Duality between predictability and reconstructability in complex systems.

Predicting the evolution of a large system of units using its structure of interaction is a fundamental problem in complex system theory. And so is the problem of reconstructing the structure of interaction from temporal observations. Here, we find an intricate relationship between predictability and reconstructability using an information-theoretical point of view. We use the mutual information between a random graph and a stochastic process evolving on this random graph to quantify their codependence. Then, we show how the uncertainty coefficients, which are intimately related to that mutual information, quantify our ability to reconstruct a graph from an observed time series, and our ability to predict the evolution of a process from the structure of its interactions. We provide analytical calculations of the uncertainty coefficients for many different systems, including continuous deterministic systems, and describe a numerical procedure when exact calculations are intractable. Interestingly, we find that predictability and reconstructability, even though closely connected by the mutual information, can behave differently, even in a dual manner. We prove how such duality universally emerges when changing the number of steps in the process. Finally, we provide evidence that predictability-reconstruction dualities may exist in dynamical processes on real networks close to criticality.

Phenobarbital treatment of alcohol withdrawal in the emergency department: A systematic review and meta-analysis.

OBJECTIVE: Despite frequent treatment of alcohol withdrawal syndrome (AWS) in the emergency department (ED), evidence for phenobarbital (PB) as an ED alternative therapy is mixed. We conducted a systematic review and meta-analysis comparing safety and efficacy of PB to benzodiazepines (BZDs) for treatment of AWS in the ED. METHODS: We searched articles and references published in English in PubMed, Web of Science, and Embase from inception through May 2022. We included randomized trials and cohort studies comparing treatment with PB to BZD controls and excluded studies focused on non-AWS conditions. Review was conducted by two blinded investigators and a third author; eight of 59 (13.6%) abstracts met inclusion criteria for review and meta-analysis using a random-effects model. Treatment superiority was evaluated through utilization, pharmacologic, and clinical outcomes. Primary outcomes for meta-analysis were the proportion of patients (1) admitted to the intensive care unit (ICU), (2) admitted to the hospital, (3) readmitted to the ED after discharge, and (4) who experienced adverse events. RESULTS: Eight studies (two randomized controlled trials, six retrospective cohorts) comprised data from 1507 patients in 2012 treatment encounters for AWS. All studies were included in meta-analysis for adverse events, seven for hospital admission, five for ICU admission, and three for readmission to the ED after discharge. Overall methodological quality was low-moderate, risk of bias moderate-high, and statistical heterogeneity moderate. Pooled relative risk of ICU admission for those treated with PB versus BZD was 0.92 (95% confidence interval [CI] 0.54-1.55). Risk for admission to the hospital was 0.98 (95% CI 0.89-1.07) and for any adverse event was 1.1 (95% CI 0.78-1.57); heterogeneity prevented meta-analysis for ED readmission. CONCLUSIONS: The current literature base does not show that treatment with PB significantly reduces ICU admissions, hospital admissions, ED readmissions, or adverse events in ED patients with AWS compared with BZDs alone.

Capnography-Assisted Learned, Monitored (CALM) breathing therapy for dysfunctional breathing in COPD: A bridge to pulmonary rehabilitation.

BACKGROUND: Although dyspnea is a primary symptom of chronic obstructive pulmonary disease (COPD), its treatment is suboptimal. In both COPD and acute anxiety, breathing patterns become dysregulated, contributing to abnormal CO2, dyspnea, and inefficient recovery from breathing challenges. While pulmonary rehabilitation (PR) improves dyspnea, only 1-2% of patients access it. Individuals with anxiety who use PR have worse outcomes. METHODS: We present the protocol of a randomized controlled trial designed to determine the feasibility and acceptability of a new, four-week mind-body intervention that we developed, called "Capnography-Assisted Learned, Monitored (CALM) Breathing," as an adjunct to PR. Eligible participants are randomized in a 1:1 ratio to either CALM Breathing program or Usual Care. CALM Breathing consists of 10 core, slow breathing exercises combined with real time biofeedback (of end-tidal CO2, respiratory rate, and airflow) and motivational interviewing. CALM Breathing promotes self-regulated breathing, linking CO2 changes to dyspnea and anxiety symptoms and targeting breathing efficiency and self-efficacy in COPD. Participants are randomized to CALM Breathing or a Usual Care control group. RESULTS: Primary outcomes include feasibility and acceptability metrics of recruitment efficiency, participant retention, intervention adherence and fidelity, PR facilitation, patient satisfaction, and favorable themes from interviews. Secondary outcomes include breathing biomarkers, symptoms, health-related quality of life, six-minute walk distance, lung function, mood, physical activity, and PR utilization and engagement. CONCLUSION: By disrupting the cycle of dyspnea and anxiety, and providing a needed bridge to PR, CALM Breathing may address a substantive gap in healthcare and optimize treatment for patients with COPD.

