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Copyright 2014 by the article author(s).Introduction: Community-associated methicillin resistant Staphylococcus aureus (CA-MRSA) has emerged as the most common cause of skin and soft-tissue infections (SSTI) in the United States. A nearly three-fold increa

This cross-sectional analysis of 86,111 visits for sickle cell disease and vaso-occlusive episodes (VOE) in U.S. pediatric emergency departments between 2013 and 2023 shows increased use of NSAIDs, ketamine, and acetaminophen, with unchanged opioid use. Hospitals with a higher volume of VOE visits more frequently administered opioids., Background: Vaso-occlusive episodes (VOEs) are a hallmark of sickle cell disease (SCD), leading to frequent emergency department (ED) visits. Effective pain management is crucial, with guidelines recommending routine use of non-steroidal anti-inflammatory drugs (NSAIDs) with opioids, and emerging evidence supporting ketamine use. However, these recommendations are based on low-certainty evidence, and the impact of these guidelines on analgesia use over time remains unclear., Objective: This study aimed to analyze trends in analgesia use over an 11-year period in pediatric SCD patients presenting to U.S. EDs with VOE and assess variations in treatment across hospitals., Methods: A cross-sectional study was conducted using data from the Pediatric Health Information System covering 34 U.S. children's hospitals from January 1, 2013, to December 31, 2023. The primary outcomes were the proportions of visits where opioids, NSAIDs, acetaminophen, and/or ketamine were administered on the first calendar day of the initial visit. Secondary outcomes included the co-administration of NSAIDs with opioids. Logistic and linear regression models were used to assess trends and hospital-level variations., Results: A total of 86,111 ED visits for VOE were analyzed. Opioids were administered in 82 % of encounters, NSAIDs in 72 %, acetaminophen in 17 %, and ketamine in 1 %. Co-administration of NSAIDs with opioids occurred in 59 % of the visits. Among discharged patients, there was a positive trend for NSAID use (slope: 1.68 %/year, 95 % CI: 0.91 %, 2.45 %) and NSAID-opioid co-administration (slope: 1.03 %/year, 95 % CI: 0.37 %, 1.69 %) over time. Acetaminophen use also increased over the study period (slope: 0.99 %/year, 95 % CI: 0.80 %, 1.17 %). In hospitalized patients, there was a significant upward trend for acetaminophen (slope: 1.29 %/year, 95 % CI: 0.69 %, 1.89 %) and ketamine (slope: 0.36 %/year, 95 % CI: 0.27 %, 0.45 %), while opioid use remained unchanged. Significant hospital-level variations were observed, with larger hospitals more likely to administer opioids but less likely to co-administer NSAIDs with opioids compared to medium-volume hospitals., Conclusion: Over the past decade, the use of NSAIDs, acetaminophen, and ketamine has increased in the management of VOE in pediatric SCD patients, while opioid use remains consistent. The co-administration of NSAIDs and opioids has also increased, reflecting guideline adherence. Variations in analgesia practices across hospitals underscore the need for standardizing pain management strategies in this population., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Importance: Although a viral etiology can be detected in most cases of pediatric pneumonia, antibiotic treatment is common. The effectiveness of antibiotics in the outpatient setting for children diagnosed with pneumonia is not known., Objective: To compare outcomes among children diagnosed with pneumonia who were and were not treated with oral antibiotics., Design, Setting, and Participants: This retrospective cohort study identified Medicaid-insured children and adolescents 17 years or younger diagnosed with pneumonia and discharged from ambulatory settings in a multistate claims database from January 1, 2017, to December 31, 2019. Propensity score matching was used to mitigate confounding. Data were analyzed from August 31, 2023, to August 16, 2024., Exposures: Antibiotic receipt, defined as an oral antibiotic dispensed from a pharmacy on the day of the index visit or on the subsequent day. Children who did not receive antibiotics included those who were not prescribed antibiotics and those who were prescribed antibiotics but did not fill the prescription., Main Outcomes and Measures: Treatment failure and severe outcomes within 2 to 14 days after the index visit. Treatment failure included hospitalization or ambulatory revisits for pneumonia, new antibiotic dispensation with a same-day ambulatory visit, or complicated pneumonia. Severe outcomes included hospitalization for pneumonia or complicated pneumonia., Results: Among the 103 854 children with pneumonia included in the analysis, the median age was 5 (IQR, 2-9) years, and 54 665 (52.6%) were male. Overall, 20 435 children (19.7%) did not receive an antibiotic within 1 day. The propensity score-matched analysis included 40 454 children (20 227 per group). Treatment failure occurred in 2167 children (10.7%) who did not receive antibiotics and 1766 (8.7%) who received antibiotics (risk difference, 1.98 [95% CI, 1.41-2.56] percentage points). Severe outcomes occurred in 234 of 20 435 children (1.1%) who did not receive antibiotics and in 133 of 83 419 (0.7%) who did (risk difference, 0.46 [95% CI, 0.28-0.64] percentage points)., Conclusions and Relevance: In this cohort study of children diagnosed with pneumonia in ambulatory settings, almost 20% did not receive antibiotics within a day of diagnosis. Although not receiving antibiotics was associated with a small increase in the risk of treatment failure, severe outcomes were uncommon regardless of whether antibiotics were received. These results suggest that some children diagnosed with pneumonia can likely be managed without antibiotics and highlight the need for prospective studies to identify these children.

