Minimal frustration underlies the usefulness of incomplete regulatory network models in biology.

Regulatory networks as large and complex as those implicated in cell-fate choice are expected to exhibit intricate, very high-dimensional dynamics. Cell-fate choice, however, is a macroscopically simple process. Additionally, regulatory network models are almost always incomplete and/or inexact, and do not incorporate all the regulators and interactions that may be involved in cell-fate regulation. In spite of these issues, regulatory network models have proven to be incredibly effective tools for understanding cell-fate choice across contexts and for making useful predictions. Here, we show that minimal frustration-a feature of biological networks across contexts but not of random networks-can compel simple, low-dimensional steady-state behavior even in large and complex networks. Moreover, the steady-state behavior of minimally frustrated networks can be recapitulated by simpler networks such as those lacking many of the nodes and edges and those that treat multiple regulators as one. The present study provides a theoretical explanation for the success of network models in biology and for the challenges in network inference.

Maintenance or Discontinuation of Antidepressants in Primary Care.

BACKGROUND: Patients with depression who are treated in primary care practices may receive antidepressants for prolonged periods. Data are limited on the effects of maintaining or discontinuing antidepressant therapy in this setting. METHODS: We conducted a randomized, double-blind trial involving adults who were being treated in 150 general practices in the United Kingdom. All the patients had a history of at least two depressive episodes or had been taking antidepressants for 2 years or longer and felt well enough to consider stopping antidepressants. Patients who had received citalopram, fluoxetine, sertraline, or mirtazapine were randomly assigned in a 1:1 ratio to maintain their current antidepressant therapy (maintenance group) or to taper and discontinue such therapy with the use of matching placebo (discontinuation group). The primary outcome was the first relapse of depression during the 52-week trial period, as evaluated in a time-to-event analysis. Secondary outcomes were depressive and anxiety symptoms, physical and withdrawal symptoms, quality of life, time to stopping an antidepressant or placebo, and global mood ratings. RESULTS: A total of 1466 patients underwent screening. Of these patients, 478 were enrolled in the trial (238 in the maintenance group and 240 in the discontinuation group). The average age of the patients was 54 years; 73% were women. Adherence to the trial assignment was 70% in the maintenance group and 52% in the discontinuation group. By 52 weeks, relapse occurred in 92 of 238 patients (39%) in the maintenance group and in 135 of 240 (56%) in the discontinuation group (hazard ratio, 2.06; 95% confidence interval, 1.56 to 2.70; P<0.001). Secondary outcomes were generally in the same direction as the primary outcome. Patients in the discontinuation group had more symptoms of depression, anxiety, and withdrawal than those in the maintenance group. CONCLUSIONS: Among patients in primary care practices who felt well enough to discontinue antidepressant therapy, those who were assigned to stop their medication had a higher risk of relapse of depression by 52 weeks than those who were assigned to maintain their current therapy. (Funded by the National Institute for Health Research; ANTLER ISRCTN number, ISRCTN15969819.).

Clinical factors associated with relapse in depression in a sample of UK primary care patients who have been on long-term antidepressant treatment.

BACKGROUND: This paper investigates whether age of onset of depression, duration of the last episode, number of episodes, and residual symptoms of depression and anxiety are associated with depression relapse in primary care patients who have been on long-term maintenance antidepressant treatment and no longer meet ICD10 criteria for depression. METHODS: An observational cohort using data from ANTLER (N = 478), a double-blind placebo-controlled trial. The primary outcome was time to relapse using the retrospective CIS-R. Participants were followed for 12 months. RESULTS: Primary outcome was available for 468 participants. Time to relapse in those with more than five previous episodes of depression was shorter, hazard ratio (HR) 1.84 (95% confidence interval [CI] 1.23-2.75) compared to people with two episodes; HR 1.57 (95% CI 1.01-2.43) after adjustment. The residual symptoms of depression at baseline were also associated with increased relapse: HR 1.05 (95% CI 1.01-1.09) and HR 1.06 (95% CI 1.01-1.12) in the adjusted model. There was evidence of reduced rate of relapse in older age of onset group: HR 0.86 (95% CI 0.78-0.95); HR attenuated after adjustment HR 0.91 (95% CI 0.81-1.02). There was no evidence of an association between duration of the current episode and residual anxiety symptoms with relapse. CONCLUSIONS: The number of previous episodes and residual symptoms of depression were associated with increased likelihood of relapse. These factors could inform joint decision making when patients are considering tapering off maintenance antidepressant treatment or considering other treatments to prevent relapse.