Extended-Release Naltrexone and Case Management for Treatment of Alcohol Use Disorder in the Emergency Department.

STUDY OBJECTIVE: To assess the feasibility of initiating treatment for alcohol use disorder with extended-release naltrexone and case management services in the emergency department (ED) and measure the intervention's impact on daily alcohol consumption and quality of life. METHODS: This is a 12-week prospective open-label single-arm study of a multimodal treatment for alcohol use disorder consisting of monthly extended-release naltrexone injections and case management services initiated at an urban academic ED. Participants were actively drinking adult patients in ED with known or suspected alcohol use disorder and an AUDIT-C score more than 4. The main feasibility outcomes included the rates of participant enrollment, retention in the study, and continuing treatment after study completion. Efficacy outcomes were the change in daily alcohol consumption (drinks per day; 14 g ethanol per drink), measured by a 14-day timeline followback, and the change in quality of life measured with a single-item Kemp quality of life scale. RESULTS: One hundred seventy-nine patients were approached, and 32 were enrolled (18%). Of the 32 enrolled patients, 25 (78%) completed all visits, and 22 (69%) continued naltrexone after the trial. The mean baseline daily alcohol consumption was 7.6 drinks per day (interquartile range, 4.5, 13.4), and the mean quality of life was 3.6 (SD 1.7) on a 7-point scale. The median daily alcohol consumption change was -7.5 drinks per day (Hodges-Lehmann 95% confidence interval -8.6, -5.9). The mean quality of life change was 1.2 points (95% confidence interval 0.5, 1.9; P<.01). CONCLUSION: We found that initiation of treatment of alcohol use disorder with extended-release naltrexone and case management is feasible in an ED setting and observed significant reductions in drinking with improved quality of life in the short term. Multicenter randomized controlled trials are needed to further validate these findings.

A 52-Year-Old Man With Chest Pain and Dyspnea.

CASE PRESENTATION: A 52-year-old man came to the cardiac surgery clinic for pulmonary thromboendarterectomy (PTE) evaluation. He had initially appeared at an outside hospital 1 year earlier, with chest pain and shortness of breath. He had no known chronic conditions. A CT pulmonary angiogram (CTPA) at that time showed a filling defect at the bifurcation of the main pulmonary artery. A transthoracic echocardiogram revealed mild mitral valve regurgitation, but otherwise the results were normal. As he was hemodynamically stable and not hypoxemic, he was treated solely by anticoagulation. Despite adhering to prescribed apixaban, he developed progressive dyspnea and reduced exercise tolerance over the subsequent year. A repeat CTPA performed 12 months after the initial presentation showed a persistent filling defect at the level of the pulmonary artery bifurcation, with a new extension now completely occluding the right main pulmonary artery. A pulmonary angiogram confirmed this complete occlusion, and right heart catheterization revealed precapillary pulmonary hypertension, with a mean pulmonary artery pressure of 50 mm Hg. His anticoagulation was transitioned to enoxaparin for presumed apixaban treatment failure, and an investigation for hypercoagulable conditions was initiated. His lupus anticoagulant test result was positive, but he did not meet the criteria for antiphospholipid syndrome because he was negative for anticardiolipin and ß2-glycoprotein antibodies. Assays for antithrombin III, protein C, prothrombin gene, and factor V Leiden mutations produced normal results.

SARS COV-2 anti-nucleocapsid and anti-spike antibodies in an emergency department healthcare worker cohort: September 2020 - April 2021.