Study Objective: The workload of clinical documentation contributes to health care costs and professional burnout. The advent of generative artificial intelligence language models presents a promising solution. The perspective of clinicians may contribute to effective and responsible implementation of such tools. This study sought to evaluate 3 uses for generative artificial intelligence for clinical documentation in pediatric emergency medicine, measuring time savings, effort reduction, and physician attitudes and identifying potential risks and barriers., Methods: This mixed-methods study was performed with 10 pediatric emergency medicine attending physicians from a single pediatric emergency department. Participants were asked to write a supervisory note for 4 clinical scenarios, with varying levels of complexity, twice without any assistance and twice with the assistance of ChatGPT Version 4.0. Participants evaluated 2 additional ChatGPT-generated clinical summaries: a structured handoff and a visit summary for a family written at an 8th grade reading level. Finally, a semistructured interview was performed to assess physicians' perspective on the use of ChatGPT in pediatric emergency medicine. Main outcomes and measures included between subjects' comparisons of the effort and time taken to complete the supervisory note with and without ChatGPT assistance. Effort was measured using a self-reported Likert scale of 0 to 10. Physicians' scoring of and attitude toward the ChatGPT-generated summaries were measured using a 0 to 10 Likert scale and open-ended questions. Summaries were scored for completeness, accuracy, efficiency, readability, and overall satisfaction. A thematic analysis was performed to analyze the content of the open-ended questions and to identify key themes., Results: ChatGPT yielded a 40% reduction in time and a 33% decrease in effort for supervisory notes in intricate cases, with no discernible effect on simpler notes. ChatGPT-generated summaries for structured handoffs and family letters were highly rated, ranging from 7.0 to 9.0 out of 10, and most participants favored their inclusion in clinical practice. However, there were several critical reservations, out of which a set of general recommendations for applying ChatGPT to clinical summaries was formulated., Conclusion: Pediatric emergency medicine attendings in our study perceived that ChatGPT can deliver high-quality summaries while saving time and effort in many scenarios, but not all., (Copyright © 2024 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Emerging evidence suggests that initial oral and intravenous (IV) antibiotics have similar efficacy in pediatric community-acquired pneumonia (CAP), but further data are needed., Objective: We determined the association between hospital-level initial oral antibiotic rates and outcomes in pediatric CAP., Designs, Settings, and Participants: This retrospective cohort study included children hospitalized with CAP at 43 hospitals in the Pediatric Health Information System (2016-2022). Hospitals were grouped by whether initial antibiotics were given orally in a high, moderate, or low proportion of patients., Main Outcome and Measures: Regression models examined associations between high versus low oral-utilizing hospitals and length of stay (LOS, primary outcome), intensive care unit (ICU) transfers, escalated respiratory care, complicated CAP, cost, readmissions, and emergency department (ED) revisits., Results: Initial oral antibiotics were used in 16% (interquartile range: 10%-20%) of 30,207 encounters, ranging from 1% to 68% across hospitals. Comparing high versus low oral-utilizing hospitals (oral rate: 32% [27%-47%] and 10% [9%-11%], respectively), there were no differences in LOS, intensive care unit, complicated CAP, cost, or ED revisits. Escalated respiratory care occurred in 1.3% and 0.5% of high and low oral-utilizing hospitals, respectively (relative ratio [RR]: 2.96 [1.12, 7.81]), and readmissions occurred in 1.5% and 0.8% (RR: 1.68 [1.31, 2.17]). Initial oral antibiotics varied across hospitals without a difference in LOS. While high oral-utilizing hospitals had higher escalated respiratory care and readmission rates, these were rare, the clinical significance of these small differences is uncertain, and there were no differences in other clinically relevant outcomes. This suggests some children may benefit from initial IV antibiotics, but most would probably do well with oral antibiotics., (© 2024 Society of Hospital Medicine.)