The lived experience of withdrawal from Selective Serotonin Reuptake Inhibitor (SSRI) antidepressants: A qualitative interview study.

BACKGROUND: Our knowledge of the broader impacts of antidepressant withdrawal, beyond physical side effects, is limited. Further research is needed to investigate the lived experiences of withdrawal, to aid clinicians on how to guide patients through the process. AIM: To explore antidepressant users' experiences and views on the withdrawal process and how it affected their quality of life across multiple life domains. DESIGN AND SETTING: We conducted in-depth qualitative interviews with 20 individuals from the community who had attempted to withdraw from Serotonin Reuptake Inhibitor antidepressants in the past year. METHOD: Semi-structured interviews were conducted online. A topic guide was used to ensure consistency across interviews. The interviews were audio-recorded and transcribed verbatim and analysed using inductive reflexive thematic analysis. RESULTS: Five themes were generated. The first highlighted the challenges of managing the release from emotional blunting and cognitive suppression following antidepressant discontinuation. The second related to the negative impact of withdrawal on close relationships and social interactions. The third showed that concurrent with negative physical symptoms, there was a positive impact on health (exercise was reported by some as a coping mechanism). The fourth theme focused on support from GPs and families, emphasising the importance of mental health literacy in others. The final theme underscored the importance of gradual and flexible tapering in enabling a manageable withdrawal experience, and the consideration of timing. CONCLUSION: The lived experience of withdrawal significantly impacts individuals' well-being. Participants emphasised that withdrawal is not just about physical side effects but also affects their emotional, cognitive, and social functioning. PATIENT AND PUBLIC INVOLVEMENT (PPI): Eight people attended individual online meetings to share their experiences of antidepressant withdrawal to help inform the study design and recruitment strategy. Insights from these meetings informed the development of the topic guide. Questions about GP involvement, family relationships, and mood and thinking changes were included based on this PPI work. This ensured the inclusion of topics important to antidepressant users and facilitated the researcher's questioning during the interviews.

Exploring the Feasibility of At-Home Lung Ultra-Portable Ultrasound: Parent-Performed Pediatric Lung Imaging.

OBJECTIVE: To determine if caregivers would be able to successfully perform in home lung ultrasounds on their children without direct supervision after undergoing a basic tutorial that would allow for expert interpretation. METHODS: A prospective exploratory single-center cohort study was conducted on patients (0-18 years) presenting to a pediatric emergency department with a respiratory complaint or COVID-related illness. Caregivers underwent a brief hands-on session and were instructed to scan the lungs daily for 7 days. Images were assessed using a modified POCUS IQ score. Descriptive statistics were used to describe the data and bivariate analysis was used to compare groups. RESULTS: Eighteen patients were enrolled; the average age of the parent scanner was 31.9 years and 78% were female. Of all participants, 77.8% scanned on day one. Parents were able to successfully perform some part of the daily scan session for an average of 3.8 out of 7 days. The average POCUS IQ score overall was 6.7 (out of 12). CONCLUSION: Our study demonstrates the feasibility and acceptability of caregiver ability to obtain adequate lung ultrasound images, at home under no guidance, using the Butterfly iQ probe. Further studies are needed to investigate the accessibility of ultra-portable ultrasound and the ability to integrate with the at-home hospital model, specifically in the pediatric population.

Critical Event Checklists for Simulated In-Hospital Dysrhythmias in Children with Heart Disease.