BACKGROUND: Emergency department (ED) workers have an increased seroprevalence of SARS-CoV-2 antibodies. However, breakthrough infections in ED workers have led to a reduced workforce within a strained healthcare system. By measuring levels of IgG antibodies to the SARS-CoV-2 nucleocapsid and spike antigens in ED workers, we determined the incidence of infection and described the course of antibody levels. We also measured the antibody response to vaccination and examined factors associated with immunogenicity. METHODS: We conducted a prospective cohort study of ED workers conducted at a single ED from September 2020-April 2021. IgG antibodies to the SARS-CoV-2 nucleocapsid antigen were measured at baseline, 3, and 6 months, and IgG antibodies to the SARS-CoV-2 spike antigen were measured at 6 months. RESULTS: At baseline, we found 5 out of 139 (3.6%) participants with prior infection. At 6 months, 4 of the 5 had antibody results below the test manufacturer's positivity threshold. We identified one incident case of SARS-COV-2 infection out of 130 seronegative participants (0.8%, 95% CI 0.02-4.2%). In 131 vaccinated participants (125 BNT162b2, 6 mRNA-1273), 131 tested positive for anti-spike antibodies. We identified predictors of anti-spike antibody levels: time since vaccination, prior COVID-19 infection, age, and vaccine type. Each additional week since vaccination was associated with an 11.1% decrease in anti-spike antibody levels. (95% CI 6.2-15.8%). CONCLUSION: ED workers experienced a low incidence of SARS-CoV-2 infection and developed antibodies in response to vaccines and prior infection. Antibody levels decreased markedly with time since infection or vaccination.

In COVID-19 Patients Who Suffer In-Hospital Cardiac Arrest, Cardiopulmonary Resuscitation Outcomes May Be Impacted by Arrest Etiology and Local Pandemic Conditions.

OBJECTIVES: The utility and risks to providers of performing cardiopulmonary resuscitation after in-hospital cardiac arrest in COVID-19 patients have been questioned. Additionally, there are discrepancies in reported COVID-19 in-hospital cardiac arrest survival rates. We describe outcomes after cardiopulmonary resuscitation for in-hospital cardiac arrest in two COVID-19 patient cohorts. DESIGN: Retrospective cohort study. SETTING: New York-Presbyterian Hospital/Columbia University Irving Medical Center in New York, NY. PATIENTS: Those admitted with COVID-19 between March 1, 2020, and May 31, 2020, as well as between March 1, 2021, and May 31, 2021, who received resuscitation after in-hospital cardiac arrest. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Among 103 patients with coronavirus disease 2019 who were resuscitated after in-hospital cardiac arrest in spring 2020, most self-identified as Hispanic/Latino or African American, 35 (34.0%) had return of spontaneous circulation for at least 20 minutes, and 15 (14.6%) survived to 30 days post-arrest. Compared with nonsurvivors, 30-day survivors experienced in-hospital cardiac arrest later (day 22 vs day 7; p = 0.008) and were more likely to have had an acute respiratory event preceding in-hospital cardiac arrest (93.3% vs 27.3%; p < 0.001). Among 30-day survivors, 11 (73.3%) survived to hospital discharge, at which point 8 (72.7%) had Cerebral Performance Category scores of 1 or 2. Among 26 COVID-19 patients resuscitated after in-hospital cardiac arrest in spring 2021, 15 (57.7%) had return of spontaneous circulation for at least 20 minutes, 3 (11.5%) survived to 30 days post in-hospital cardiac arrest, and 2 (7.7%) survived to hospital discharge, both with Cerebral Performance Category scores of 2 or less. Those who survived to 30 days post in-hospital cardiac arrest were younger (46.3 vs 67.8; p = 0.03), but otherwise there were no significant differences between groups. CONCLUSIONS: Patients with COVID-19 who received cardiopulmonary resuscitation after in-hospital cardiac arrest had low survival rates. Our findings additionally show return of spontaneous circulation rates in these patients may be impacted by hospital strain and that patients with in-hospital cardiac arrest preceded by acute respiratory events might be more likely to survive to 30 days, suggesting Advanced Cardiac Life Support efforts may be more successful in this subpopulation.

Effect of extended-release naltrexone on alcohol consumption: a systematic review and meta-analysis.