Necroptosis is a programmed lytic cell death involving active cytokine production and plasma membrane rupture through distinct signaling cascades. However, it remains challenging to delineate this inflammatory cell death pathway at specific signaling nodes with spatiotemporal accuracy. To address this challenge, we developed an optogenetic system, termed Light-activatable Receptor-Interacting Protein Kinase 3 or La-RIPK3, to enable ligand-free, optical induction of RIPK3 oligomerization. La-RIPK3 activation dissects RIPK3-centric lytic cell death through the induction of RIPK3-containing necrosome, which mediates cytokine production and plasma membrane rupture. Bulk RNA-Seq analysis reveals that RIPK3 oligomerization results in partially overlapped gene expression compared to pharmacological induction of necroptosis. Additionally, La-RIPK3 activates separated groups of genes regulated by RIPK3 kinase-dependent and -independent processes. Using patterned light stimulation delivered by a spatial light modulator, we demonstrate precise spatiotemporal control of necroptosis in La-RIPK3-transduced HT-29 cells. Optogenetic control of proinflammatory lytic cell death could lead to the development of innovative experimental strategies to finetune the immune landscape for disease intervention., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Although characteristics of preventable hospitalizations for ambulatory care-sensitive conditions (ACSCs) have been described, less is known about patterns of emergency and other acute care utilization for ACSCs among children who are not hospitalized. We sought to describe patterns of utilization for ACSCs according to the initial site of care and to determine characteristics associated with seeking initial care in an acute care setting rather than in an office. A better understanding of the sequence of health care utilization for ACSCs may inform efforts to shift care for these common conditions to the medical home., Methods: We performed a retrospective analysis of pediatric encounters for ACSCs between 2017 and 2019 using data from the IBM Watson MarketScan Medicaid database. The database includes insurance claims for Medicaid-insured children in 10 anonymized states. We assessed the initial sites of care for ACSC encounters, which were defined as either acute care settings (emergency or urgent care) or office-based settings. We used generalized estimating equations clustered on patient to identify associations between encounter characteristics and the initial site of care., Results: Among 7,128,515 encounters for ACSCs, acute care settings were the initial site of care in 27.9%. Diagnoses with the greatest proportion of episodes presenting to acute care settings were urinary tract infection (52.0% of episodes) and pneumonia (44.6%). Encounters on the weekend (adjusted odds ratio [aOR] 6.30, 95% confidence interval [CI] 6.27-6.34 compared with weekday) and among children with capitated insurance (aOR 1.55, 95% CI 1.54-1.56 compared with fee for service) were associated with increased odds of seeking care first in an acute care setting., Conclusions: Acute care settings are the initial sites of care for more than one in four encounters for ACSCs among publicly insured children. Expanded access to primary care on weekends may shift care for ACSCs to the medical home., (© 2024 Society for Academic Emergency Medicine.)

We compared antibiotic prescribing rates for respiratory conditions in a national sample of outpatient visits from 2010 to 2018 between physicians and advanced practice clinicians (APCs). APCs prescribed antibiotics more frequently than physicians (58% vs 52%), but there were no differences in selection of guideline recommended first-line agents between specialties.

Background: Incomplete uptake of guidelines can lead to nonstandardized care, increased expenditures, and adverse clinical outcomes. The objective of this study was to evaluate the impact of the 2011 Pediatric Infectious Diseases Society and Infectious Diseases Society of America (PIDS/IDSA) pediatric community-acquired pneumonia (CAP) guideline that emphasized aminopenicillin use and de-emphasized the use of chest radiographs (CXRs) in certain populations., Methods: This quasi-experimental study queried a national administrative database of children's hospitals to identify children aged 3 months-18 years with CAP who visited 1 of 28 participating hospitals from 2009 to 2021. PIDS/IDSA pediatric CAP guideline recommendations regarding antibiotic therapy, diagnostic testing, and imaging were evaluated. Segmented regression interrupted time series was used to measure guideline-concordant practices with interruptions for guideline publication and the Coronavirus Disease 2019 (COVID-19) pandemic., Results: Of 315 384 children with CAP, 71 804 (22.8%) were hospitalized. Among hospitalized children, there was a decrease in blood culture performance (0.5% per quarter) and increase in aminopenicillin prescribing (1.1% per quarter). Among children discharged from the emergency department (ED), there was an increase in aminopenicillin prescription (0.45% per quarter), whereas the rate of obtaining CXRs declined (0.12% per quarter). However, use of CXRs rebounded during the COVID-19 pandemic (increase of 1.56% per quarter). Hospital length of stay, ED revisit rates, and hospital readmission rates remained stable., Conclusions: Guideline publication was associated with an increase of aminopenicillin prescribing. However, rates of diagnostic testing did not materially change, suggesting the need to consider implementation strategies to meaningfully change clinical practice for children with CAP., Competing Interests: Potential conflicts of interest. L. A.'s institution receives funding from Pfizer Inc on her behalf for an unrelated study and also reports support from the National Institute of Allergy and Infectious Diseases, unrelated to this work (grant numbers K01AI125413 and R21AI154239). D. J. S. reports a grant or contract from the Agency for Healthcare Quality and Research, unrelated to this work (T32HS000063-28). J. C. reports grants or contracts unrelated to this work from Pfizer Inc. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: We aimed to compare the prescribing patterns of preventive medications between pediatric and adult neurologists for young adults with migraine., Background: Although preventive medications are effective for adults with migraine, studies in children have failed to demonstrate similar efficacy. As a result, lifestyle modifications and non-pharmacological interventions are often emphasized in children. It is not known whether young adults are prescribed preventive medications at different rates according to whether they are cared for by an adult or pediatric neurologist., Methods: We performed a multicenter retrospective cohort analysis of patients with migraine aged 18-25 years who were seen by a pediatric or adult neurologist at Mass General Brigham Hospital between 2017 and 2021. The primary outcome was whether the patient received a prescription for any preventive medication during the study period., Results: Among the 767 included patients, 290 (37.8%) were seen by a pediatric neurologist. Preventive medications were prescribed for 131/290 (45.2%; 95% confidence interval [CI]: 39.5%, 51.0%) patients seen by a pediatric neurologist and 206/477 (43.2%; 95% CI: 39.0%, 47.7%) patients seen by an adult neurologist (p = 0.591). In the mixed effects logistic regression model, clinician specialty was not associated with preventive medication use (adjusted odds ratio [AOR] 1.20, 95% CI: 0.62, 2.31). Female sex (AOR 1.69, 95% CI: 1.07, 2.66) and number of visits during the study period (AOR 1.64, 95% CI: 1.49, 1.80) were associated with receiving preventive medication., Conclusion: Approximately two fifths of young adults with migraine were prescribed preventive medications, and this proportion did not differ according to clinician specialty. Although these findings suggest that pediatric and adult neurologists provide comparable care, both specialties may be underusing preventive medications in this patient population., (© 2023 The Authors. Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

