinal neural tube closure, disrupted orientation of the stereocilia bundles in the cochlea and delayed wound healing, demonstrating a strong genetic interaction. In Xenopus, co-injection of suboptimal amounts of Sdc4 and Vangl2 morpholinos resulted in a significantly greater proportion of embryos with defective neural tube closure than each individual morpholino alone. To probe the mechanism of this interaction, we overexpressed or knocked down Vangl2 function in HEK293 cells. The Sdc4 and Vangl2 proteins colocalize, and Vangl2, particularly the Vangl2(Lp) mutant form, diminishes Sdc4 protein levels. Conversely, Vangl2 knockdown enhances Sdc4 protein levels. Overall HSPG steady-state levels were regulated by Vangl2, suggesting a molecular mechanism for the genetic interaction in which Vangl2(Lp/+) enhances the Sdc4-null phenotype. This could be mediated via heparan sulfate residues, as Vangl2(Lp/+) embryos fail to initiate neural tube closure and develop craniorachischisis (usually seen only in Vangl2(Lp/Lp)) when cultured in the presence of chlorate, a sulfation inhibitor. These results demonstrate that Sdc4 can participate in the Wnt/PCP pathway, unveiling its importance during neural tube closure in mammalian embryos.

Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders.

To present a summary of current scientific evidence about the cannabinoid, cannabidiol (CBD) with regard to its relevance to epilepsy and other selected neuropsychiatric disorders. We summarize the presentations from a conference in which invited participants reviewed relevant aspects of the physiology, mechanisms of action, pharmacology, and data from studies with animal models and human subjects. Cannabis has been used to treat disease since ancient times. Δ(9) -Tetrahydrocannabinol (Δ(9) -THC) is the major psychoactive ingredient and CBD is the major nonpsychoactive ingredient in cannabis. Cannabis and Δ(9) -THC are anticonvulsant in most animal models but can be proconvulsant in some healthy animals. The psychotropic effects of Δ(9) -THC limit tolerability. CBD is anticonvulsant in many acute animal models, but there are limited data in chronic models. The antiepileptic mechanisms of CBD are not known, but may include effects on the equilibrative nucleoside transporter; the orphan G-protein-coupled receptor GPR55; the transient receptor potential of vanilloid type-1 channel; the 5-HT1a receptor; and the α3 and α1 glycine receptors. CBD has neuroprotective and antiinflammatory effects, and it appears to be well tolerated in humans, but small and methodologically limited studies of CBD in human epilepsy have been inconclusive. More recent anecdotal reports of high-ratio CBD:Δ(9) -THC medical marijuana have claimed efficacy, but studies were not controlled. CBD bears investigation in epilepsy and other neuropsychiatric disorders, including anxiety, schizophrenia, addiction, and neonatal hypoxic-ischemic encephalopathy. However, we lack data from well-powered double-blind randomized, controlled studies on the efficacy of pure CBD for any disorder. Initial dose-tolerability and double-blind randomized, controlled studies focusing on target intractable epilepsy populations such as patients with Dravet and Lennox-Gastaut syndromes are being planned. Trials in other treatment-resistant epilepsies may also be warranted. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Population-based estimated reference creatinine values: a novel method of a robust electronic acute kidney injury alert system.

BACKGROUND: Acute kidney injury (AKI) is common in hospitalized patients. Despite the progress that has been made in the last decade, early identification of AKI cases remains a challenge. In recent years, electronic AKI alert (e-AKI alert) systems have been tested and are usually based on changes in serum creatinine (Cr) values. However, these methods do not include one of the common scenarios, i.e. when there is no available preadmission Cr value available for a patient to compare and hence an e-AKI alert cannot be issued. Therefore, it is essential to have an alternative algorithm to produce e-AKI alerts in such scenarios. METHOD: We have developed e-AKI alert algorithms which compare serum Cr values at presentation with previous results, within KDIGO AKI guideline-specified classifications. However, where a comparator is not available, we have produced a 'population-based reference Cr value' age and sex matched from 137,000 serum Cr values extracted from blood tests in general practice from our Telepath system. RESULTS: Cr results were split by gender, and then within each group the Cr were stratified according to year of age. The median Cr for each individual year of age was identified and plotted versus age to give separate graphs for males and females that gave excellent fits (R(2)) to cubic regressions. CONCLUSION: Population-based estimated reference Cr measurements from community blood test results is a more robust method of baseline Cr value estimation in generating potential e-AKI alerts to help early recognition and treatment of AKI cases leading to improved outcome.

A thematic analysis of staff perspectives on the impact of a mental health nurse (RMN) in a critical care unit.

Background: Recent guidelines in the UK have shaped Critical Care Units (CCUs) to bring the mental health needs of patients, and staff wellbeing to the forefront of service provision. A health board based in NHS Wales has trialled the secondment of a Mental Health Nurse (RMN) within a CCU to help service provision adhere to such guidelines. Methods: Critical care staff were invited to attend focus groups to share their experiences of how the RMN influenced service provision. Results: Thematic analysis identified five main themes; including 'smoother care pathways', 'a holistic approach to care', 'co-production', 'knowledge and confidence' and 'staff wellbeing'. Each of these themes reflected how the RMN had both direct and indirect benefits on patient and staff wellbeing. Conclusion: This qualitative exploration suggests that staff perceived value in the role of the RMN for both staff and patient outcomes, although further measures were considered necessary to improve staff-wellbeing within a critical care environment. This service evaluation supports recommendations for commissioning a RMN permanently in a CCU.

Predictors of recovery in a medium secure service: Influence of the Welsh Government's Mental Health (2010) Measure.

BACKGROUND: Research to date has failed to examine the effectiveness of MSUs in facilitating recovery, or the influence that mental health policy may have on this process. Examining predictors of short-term clinical outcomes during inpatient admission and the effects of policy changes may inform future policy, treatment planning and may improve service user outcomes. AIMS: To examine whether service user admission characteristics and length of stay predicted recovery status at discharge from medium secure care and whether a recovery-focused change in policy (introduction of the Mental Health (Wales) Measure (2010)) impacted either on recovery or the relationship between service user characteristics and recovery. METHODS: The study adopted a retrospective analysis of quantitative data obtained from healthcare records from a Welsh MSU between 2007 and 2017 (n = 198). The DUNDUM-4 scale assessed recovery whilst DUNDRUM-2 assessed security need at admission. Service user admission characteristics included HCR-20 subscale scores, previous security-level transitions, adverse childhood experiences, substance misuse histories. RESULTS: Shorter inpatient stays and higher scores on the dynamic HCR-20 clinical subscale were associated with poorer recovery outcomes. The relationship between admission characteristics and recovery endured despite changes in policy. Implementation of recovery focused legislation was associated with improved recovery. CONCLUSIONS: The findings suggest that treatment should focus on dynamic risk factors to improve service user outcomes and highlights the need for long-term medium-secure provision for some. Further research is needed to evaluate the success of MSUs and the validity of the DUNDRUM-4 across UK secure services.