AIMS: The aims of this study were to (1) estimate the effect of extended-release naltrexone compared with placebo on alcohol consumption in patients with alcohol use disorder (AUD) and (2) conduct pre-planned subgroup analyses to test whether being abstinent when initiating treatment (lead-in abstinence) or the duration of treatment improves treatment efficacy. DESIGN: Systematic review and random-effects meta-analysis of blinded randomized placebo-controlled trials reporting the effect extended-release naltrexone on alcohol consumption. SETTING: Outpatient clinics. PARTICIPANTS: Seven trials evaluating a total of 1500 adults with AUD receiving monthly injections of either placebo or extended-release naltrexone at doses of 150-400 mg for 2-6 months and some form of behavioral therapy. MEASUREMENTS: Pooled weighted mean difference (WMD) in drinking days per month and heavy drinking days per month. FINDINGS: The WMD was -2.0 [95% confidence interval (CI) = -3.4, -0.6; P = 0.03] in favor of extended-release naltrexone for drinking days per month and -1.2 (95% CI = -0.2, -2.1; P = 0.02) for heavy drinking days per month, indicating that treatment resulted in two fewer drinking days per month and 1.2 fewer heavy drinking days per month compared with placebo. Trials not requiring lead-in abstinence and those lasting longer than 3 months reported larger reductions in heavy drinking days per month; WMD -2.0 (95% CI = -3.52, -0.48; P = 0.01) and -1.9 (95% CI = -3.2, -0.5; P = 0.01), respectively. In all cases, the I2 statistics (0-7.2%) did not suggest substantial heterogeneity. CONCLUSIONS: Extended-release naltrexone reduces drinking days and heavy drinking days per month compared with placebo. Reductions are larger with a longer duration of treatment.

Return Encounters in Emergency Department Patients Treated with Phenobarbital Versus Benzodiazepines for Alcohol Withdrawal.

INTRODUCTION: Phenobarbital has been successfully used in the emergency department (ED) to manage symptoms of alcohol withdrawal, but few studies have reported outcomes for ED patients who receive phenobarbital and are discharged. We compared return encounter rates in discharged ED patients with alcohol withdrawal who were treated with benzodiazepines and phenobarbital. METHODS: This is a retrospective cohort study conducted at a single academic medical center utilizing chart review of discharged ED patients with alcohol withdrawal from July 1, 2016, to June 30, 2019. Patients were stratified according to ED management with benzodiazepines, phenobarbital, or a combination of both agents. The primary outcome was return ED encounter within three days of the index ED encounter. Multivariate logistic regression identified significant covariates of an ED return encounter. RESULTS: Of 470 patients who were discharged with the diagnosis of alcohol withdrawal, 235 were treated with benzodiazepines, 133 with phenobarbital, and 102 with a combination of both. Baseline characteristics were similar among the groups. However, patients who received phenobarbital were provided significantly more lorazepam equivalents compared to patients who received benzodiazepines alone. Treatment with phenobarbital, alone or in combination with benzodiazepines, was associated with significantly lower odds of a return ED visit within three days compared with benzodiazepines alone [AOR 0.45 (95% CI 0.23, 0.88) p = 0.02 and AOR 0.33 (95% CI 0.15, 0.74) p = 0.007]. CONCLUSIONS: Patients who received phenobarbital for alcohol withdrawal were less likely to return to the ED within three days of the index encounter. Despite similar baseline characteristics, patients who received phenobarbital, with or without benzodiazepines, were provided greater lorazepam equivalents the ED.

Deep learning of contagion dynamics on complex networks.

Forecasting the evolution of contagion dynamics is still an open problem to which mechanistic models only offer a partial answer. To remain mathematically or computationally tractable, these models must rely on simplifying assumptions, thereby limiting the quantitative accuracy of their predictions and the complexity of the dynamics they can model. Here, we propose a complementary approach based on deep learning where effective local mechanisms governing a dynamic on a network are learned from time series data. Our graph neural network architecture makes very few assumptions about the dynamics, and we demonstrate its accuracy using different contagion dynamics of increasing complexity. By allowing simulations on arbitrary network structures, our approach makes it possible to explore the properties of the learned dynamics beyond the training data. Finally, we illustrate the applicability of our approach using real data of the COVID-19 outbreak in Spain. Our results demonstrate how deep learning offers a new and complementary perspective to build effective models of contagion dynamics on networks.

GLUT5 (SLC2A5) enables fructose-mediated proliferation independent of ketohexokinase.