Several emerging therapies kill cancer cells primarily by inducing necrosis. As necrosis activates immune cells, potentially, uncovering the molecular drivers of anticancer therapy-induced necrosis could reveal approaches for enhancing immunotherapy efficacy. To identify necrosis-associated genes, we performed a genome-wide CRISPR-Cas9 screen with negative selection against necrosis-inducing preclinical agents BHPI and conducted follow-on experiments with ErSO. The screen identified transient receptor potential melastatin member 4 (TRPM4), a calcium-activated, ATP-inhibited, sodium-selective plasma membrane channel. Cancer cells selected for resistance to BHPI and ErSO exhibited robust TRPM4 downregulation, and TRPM4 reexpression restored sensitivity to ErSO. Notably, TRPM4 knockout (TKO) abolished ErSO-induced regression of breast tumors in mice. Supporting a broad role for TRPM4 in necrosis, knockout of TRPM4 reversed cell death induced by four additional diverse necrosis-inducing cancer therapies. ErSO induced anticipatory unfolded protein response (a-UPR) hyperactivation, long-term necrotic cell death, and release of damage-associated molecular patterns that activated macrophages and increased monocyte migration, all of which was abolished by TKO. Furthermore, loss of TRPM4 suppressed the ErSO-induced increase in cell volume and depletion of ATP. These data suggest that ErSO triggers initial activation of the a-UPR but that it is TRPM4-mediated sodium influx and cell swelling, resulting in osmotic stress, which sustains and propagates lethal a-UPR hyperactivation. Thus, TRPM4 plays a pivotal role in sustaining lethal a-UPR hyperactivation that mediates the anticancer activity of diverse necrosis-inducing therapies., Significance: A genome-wide CRISPR screen reveals a pivotal role for TRPM4 in cell death and immune activation following treatment with diverse necrosis-inducing anticancer therapies, which could facilitate development of necrosis-based cancer immunotherapies., (©2023 American Association for Cancer Research.)

Background: While children discharged from the emergency department (ED) are frequently advised to follow up with ambulatory care providers, the extent to which this occurs is unknown. We sought to characterize the proportion of publicly insured children who have an ambulatory visit following ED discharge, identify factors associated with ambulatory follow-up, and evaluate the association of ambulatory follow-up with subsequent hospital-based health care utilization., Methods: We performed a cross-sectional study of pediatric (<18 years) encounters during 2019 included in the IBM Watson Medicaid MarketScan claims database from seven U.S. states. Our primary outcome was an ambulatory follow-up visit within 7 days of ED discharge. Secondary outcomes were 7-day ED return visits and hospitalizations. Logistic regression and Cox proportional hazards were used for multivariable modeling., Results: We included 1,408,406 index ED encounters (median age 5 years, IQR 2-10 years), for which a 7-day ambulatory visit occurred in 280,602 (19.9%). Conditions with the highest proportion of 7-day ambulatory follow-up included seizures (36.4%); allergic, immunologic, and rheumatologic diseases (24.6%); other gastrointestinal diseases (24.5%); and fever (24.1%). Ambulatory follow-up was associated with younger age, Hispanic ethnicity, weekend ED discharge, ambulatory encounters prior to the ED visit, and diagnostic testing performed during the ED encounter. Ambulatory follow-up was inversely associated with Black race and ambulatory care-sensitive or complex chronic conditions. In Cox models, ambulatory follow-up was associated with a higher hazard ratio (HR) of subsequent ED return (HR range 1.32-1.65) visit and hospitalization (HR range 3.10-4.03)., Conclusions: One-fifth of children discharged from the ED have an ambulatory visit within 7 days, which varied by patient characteristics and diagnoses. Children with ambulatory follow-up have a greater subsequent health care utilization, including subsequent ED visit and/or hospitalization. These findings identify the need to further research the role and costs associated with routine post-ED visit follow-up., (© 2023 The Authors. Academic Emergency Medicine published by Wiley Periodicals LLC on behalf of Society for Academic Emergency Medicine.)