Children with heart disease are at increased risk of unstable dysrhythmias and in-hospital cardiac arrest (IHCA). Clinician adherence to lifesaving processes of care is an important contributor to improving patient outcomes. This study evaluated whether critical event checklists improve adherence to lifesaving processes during simulated acute events secondary to unstable dysrhythmias. A randomized controlled trial was conducted in a cardiac ward in a tertiary care, academic children's hospital. Unannounced simulated emergencies involving dysrhythmias in pediatric patients with underlying cardiac disease were conducted weekly. Responders were pediatric and anesthesiology residents, respiratory therapists, and bedside registered nurses. Six teams were randomized into two groups-three received checklists (intervention) and three did not (control). Each team participated in four simulated scenarios over a 4-week pediatric cardiology rotation. Participants received a brief slideshow presentation, which included a checklist orientation, at the start of their rotation. Simulations were video and audio recorded and those with three or more participants were included for analysis. The primary outcome was team adherence to lifesaving processes, expressed as the percentage of completed critical management steps. Secondary outcomes included participant perceptions of the checklist usefulness in identifying and managing dysrhythmias. We used generalized estimating equations (GEE) models, which accounted for clustering within groups, to evaluate the effects of the intervention. A total of 24 simulations were conducted; one of the 24 simulations was excluded due to an insufficient number of participants. In our GEE analysis, 81.21% (78.96%, 83.47%) of critical steps were completed with checklists available versus 68.06% (59.38%, 76.74%) without checklists (p = 0.004). Ninety-three percent of study participants reported that they would use the checklists during an unstable dysrhythmia of a child with underlying cardiac disease. Checklists were associated with improved adherence to lifesaving processes during simulated resuscitations for unstable pediatric dysrhythmias. These findings support the use of scenario specific checklists for the management of unstable dysrhythmias in simulations involving pediatric patients with underlying cardiac disease. Future studies should investigate whether checklists are as effective in actual pediatric in-hospital emergencies.

Diaphragmatic Ultrasound in Children With Asthma Exacerbations.

OBJECTIVES: Asthma is a leading cause of pediatric emergency department visits, yet few tools exist to objectively measure asthma severity. Diaphragmatic ultrasound (DUS) is a novel method of assessing respiratory distress; however, data are lacking for children.Our primary aim was to determine if diaphragmatic excursion (DE), diaphragmatic thickening (DT), or diaphragmatic thickening fraction (TF) correlated with asthma severity as determined by the Pediatric Respiratory Assessment Measure (PRAM) score. Secondarily, we examined if these parameters correlated with need for respiratory support and evaluated interrater reliability. METHODS: We conducted a prospective study of children 5-18 years presenting to a pediatric emergency department with an asthma exacerbation. Diaphragmatic ultrasound was performed by a trained pediatric emergency medicine sonologist in subcostal (DE) and midaxillary (DT). Thickening fraction was calculated from DT values as previously described in literature. To evaluate interrater reliability, a subset of subjects had DUS performed by a second sonologist. RESULTS: We enrolled 47 subjects for a total of 51 encounters. The mean age was 9.1 ± 3.7 years. Twenty-five (49%) had mild, 24 (47%) had moderate, and 2 (4%) had severe asthma. There was a significant difference in midaxillary DT and TF between children with mild and moderate asthma ( P = 0.02; mean difference, 0.2 mm; 95% confidence interval [CI], 0.03-0.4 and P = 0.02; mean difference, 0.11 mm; 95% CI, 0.02-0.2, respectively). No difference was found in subcostal DE ( P = 0.43; mean difference, 1.4 mm; 95% CI, -2.1 to 4.8). No association was found between use of positive pressure and DUS parameters. Fourteen encounters had 2 sonologists perform DUS, with strong interrater reliability found for midaxillary DT (Pearson correlation, 0.56) and poor association for subcostal DE (Pearson correlation, 0.18). CONCLUSIONS: In this pilot study, we conclude that DUS may be helpful in assessing severity of asthma. The midaxillary view assessment for DT and TF had the best correlation with asthma severity and the best interrater reliability. Future studies may benefit from focusing on the midaxillary view for DT and TF.

Self-processing in relation to emotion and reward processing in depression.