BACKGROUND: Fructose is an abundant source of carbon and energy for cells to use for metabolism, but only certain cell types use fructose to proliferate. Tumor cells that acquire the ability to metabolize fructose have a fitness advantage over their neighboring cells, but the proteins that mediate fructose metabolism in this context are unknown. Here, we investigated the determinants of fructose-mediated cell proliferation. METHODS: Live cell imaging and crystal violet assays were used to characterize the ability of several cell lines (RKO, H508, HepG2, Huh7, HEK293T (293T), A172, U118-MG, U87, MCF-7, MDA-MB-468, PC3, DLD1 HCT116, and 22RV1) to proliferate in fructose (i.e., the fructolytic ability). Fructose metabolism gene expression was determined by RT-qPCR and western blot for each cell line. A positive selection approach was used to "train" non-fructolytic PC3 cells to utilize fructose for proliferation. RNA-seq was performed on parental and trained PC3 cells to find key transcripts associated with fructolytic ability. A CRISPR-cas9 plasmid containing KHK-specific sgRNA was transfected in 293T cells to generate KHK-/- cells. Lentiviral transduction was used to overexpress empty vector, KHK, or GLUT5 in cells. Metabolic profiling was done with seahorse metabolic flux analysis as well as LC/MS metabolomics. Cell Titer Glo was used to determine cell sensitivity to 2-deoxyglucose in media containing either fructose or glucose. RESULTS: We found that neither the tissue of origin nor expression level of any single gene related to fructose catabolism determine the fructolytic ability. However, cells cultured chronically in fructose can develop fructolytic ability. SLC2A5, encoding the fructose transporter, GLUT5, was specifically upregulated in these cells. Overexpression of GLUT5 in non-fructolytic cells enabled growth in fructose-containing media across cells of different origins. GLUT5 permitted fructose to flux through glycolysis using hexokinase (HK) and not ketohexokinase (KHK). CONCLUSIONS: We show that GLUT5 is a robust and generalizable driver of fructose-dependent cell proliferation. This indicates that fructose uptake is the limiting factor for fructose-mediated cell proliferation. We further demonstrate that cellular proliferation with fructose is independent of KHK.

Impact of a Critical Care Specialist Intervention on First Pass Success for Emergency Airway Management Outside the ICU.

BACKGROUND: There has been limited investigation into the procedural outcomes of patients undergoing emergent endotracheal intubation (EEI) by a critical care medicine (CCM) specialist outside the intensive care unit (ICU). We hypothesized that EEI outside an ICU would be associated with lower rates of first pass success (FPS) as compared to inside an ICU. METHODS: We performed a retrospective cohort study of all adult patients admitted to our academic medical center between January 1, 2016, and July 31, 2018, who underwent EEI by a CCM practitioner. The primary outcome of FPS was identified in the EEI procedure note. Secondary outcomes included difficult intubation (> 2 attempts at laryngoscopy) and mortality following EEI. RESULTS: In total, 1958 patients (1035 [52.9%] inside ICU and 923 [47.1%]) outside an ICU) were included in the final cohort. Unadjusted rate of FPS was not different between patients intubated out of the ICU and patients intubated inside of the ICU (689 [74.7%] vs 775 [74.9%]; P = .91). There was also no difference in FPS between groups after adjusting for predictors of difficult intubation and baseline covariates (odds ratio: 0.95; 95% confidence interval, 0.75-1.2, P = .65). Mortality of patients undergoing EEI out of the ICU was higher at each examined time interval following EEI. DISCUSSION: For EEI done by CCM practitioners, rate of FPS is not different between patients undergoing EEI outside an ICU as compared to inside an ICU. Despite the lack of difference between rates of procedural success, patient mortality following EEI outside an ICU is higher than EEI inside an ICU at all examined time points during hospitalization.

Transradial access in acute myocardial infarction complicated by cardiogenic shock: Stratified analysis by shock severity.