Background: Limited data exist to inform antibiotic selection among people with cystic fibrosis (CF) with airway infection by multiple CF-related microorganisms. This study aimed to determine among children with CF co-infected with methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (Pa) if the addition of anti-MRSA antibiotics to antipseudomonal antibiotic treatment for pulmonary exacerbations (PEx) would be associated with improved clinical outcomes compared with antipseudomonal antibiotics alone., Methods: Retrospective cohort study using data from the CF Foundation Patient Registry-Pediatric Health Information System linked dataset. The odds of returning to baseline lung function and having a subsequent PEx requiring intravenous antibiotics were compared between PEx treated with anti-MRSA and antipseudomonal antibiotics and those treated with antipseudomonal antibiotics alone, adjusting for confounding by indication using inverse probability of treatment weighting., Results: 943 children with CF co-infected with MRSA and Pa contributed 2,989 PEx for analysis. Of these, 2,331 (78%) PEx were treated with both anti-MRSA and antipseudomonal antibiotics and 658 (22%) PEx were treated with antipseudomonal antibiotics alone. Compared with PEx treated with antipseudomonal antibiotics alone, the addition of anti-MRSA antibiotics to antipseudomonal antibiotic therapy was not associated with a higher odds of returning to ≥90% or ≥100% of baseline lung function or a lower odds of future PEx requiring intravenous antibiotics., Conclusions: Children with CF co-infected with MRSA and Pa may not benefit from the addition of anti-MRSA antibiotics for PEx treatment. Prospective studies evaluating optimal antibiotic selection strategies for PEx treatment are needed to optimize clinical outcomes following PEx treatment., Competing Interests: Declaration of Competing Interest Drs. Cogen and Ms. Faino received support from the Cystic Fibrosis Foundation (COGEN19A0) Dr. Gibson received support from the Cystic Fibrosis Foundation (GIBSON1R0) Drs. Hall, Ambroggio, Blaschke, Brogan, Cotter, Grijalva, Hersh, Lipsett, Shah, Shapiro, Neuman and Gerber have nothing to disclose at it relates to this manuscript., (Copyright © 2022 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Despite the increased availability of diagnostic tests for respiratory viruses, their clinical utility for children with community-acquired pneumonia (CAP) remains uncertain., Objective: To identify patterns of respiratory virus testing across children's hospitals prior to the COVID-19 pandemic and to determine whether hospital-level rates of viral testing were associated with clinical outcomes., Design, Setting, and Participants: Multicenter retrospective cohort study of children hospitalized for CAP at 19 children's hospitals in the United States from 2010-2019., Main Outcomes and Measures: Using a novel method to identify the performance of viral testing, we assessed time trends in the use of viral tests, both overall and stratified by testing method. Adjusted proportions of encounters with viral testing were compared across hospitals and were correlated with length of stay, antibiotic and oseltamivir use, and performance of ancillary laboratory testing., Results: There were 46,038 hospitalizations for non-severe CAP among children without complex chronic conditions. The proportion with viral testing increased from 38.8% to 44.2% during the study period (p < .001). Molecular testing increased (27.2% to 40.0%, p < .001) and antigen testing decreased (33.2% to 7.8%, p < .001). Hospital-specific adjusted proportions of testing ranged from 10.0% to 83.5% and were not associated with length of stay, antibiotic use, or antiviral use. Hospitals that performed more viral testing did not have lower rates of ancillary laboratory testing., Conclusions: Viral testing practices varied widely across children's hospitals and were not associated with clinically important process or outcome measures. Viral testing may not influence clinical management for many children hospitalized with CAP., (© 2022 Society of Hospital Medicine.)

Time constraints have been suggested as a potential driver of antibiotic overuse for acute respiratory tract infections. In this cross-sectional analysis of national data from visits to offices and emergency departments, we identified no statistically significant association between antibiotic prescribing and the duration of visits for acute respiratory tract infections.

Estrogen receptor-positive (ER+) metastatic tumors contribute to nearly 70% of breast cancer-related deaths. Most patients with ER+ metastatic breast cancer (MBC) undergo treatment with the estrogen receptor antagonist fulvestrant as standard of care. Yet, among such patients, metastasis in liver is associated with reduced overall survival compared with other metastasis sites. The factors underlying the reduced responsiveness of liver metastases to ER-targeting agents remain unknown, impeding the development of more effective treatment approaches to improve outcomes for patients with ER+ liver metastases. We therefore evaluated site-specific changes in MBC cells and determined the mechanisms through which the liver metastatic niche specifically influences ER+ tumor metabolism and drug resistance. We characterized ER activity of MBC cells both in vitro, using a novel system of tissue-specific extracellular matrix hydrogels representing the stroma of ER+ tumor metastatic sites (liver, lung, and bone), and in vivo, in liver and lung metastasis mouse models. ER+ metastatic liver tumors and MBC cells grown in liver hydrogels displayed upregulated expression of glucose metabolism enzymes in response to fulvestrant. Furthermore, differential ERα activity, but not expression, was detected in liver hydrogels. In vivo, increased glucose metabolism led to increased glycogen deposition in liver metastatic tumors, while a fasting-mimicking diet increased efficacy of fulvestrant treatment to reduce the metastatic burden. Our findings identify a novel mechanism of endocrine resistance driven by the liver tumor microenvironment., Implications: These results may guide the development of dietary strategies to circumvent drug resistance in liver metastasis, with potential applicability in other metastatic diseases., (©2022 American Association for Cancer Research.)