BACKGROUND: Depression is characterised by a heightened self-focus, which is believed to be associated with differences in emotion and reward processing. However, the precise relationship between these cognitive domains is not well understood. We examined the role of self-reference in emotion and reward processing, separately and in combination, in relation to depression. METHODS: Adults experiencing varying levels of depression (n = 144) completed self-report depression measures (PHQ-9, BDI-II). We measured self, emotion and reward processing, separately and in combination, using three cognitive tasks. RESULTS: When self-processing was measured independently of emotion and reward, in a simple associative learning task, there was little association with depression. However, when self and emotion processing occurred in combination in a self-esteem go/no-go task, depression was associated with an increased positive other bias [b = 3.51, 95% confidence interval (CI) 1.24-5.79]. When the self was processed in relation to emotion and reward, in a social evaluation learning task, depression was associated with reduced positive self-biases (b = 0.11, 95% CI 0.05-0.17). CONCLUSIONS: Depression was associated with enhanced positive implicit associations with others, and reduced positive learning about the self, culminating in reduced self-favouring biases. However, when self, emotion and reward processing occurred independently there was little evidence of an association with depression. Treatments targeting reduced positive self-biases may provide more sensitive targets for therapeutic intervention and potential biomarkers of treatment responses, allowing the development of more effective interventions.

Role of regional anesthesia in patients with acute sickle cell pain: A scoping review.

Sickle cell disease is the most prevalent inherited blood disorder in the world, with significant morbidity and mortality. Patients often have recurrent painful vaso-occlusive episodes, and the American Society of Hematology gives a conditional recommendation for the use of regional anesthesia for acute sickle cell pain management. This scoping review summarizes the current evidence and identifies gaps for future research. Our screening process is outlined, and articles that mentioned the use of regional anesthesia for acute sickle cell crises were included. We present and interpret our results and highlight opportunities for future investigation.

Acceptability of integrating smoking cessation treatment into routine care for people with mental illness: A qualitative study.

INTRODUCTION: Improving Access to Psychological Therapies (IAPTs) Services could offer smoking cessation treatment to improve physical and psychological outcomes for service users, but it currently does not. This study aimed to understand participants' views and experiences of receiving a novel smoking cessation intervention as part of the ESCAPE trial (intEgrating Smoking Cessation treatment As part of usual Psychological care for dEpression and anxiety). We used the Capability, Opportunity and Motivation Model of Behaviour (COM-B) to understand the (i) acceptability of the integrated smoking cessation treatment, (ii) views of psychological well-being practitioners' (PWPs) ability to deliver the smoking cessation treatment and (iii) positive and negative impacts of smoking cessation treatment. METHODS: This was a qualitative study embedded within a feasibility randomized-controlled trial (ESCAPE) in primary care services in the United Kingdom (IAPT). Thirty-six participants (53% female) from both usual care and intervention arms of the ESCAPE trial, including both quitters and nonquitters, were interviewed using semi-structured interviews. Data were analysed using a framework approach to thematic analysis, using the COM-B as a theoretical frame. RESULTS: Psychological Capability: Integrated smoking cessation treatment was acceptable and encouraged participants to reflect on their mental health. Some participants found it difficult to understand nicotine withdrawal symptoms. MOTIVATION: Participants were open to change during the event of presenting to IAPT. Some described being motivated to take part in the intervention by curiosity, to see whether quitting smoking would help their mental health. Physical Opportunity: IAPT has a natural infrastructure for supporting integrated treatment, but there were some barriers such as session duration and interventions feeling segmented. Social Opportunity: Participants viewed PWPs as having good interpersonal skills to deliver a smoking cessation intervention. CONCLUSION: People with common mental illness generally accepted integrated smoking cessation and mental health treatment. Smoking cessation treatment fits well within IAPT's structure; however, there are barriers to implementation. PATIENT OR PUBLIC CONTRIBUTION: Before data collection, we consulted with people with lived experience of smoking and/or mental illness and lay public members regarding the aims, design and interview schedules. After analysis, two people with lived experience of smoking and mental illness individually gave feedback on the final themes and quotes.

Development and Validation of a Point-of-Care-Ultrasound Image Quality Assessment Tool: The POCUS IQ Scale.