BACKGROUND: Transradial access (TRA) is associated with improved survival and reduced vascular complications in acute myocardial infarction (AMI). Limited data exist regarding TRA utilization and outcomes for AMI complicated by cardiogenic shock (CS). We sought to assess the safety, feasibility, and clinical outcomes of TRA in AMI-CS. METHODS: One-hundred and fifty-three patients with AMI-CS were stratified into tertiles of disease severity using the CardShock score. The primary endpoint was successful percutaneous coronary intervention (PCI), defined as Thrombolysis in Myocardial Infarction III flow with survival to 30 days. RESULTS: Mean age was 66 years, 72% were men, and 47% had diabetes. TRA was the preferred access site in patients with low and intermediate disease severity. Overall, 50 (32%) patients experienced major adverse cardiac and cerebrovascular events; most events (78%) occurred in patients undergoing transfemoral access (TFA) in the intermediate-high tertiles of CS severity. Of the 41 (27%) total bleeding events, 32% occurred at the coronary angiography access site, of which 92% were in the TFA group. The use of ultrasound (US) guidance for TFA resulted in reduced coronary access-site bleeding (8.5 vs. 33.0%, p = .01). In a hierarchical logistic regression model, utilizing TRA did not result in lower odds of successful PCI (Odds ratio [OR]: 1.36; 95% confidence interval [CI]: 0.54-3.40). CONCLUSION: This study suggests that TRA is feasible across the entire spectrum of AMI-CS and is associated with reduced coronary access-site bleeding. In addition, US-guided TFA is associated with reductions in access-site bleeding and vascular complications. Concerted efforts should be made to incorporate vascular access protocols into existing CS algorithms in dedicated shock care centers.

Network comparison and the within-ensemble graph distance.

Quantifying the differences between networks is a challenging and ever-present problem in network science. In recent years, a multitude of diverse, ad hoc solutions to this problem have been introduced. Here, we propose that simple and well-understood ensembles of random networks-such as Erdos-Rényi graphs, random geometric graphs, Watts-Strogatz graphs, the configuration model and preferential attachment networks-are natural benchmarks for network comparison methods. Moreover, we show that the expected distance between two networks independently sampled from a generative model is a useful property that encapsulates many key features of that model. To illustrate our results, we calculate this within-ensemble graph distance and related quantities for classic network models (and several parameterizations thereof) using 20 distance measures commonly used to compare graphs. The within-ensemble graph distance provides a new framework for developers of graph distances to better understand their creations and for practitioners to better choose an appropriate tool for their particular task.

Association Between Methamphetamine Use and Psychiatric Hospitalization, Chemical Restraint, and Emergency Department Length of Stay.

OBJECTIVES: Methamphetamine intoxication is an increasing cause of emergency department (ED) visits in the United States, particularly in the west. In San Francisco, California, 47% of patients visiting psychiatric emergency services are intoxicated with methamphetamine. Such patients often visit the ED due to acute psychiatric symptoms, yet ED-based research investigating the outcomes and resource utilization of these visits is limited. METHODS: We examined a retrospective cohort of ED patients requiring ED-based psychiatric consultation from June 2017 to July 2018. We evaluated the association between methamphetamine visits and need for chemical restraint, psychiatric hospitalization, and length of stay (LOS). RESULTS: We identified 2,087 ED visits with psychiatric consults. Based on urine toxicology results and discharge diagnosis, 403 visits involved methamphetamine with or without other drugs, 480 involved other drugs without methamphetamine, and 1,204 had no evidence of drug use. Methamphetamine visits were associated with increased odds of chemical restraint compared to visits without drug use (adjusted odds ratio [AOR] = 3.2, 95% CI = 2.1 to 5.2, p < 0.001), but not other drug visits (AOR = 1.2, 95% CI = 0.8 to 1.9, p = 0.4). Methamphetamine visits had lower odds of psychiatric hospitalization than other drug visits (AOR = 0.62, 95% CI = 0.41 to 0.95, p = 0.03) and longer adjusted LOS than visits without drug use (+4.3 hours, 95% CI = 4.1 to 8.3 hours, p < 0.001) but not other drug visits (+1.5 hours, 95% CI = -0.6 to 3.7 hours, p = 0.2). CONCLUSIONS: Methamphetamine ED visits were associated with increased odds of needing chemical restraint and of an increased ED LOS but not with psychiatric inpatient admission. These results indicate an opportunity to improve the efficiency of ED care for these patients.

The INPP4B Tumor Suppressor Modulates EGFR Trafficking and Promotes Triple-Negative Breast Cancer.