Approximately 75% of breast cancers are estrogen receptor alpha-positive (ERα+), and targeting ERα directly with ERα antagonists/degraders or indirectly with aromatase inhibitors is a successful therapeutic strategy. However, such treatments are rarely curative and development of resistance is universal. We recently reported ErSO , a compound that induces ERα-dependent cancer cell death through a mechanism distinct from clinically approved ERα drugs, via hyperactivation of the anticipatory unfolded protein response. ErSO has remarkable tumor-eradicative activity in multiple ERα+ tumor models. While ErSO has promise as a new drug, it has effects on ERα-negative (ERα-) cells in certain contexts. Herein, we construct modified versions of ErSO and identify variants with enhanced differential activity between ERα+ and ERα- cells. We report ErSO-DFP , a compound that maintains antitumor efficacy, has enhanced selectivity for ERα+ cancer cells, and is well tolerated in rodents. ErSO-DFP and related compounds represent an intriguing new class for the treatment of ERα+ cancers.

Systemic corticosteroids are not recommended to treat children with acute respiratory tract infections (ARTIs). Using data from a national commercial health care company, we found that corticosteroid treatment occurred in 3.2% of ARTI encounters. The adjusted odds of corticosteroid treatment were highest for bronchitis/bronchiolitis, in emergency departments, and in the South., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Previous research has identified ethnic differences in parents' beliefs about fever, but whether patient ethnicity is associated with health care use for fever is uncertain. Our objectives were to describe the national rate of pediatric visits to the emergency department (ED) for fever and to determine whether there is variation in this rate by patient ethnicity., Methods: Using the National Hospital Ambulatory Medical Care Survey between 2012 and 2015, we estimated the proportion of ED visits with a complaint of fever by patients 0 to 18 years old and compared this proportion across patient ethnicity. We performed multivariable logistic regression controlling for sociodemographic characteristics and visit acuity to determine whether patient ethnicity was independently associated with visits for fever., Results: Fever was the reason for 19% [95% confidence interval (CI), 18%-20%] of pediatric visits to the ED, and the proportion of visits for fever was highest among Hispanic patients (25%; 95% CI, 23%-27%) and lowest among non-Hispanic white patients (15%; 95% CI, 14%-17%). In multivariable analysis, the adjusted odds of visits for fever were greater for Hispanic patients (odds ratio, 1.56; 95% CI, 1.38-1.83) and non-Hispanic non-black patients of other races (1.34; 95% CI, 1.02-1.77) compared with non-Hispanic white patients., Conclusions: There is significant ethnic variation in the use of emergency medical services for fever in the United States, and these disparities are not fully explained by differences in the acuity of illness or differences in socioeconomic status. Interventions to empower parents to manage nonurgent pediatric fever should incorporate ethnocultural differences in parents' understanding of fever., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.)

Metastatic estrogen receptor α (ERα)-positive breast cancer is presently incurable. Seeking to target these drug-resistant cancers, we report the discovery of a compound, called ErSO, that activates the anticipatory unfolded protein response (a-UPR) and induces rapid and selective necrosis of ERα-positive breast cancer cell lines in vitro. We then tested ErSO in vivo in several preclinical orthotopic and metastasis mouse models carrying different xenografts of human breast cancer lines or patient-derived breast tumors. In multiple orthotopic models, ErSO treatment given either orally or intraperitoneally for 14 to 21 days induced tumor regression without recurrence. In a cell line tail vein metastasis model, ErSO was also effective at inducing regression of most lung, bone, and liver metastases. ErSO treatment induced almost complete regression of brain metastases in mice carrying intracranial human breast cancer cell line xenografts. Tumors that did not undergo complete regression and regrew remained sensitive to retreatment with ErSO. ErSO was well tolerated in mice, rats, and dogs at doses above those needed for therapeutic responses and had little or no effect on normal ERα-expressing murine tissues. ErSO mediated its anticancer effects through activation of the a-UPR, suggesting that activation of a tumor protective pathway could induce tumor regression., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Objective: To identify practice patterns in the duration of prescribed antibiotics for the treatment of ambulatory children with community-acquired pneumonia (CAP) and to compare the frequency of adverse clinical outcomes between children prescribed short-vs prolonged-duration antibiotics., Study Design: We performed a retrospective cohort study from 2010-2016 using the IBM Watson MarketScan Medicaid Database, a claims database of publicly insured patients from 11 states. We included children 1-18 years old with outpatient CAP who filled a prescription for oral antibiotics (n = 121 846 encounters). We used multivariable logistic regression to determine associations between the duration of prescribed antibiotics (5-9 days vs 10-14 days) and subsequent hospitalizations, new antibiotic prescriptions, and acute care visits. Outcomes were measured during the 14 days following the end of the dispensed antibiotic course., Results: The most commonly prescribed duration of antibiotics was 10 days (82.8% of prescriptions), and 10.5% of patients received short-duration therapy. During the follow-up period, 0.2% of patients were hospitalized, 6.2% filled a new antibiotic prescription, and 5.1% had an acute care visit. Compared with the prolonged-duration group, the aORs for hospitalization, new antibiotic prescriptions, and acute care visits in the short-duration group were 1.16 (95% CI 0.80-1.66), 0.93 (95% CI 0.85-1.01), and 1.06 (95% CI 0.98-1.15), respectively., Conclusions: Most children treated for CAP as outpatients are prescribed at least 10 days of antibiotic therapy. Among pediatric outpatients with CAP, no significant differences were found in rates of adverse clinical outcomes between patients prescribed short-vs prolonged-duration antibiotics., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Case Presentation: A 16-month-old boy presented with a temperature of 99°Fahrenheit (F) (down from 102°F at home after antipyretics), grunting, and tachypnea. On examination, he was tachycardic, tachypneic, and ill-appearing with abdominal distention and diffuse tenderness. A plain film abdominal radiograph showed moderate free air, and emergent laparoscopy revealed perforated Meckel's diverticulitis with peritonitis., Discussion: Although tachypnea and grunting in preverbal or nonverbal patients are often considered to be signs of respiratory illness, these findings may reflect intra-abdominal emergencies. Perforated Meckel's diverticulitis is an important differential consideration in patients with pneumoperitoneum.