OBJECTIVES: We aimed to develop a standardized scoring tool to measure point-of-care ultrasound (POCUS) image quality and to determine validity evidence for its use to assess lung ultrasound image quality. METHODS: The POCUS Image Quality (POCUS IQ) scale was developed by POCUS-trained physicians to assess sonographers' image acquisition skills by evaluating image quality for any POCUS application. The scale was piloted using lung images of healthy standardized patients acquired by three expert sonographers compared to three novices before and after training. All images (experts, novices pre-training, novices post-training) were scored on the POCUS IQ scale by three blinded POCUS-trained physicians. Reliability was assessed with fully-crossed generalizability and decision studies. Validity was assessed using Messick's framework. RESULTS: Content validity was supported by the tool's development process of literature review, expert consensus, and pilot testing. Response process was supported by reviewer training and the blinded scoring process. Relation to other variables was supported by scores relating to sonographer experience: median expert score = 10.5/14 (IQR: 4), median novice pre-training score = 6/14 (IQR: 2.25), and novices' improvement after training (median post-training score = 12/14, IQR: 3.25). Internal structure was supported by internal consistency data (coefficient alpha = 0.84, omega coefficient = 0.91) and the generalizability study showing the main contributor to score variability was the sonographer (51%). The G-coefficient was 0.89, suggesting very good internal structure, however, Gwet's AC2  was 0.5, indicating moderate interrater reliability. The D study projected a minimum of 1 reviewer and 2 patients are needed for good psychometric reliability. CONCLUSIONS: The POCUS scale has good preliminary validity evidence as an assessment tool for lung POCUS image acquisition skills. Further studies are needed to demonstrate its utility for other POCUS applications and as a feedback tool for POCUS learners.

Phenomenological Approach to Cancer Cell Persistence.

Drug persistence is a phenomenon by which a small percentage of cancer cells survive the presentation of targeted therapy by transitioning to a quiescent state. Eventually some of these persister cells can transition back to an active growing state and give rise to resistant tumors. Here we introduce a quantitative genetics approach to drug-exposed populations of cancer cells in order to interpret recent experimental data regarding inheritance of persister probability. Our results indicate that alternating periods of drug treatment and drug removal may not be an effective strategy for eliminating persisters.

Discrete Sampling of Extreme Events Modifies Their Statistics.

Extreme value (EV) statistics of correlated systems are widely investigated in many fields, spanning the spectrum from weather forecasting to earthquake prediction. Does the unavoidable discrete sampling of a continuous correlated stochastic process change its EV distribution? We explore this question for correlated random variables modeled via Langevin dynamics for a particle in a potential field. For potentials growing at infinity faster than linearly and for long measurement times, we find that the EV distribution of the discretely sampled process diverges from that of the full continuous dataset and converges to that of independent and identically distributed random variables drawn from the process's equilibrium measure. However, for processes with sublinear potentials, the long-time limit is the EV statistics of the continuously sampled data. We treat processes whose equilibrium measures belong to the three EV attractors: Gumbel, Fréchet, and Weibull. Our Letter shows that the EV statistics can be extremely sensitive to the sampling rate of the data.

How much change is enough? Evidence from a longitudinal study on depression in UK primary care.

BACKGROUND: The Patient Health Questionnaire (PHQ-9), the Beck Depression Inventory (BDI-II) and the Generalised Anxiety Disorder Assessment (GAD-7) are widely used in the evaluation of interventions for depression and anxiety. The smallest reduction in depressive symptoms that matter to patients is known as the Minimum Clinically Important Difference (MCID). Little empirical study of the MCID for these scales exists. METHODS: A prospective cohort of 400 patients in UK primary care were interviewed on four occasions, 2 weeks apart. At each time point, participants completed all three questionnaires and a 'global rating of change' scale (GRS). MCID estimation relied on estimated changes in symptoms according to reported improvement on the GRS scale, stratified by baseline severity on the Clinical Interview Schedule (CIS-R). RESULTS: For moderate baseline severity, those who reported improvement on the GRS had a reduction of 21% (95% confidence interval (CI) -26.7 to -14.9) on the PHQ-9; 23% (95% CI -27.8 to -18.0) on the BDI-II and 26.8% (95% CI -33.5 to -20.1) on the GAD-7. The corresponding threshold scores below which participants were more likely to report improvement were -1.7, -3.5 and -1.5 points on the PHQ-9, BDI-II and GAD-7, respectively. Patients with milder symptoms require much larger reductions as percentage of their baseline to endorse improvement. CONCLUSIONS: An MCID representing 20% reduction of scores in these scales, is a useful guide for patients with moderately severe symptoms. If treatment had the same effect on patients irrespective of baseline severity, those with low symptoms are unlikely to notice a benefit. FUNDING: Funding. National Institute for Health Research.