Inactivation of the tumor suppressor lipid phosphatase INPP4B is common in triple-negative breast cancer (TNBC). We generated a genetically engineered TNBC mouse model deficient in INPP4B. We found a dose-dependent increase in tumor incidence in INPP4B homozygous and heterozygous knockout mice compared with wild-type (WT), supporting a role for INPP4B as a tumor suppressor in TNBC. Tumors derived from INPP4B knockout mice are enriched for AKT and MEK gene signatures. Consequently, mice with INPP4B deficiency are more sensitive to PI3K or MEK inhibitors compared with WT mice. Mechanistically, we found that INPP4B deficiency increases PI(3,4)P2 levels in endocytic vesicles but not at the plasma membrane. Moreover, INPP4B loss delays degradation of EGFR and MET, while promoting recycling of receptor tyrosine kinases (RTK), thus enhancing the duration and amplitude of signaling output upon growth factor stimulation. Therefore, INPP4B inactivation in TNBC promotes tumorigenesis by modulating RTK recycling and signaling duration. SIGNIFICANCE: Inactivation of the lipid phosphatase INPP4B is frequent in TNBC. Using a genetically engineered mouse model, we show that INPP4B functions as a tumor suppressor in TNBC. INPP4B regulates RTK trafficking and degradation, such that loss of INPP4B prolongs both PI3K and ERK activation.This article is highlighted in the In This Issue feature, p. 1079.

Inferior vena cava filters do not increase the risk of blood stream infections in patients with newly diagnosed VTE.

BACKGROUND: The association between inferior vena cava (IVC) filter presence and subsequent bloodstream infection (BSI) is unknown. We hypothesized among patients with a new diagnosis of venous thromboembolism (VTE), incidence of BSI after 1 year would be higher in patients who had presence of an IVC filter. METHODS: We performed a retrospective cohort study of patients with newly diagnosed VTE but no IVC filter (N = 4,053) and patients with IVC filter (N = 635) admitted to a metropolitan hospital system from 2006 to 2009 comparing incidence of BSI within 1 year of inclusion. Multivariable regression modeling was used to evaluate the association of IVC filter placement with BSI 1 year after placement. RESULTS: Patients with an IVC filter placed were more likely to be older with higher Charlson co-morbidity score (median 4 vs 1; P < .001). The incidence of BSI was not different between the group with IVC filter and the group without (10.7% vs 8.8%; P = .12). There was no association with IVC filter placement and BSI before or after multivariable adjustment. CONCLUSIONS: In patients newly diagnosed with VTE, we found no association between IVC filter placement and increased incidence of BSI after 1 year.

Lineage Reversion Drives WNT Independence in Intestinal Cancer.

The WNT pathway is a fundamental regulator of intestinal homeostasis, and hyperactivation of WNT signaling is the major oncogenic driver in colorectal cancer. To date, there are no described mechanisms that bypass WNT dependence in intestinal tumors. Here, we show that although WNT suppression blocks tumor growth in most organoid and in vivo colorectal cancer models, the accumulation of colorectal cancer-associated genetic alterations enables drug resistance and WNT-independent growth. In intestinal epithelial cells harboring mutations in KRAS or BRAF, together with disruption of TP53 and SMAD4, transient TGFß exposure drives YAP/TAZ-dependent transcriptional reprogramming and lineage reversion. Acquisition of embryonic intestinal identity is accompanied by a permanent loss of adult intestinal lineages, and long-term WNT-independent growth. This work identifies genetic and microenvironmental factors that drive WNT inhibitor resistance, defines a new mechanism for WNT-independent colorectal cancer growth, and reveals how integration of associated genetic alterations and extracellular signals can overcome lineage-dependent oncogenic programs. SIGNIFICANCE: Colorectal and intestinal cancers are driven by mutations in the WNT pathway, and drugs aimed at suppressing WNT signaling are in active clinical development. Our study identifies a mechanism of acquired resistance to WNT inhibition and highlights a potential strategy to target those drug-resistant cells.This article is highlighted in the In This Issue feature, p. 1426.

Influenza in the emergency department: 2020 update

Emergency clinicians must be aware of the current diagnostic and therapeutic recommendations for influenza and the available resources to guide management. This comprehensive review outlines the classification of influenza viruses, influenza pathophysiology, the identification of high-risk patients, and the importance of vaccination, with an update on the 2019-2020 influenza season. Seasonal variations of influenza are discussed, as well as the rationale for limiting testing during periods of high prevalence. Differences between strains of influenza are discussed, as well as the challenges in achieving optimal vaccine effectiveness. Recommendations for use of the currently available oral, intranasal, and intravenous antiviral treatments are provided, as well as utilizing shared decision-making with patients regarding risks and benefits of treatment.