The proportion of antibiotic prescriptions prescribed in US physician offices and emergency departments that were unnecessary decreased slightly, from 30% in 2010-2011 to 28% in 2014-2015. However, a greater decrease occurred in children: 32% in 2010-2011 to 19% in 2014-2015. Unnecessary prescribing in adults did not change during this period., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Breast cancer remains one of the leading causes of cancer mortality in the US. Elevated cholesterol is a major risk factor for breast cancer onset and recurrence, while cholesterol-lowering drugs, such as statins, are associated with a good prognosis. Previous work in murine models showed that cholesterol increases breast cancer metastasis, and the pro-metastatic effects of cholesterol were due to its primary metabolite, 27-hydroxycholesterol (27HC). In our prior work, myeloid cells were found to be required for the pro-metastatic effects of 27HC, but their precise contribution remains unclear. Here we report that 27HC impairs T cell expansion and cytotoxic function through its actions on myeloid cells, including macrophages, in a Liver X receptor (LXR) dependent manner. Many oxysterols and LXR ligands had similar effects on T cell expansion. Moreover, their ability to induce the LXR target gene ABCA1 was associated with their effectiveness in impairing T cell expansion. Induction of T cell apoptosis was likely one mediator of this impairment. Interestingly, the enzyme responsible for the synthesis of 27HC, CYP27A1, is highly expressed in myeloid cells, suggesting that 27HC may have important autocrine or paracrine functions in these cells, a hypothesis supported by our finding that breast cancer metastasis was reduced in mice with a myeloid specific knockout of CYP27A1. Importantly, pharmacologic inhibition of CYP27A1 reduced metastatic growth and improved the efficacy of checkpoint inhibitor, anti-PD-L1. Taken together, our work suggests that targeting the CYP27A1 axis in myeloid cells may present therapeutic benefits and improve the response rate to immune therapies in breast cancer., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Accumulation of unfolded protein, or other stresses, activates the classical reactive unfolded protein response (UPR). In the recently characterized anticipatory UPR, receptor-bound estrogen, progesterone and other mitogenic hormones rapidly elicit phosphorylation of phospholipase C γ (PLCγ), activating the anticipatory UPR. How estrogen and progesterone activating their receptors couples to PLCγ phosphorylation and anticipatory UPR activation was unknown. We show that the oncogene c-Src is a rate-limiting regulator whose tyrosine kinase activity links estrogen and progesterone activating their receptors to anticipatory UPR activation. Supporting Src coupling estrogen and progesterone to anticipatory UPR activation, we identified extranuclear complexes of estrogen receptor α (ERα):Src:PLCγ and progesterone receptor:Src:PLCγ. Moreover, Src inhibition protected cancer cells against cell death. To probe Src's role, we used the preclinical ERα biomodulator, BHPI, which kills cancer cells by inducing lethal anticipatory UPR hyperactivation. Notably, Src inhibition blocked BHPI-mediated anticipatory UPR activation and the resulting rapid increase in intracellular calcium. After unbiased long-term selection for BHPI-resistant human breast cancer cells, 4/11 BHPI-resistant T47D clones, and nearly all MCF-7 clones, exhibited reduced levels of normally growth-stimulating Src. Notably, Src overexpression by virus transduction restored sensitivity to BHPI. Furthermore, in wild type cells, several-fold knockdown of Src, but not of ERα, strongly blocked BHPI-mediated UPR activation and subsequent HMGB1 release and necrotic cell death. Thus, Src plays a previously undescribed pivotal role in activation of the tumor-protective anticipatory UPR, thereby increasing the resilience of breast cancer cells. This is a new role for Src and the anticipatory UPR in breast cancer., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: Antibiotic allergies are overdiagnosed. This may lead to unnecessary use of second-line broader-spectrum agents in place of narrower-spectrum guideline-recommended first-line therapies especially for uncomplicated respiratory tract infections. The extent to which this occurs for children with respiratory tract infections is unknown., Methods: We included outpatient encounters for patients < 18 years with acute respiratory tract infections (sinusitis, bronchitis, bronchiolitis, upper respiratory tract infection, pharyngitis, otitis media). Patients were classified as penicillin allergic based on the presence of an allergy label in the electronic medical record. First-line guideline-recommended antibiotics included penicillin, amoxicillin or amoxicillin-clavulanate; all others were considered second line. The percentage of patients treated with first-line versus second-line antibiotics was compared between those with and without penicillin allergy. Additionally, we calculated the contribution of penicillin allergy to overall use of second-line antibiotics., Results: Among 17,578 eligible encounters for respiratory tract infections, 1332 (8%) included patients with a penicillin allergy label. Overall, second-line antibiotics were prescribed in 15% of encounters. Second-line antibiotics were prescribed in 91% of encounters for penicillin-allergic patients, compared with 8% of encounters for non-allergic patients (P < 0.001). Patients with penicillin allergy labels accounted for 47% of all second-line antibiotic prescriptions., Conclusion: In a large population of pediatric outpatient encounters for acute respiratory tract infections, patients labeled with a penicillin allergy accounted for nearly half of second-line antibiotics, which are often broader spectrum. Efforts to de-label children with penicillin allergies have the potential to reduce broader-spectrum antibiotic use.