Trends in the recording of anxiety in UK primary care: a multi-method approach.

PURPOSE: Anxiety disorders are common. Between 1998 and 2008, in the UK, GP recording of anxiety symptoms increased, but the recording of anxiety disorders decreased. We do not know whether such trends have continued. This study examined recent trends in the recording of anxiety and explored factors that may influence GPs' coding of anxiety. METHODS: We used data from adults (n = 2,569,153) registered with UK general practices (n = 176) that contributed to the Clinical Practice Research Datalink between 2003 and 2018. Incidence rates and 95% confidence intervals were calculated for recorded anxiety symptoms and diagnoses and were stratified by age and gender. Joinpoint regression was used to estimate the years trends changed. In addition, in-depth interviews were conducted with 15 GPs to explore their views and management of anxiety. Interviews were audio-recorded, transcribed verbatim and analysed thematically. RESULTS: The incidence of anxiety symptoms rose from 6.2/1000 person-years at risk (PYAR) in 2003 to 14.7/1000 PYAR in 2018. Between 2003 and 2008, the incidence of anxiety diagnoses fell from 13.2 to 10.1/1000 PYAR; markedly increasing between 2013 and 2018 to 15.3/1000 PYAR. GPs mentioned that they preferred using symptom codes to diagnostic codes to avoid assigning potentially stigmatising or unhelpful labels, and commented on a rise in anxiety in recent years, especially in young adults. CONCLUSION: Recent increases in the recording of both anxiety diagnoses and symptoms may reflect increased presentation to primary care, especially in young adults. There is a clear need to understand the reasons for this, and this knowledge may be critical in the prevention and treatment of anxiety.

Lack of Association Between a Quantified Lung Ultrasound Score and Illness Severity in Pediatric Emergency Department Patients With Acute Lower Respiratory Infections.

OBJECTIVES: Lung ultrasound (LUS) may help determine illness severity in children with acute lower respiratory tract infections (LRTI) but limited pediatric studies exist. Our objective was to determine the association between LUS findings and illness severity in children with LRTI. METHODS: We conducted a prospective study of patients <20 years with LRTI. Trained investigators performed standardized LUS examinations of 12 regions. Blinded sonologists reviewed examinations for individual pathologic features and also calculated a Quantified Lung Ultrasound Score (QLUS). We defined focal severity as QLUS of ≥2 in ≥1 region, and diffuse severity as QLUS of ≥1 in ≥3 regions. The primary outcome was the Respiratory component of the Pediatric Early Warning Score (RPEWS), a 14-item scale measuring respiratory illness severity. Secondary outcomes included hospital admission, length of stay, supplemental oxygen, and antibiotic use. RESULTS: We enrolled 85 patients with LRTIs, 46 (54%) whom were hospitalized (5.4% intensive care). Median RPEWS was 1 (interquartile range 2). Neither individual features on ultrasound nor total QLUS were associated with RPEWS, hospitalization, length of stay, or oxygen use. Mean RPEWS was similar for participants regardless of focal (1.46 versus 1.26, P = .57) or diffuse (1.47 versus 1.21, P = .47) severity findings, but those with focal or diffuse severity, or isolated consolidation, had greater antibiotic administration (P < .001). CONCLUSIONS: In children with LRTI, neither individual features nor QLUS were associated with illness severity. Antibiotics were more likely in patients with either focal or diffuse severity or presence of consolidation on ultrasound.

Core Components of a Pediatric Critical Care Transport Communication Curriculum: A Modified Delphi Approach.

OBJECTIVE: Interfacility transport of critically ill infants and children is an essential part of the care of children in the United States. However, there is tremendous variation in how transports are coordinated and performed. Pediatric critical care medicine (PCCM) fellows have differing experiences in their fellowships, and there is no standardized way of training medical command for the transport process. The aim of this study was to use a consensus-building process to establish core components of a PCCM transport curriculum focused on communication. METHODS: A national group of experts in transport medicine rated 51 total possible topics for their importance to include in a fellowship curriculum. Three rounds of surveys were completed. RESULTS: Fifty-two of 372 invitees (14%) participated in round 1. Consensus was reached to include 15 items in a PCCM curriculum. Twenty of 52 (38%) experts completed round 2, reaching consensus on 2 additional items. Seventeen of 20 (85%) experts completed round 3. No additional items reached consensus. CONCLUSION: Experts reached consensus on 17 core components to include in a PCCM fellowship transport communication curriculum. This curriculum could likely be adapted to train providers from different disciplines in the transport process.

Improving Pediatric Readiness in General Emergency Departments: A Prospective Interventional Study.

OBJECTIVE: To describe the impact of a national interventional collaborative on pediatric readiness within general emergency departments (EDs). STUDY DESIGN: A prospective, multicenter, interventional study measured pediatric readiness in general EDs before and after participation in a pediatric readiness improvement intervention. Pediatric readiness was assessed using the weighted pediatric readiness score (WPRS) on a 100-point scale. The study protocol extended over 6 months and involved 3 phases: (1) a baseline on-site assessment of pediatric readiness and simulated quality of care; (2) pediatric readiness interventions; and (3) a follow-up on-site assessment of WPRS. The intervention phase included a benchmarking performance report, resources toolkits, and ongoing interactions between general EDs and academic medical centers. RESULTS: Thirty-six general EDs were enrolled, and 34 (94%) completed the study. Four EDs (11%) were located in Canada, and the rest were in the US. The mean improvement in WPRS was 16.3 (P < .001) from a baseline of 62.4 (SEM = 2.2) to 78.7 (SEM = 2.1), with significant improvement in the domains of administration/coordination of care; policies, protocol, and procedures; and quality improvement. Six EDs (17%) were fully adherent to the protocol timeline. CONCLUSIONS: Implementing a collaborative intervention model including simulation and quality improvement initiatives is associated with improvement in WPRS when disseminated to a diverse group of general EDs partnering with their regional pediatric academic medical centers. This work provides evidence that innovative collaboration facilitated by academic medical centers can serve as an effective strategy to improve pediatric readiness and processes of care.

Detecting Heterogeneity of Intervention Effects Using Analysis and Meta-analysis of Differences in Variance Between Trial Arms.

BACKGROUND: Randomized controlled trials (RCTs) with continuous outcomes usually only examine mean differences in response between trial arms. If the intervention has heterogeneous effects, then outcome variances will also differ between arms. Power of an individual trial to assess heterogeneity is lower than the power to detect the same size of main effect. METHODS: We describe several methods for assessing differences in variance in trial arms and apply them to a single trial with individual patient data and to meta-analyses using summary data. Where individual data are available, we use regression-based methods to examine the effects of covariates on variation. We present an additional method to meta-analyze differences in variances with summary data. RESULTS: In the single trial, there was agreement between methods, and the difference in variance was largely due to differences in prevalence of depression at baseline. In two meta-analyses, most individual trials did not show strong evidence of a difference in variance between arms, with wide confidence intervals. However, both meta-analyses showed evidence of greater variance in the control arm, and in one example, this was perhaps because mean outcome in the control arm was higher. CONCLUSIONS: Using meta-analysis, we overcame low power of individual trials to examine differences in variance using meta-analysis. Evidence of differences in variance should be followed up to identify potential effect modifiers and explore other possible causes such as varying compliance.

Ordered hexagonal patterns via notch-delta signaling.

Many developmental processes in biology utilize notch-delta signaling to construct an ordered pattern of cellular differentiation. This signaling modality is based on nearest-neighbor contact, as opposed to the more familiar mechanism driven by the release of diffusible ligands. Here, exploiting this 'juxtacrine' property, we present an exact treatment of the pattern formation problem via a system of nine coupled ordinary differential equations. The possible patterns that are realized for realistic parameters can be analyzed by considering a co-dimension 2 pitchfork bifurcation of this system. This analysis explains the observed prevalence of hexagonal patterns with high delta at their center, as opposed to those with central high notch levels (referred to as anti-hexagons). We show that outside this range of parameters, in particular for lowcis-coupling, a novel kind of pattern is produced, where high delta cells have high notch as well. It also suggests that the biological system is only weakly first order, so that an additional mechanism is required to generate the observed defect-free patterns. We construct a simple strategy for producing such defect-free patterns.