The majority of breast cancer specific deaths in women with estrogen receptor positive (ER + ) tumors occur due to metastases that are resistant to therapy. There is a critical need for novel therapeutic approaches to achieve tumor regression and/or maintain therapy responsiveness in metastatic ER + tumors. The objective of this study was to elucidate the role of metabolic pathways that undermine therapy efficacy in ER + breast cancers. Our previous studies identified Exportin 1 (XPO1), a nuclear export protein, as an important player in endocrine resistance progression and showed that combining selinexor (SEL), an FDA-approved XPO1 antagonist, synergized with endocrine agents and provided sustained tumor regression. In the current study, using a combination of transcriptomics, metabolomics and metabolic flux experiments, we identified certain mitochondrial pathways to be upregulated during endocrine resistance. When endocrine resistant cells were treated with single agents in media conditions that mimic a nutrient deprived tumor microenvironment, their glutamine dependence for continuation of mitochondrial respiration increased. The effect of glutamine was dependent on conversion of the glutamine to glutamate, and generation of NAD + . PGC1α, a key regulator of metabolism, was the main driver of the rewired metabolic phenotype. Remodeling metabolic pathways to regenerate new vulnerabilities in endocrine resistant breast tumors is novel, and our findings reveal a critical role that ERα-XPO1 crosstalk plays in reducing cancer recurrences. Combining SEL with current therapies used in clinical management of ER + metastatic breast cancer shows promise for treating and keeping these cancers responsive to therapies in already metastasized patients.

Nationally representative data from 2000-2015 demonstrated a rise in the incidence of outpatient visits for skin infections, peaking in 2010-2013, followed by a plateau. While cephalexin was the most frequently prescribed antibiotic at the beginning, trimethoprim-sulfamethoxazole was most frequently prescribed by the end of the study period., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objectives: To determine the prevalence of features of viral illness in a national sample of visits involving children tested for group A Streptococcus pharyngitis. Additionally, we sought to derive a decision rule to identify patients with features of viral illness who were at low risk of having group A Streptococcus and for whom laboratory testing might be avoided., Study Design: Retrospective validation study using data from electronic health records of patients 3-21 years old evaluated for sore throat in a national network of retail health clinics (n = 67 127). We determined the prevalence of features of viral illness in patients tested for group A Streptococcus and developed a decision tree algorithm to identify patients with features of viral illness at low risk (<15%) of having group A Streptococcus., Results: Overall, 54% of patients had features of viral illness. Among patients with features of viral illness, those without tonsillar exudates who were 11 years or older and either lacked cervical adenopathy or had cervical adenopathy and lacked fever were identified as at low risk for group A Streptococcus according to the decision rule. This group comprised 34% of patients with features of viral illness, or 19% of all patients tested for group A Streptococcus infection., Conclusions: Our findings provide an objective way to identify patients with features of viral illness who are at low risk of having group A Streptococcus. Improved identification such patients at low risk of group A Streptococcus could improve appropriate testing and antibiotic prescribing for pharyngitis., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: National guidelines published in 2011 recommend amoxicillin as first-line treatment for non-hospitalized children with community-acquired pneumonia (CAP). We aimed to understand visit rates, antibiotic selection, and factors associated with amoxicillin prescribing for children with CAP since guideline publication., Methods: We performed a cross-sectional retrospective study of patients aged 90 days-18 years with an outpatient clinic or emergency department (ED) visit from 2008 to 2015 using the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey ED data files, respectively. We estimated the incidence rates of ambulatory CAP visits, examined time trends in antibiotics prescribed at CAP visits, and determined factors independently associated with first-line guideline-recommended antibiotic prescribing using multivariable logistic regression, including patient age, setting, and US census region., Results: From 2008 to 2015, there were an estimated 1.5 million [95% confidence interval (CI) 1.3-1.7 million] pediatric CAP visits annually. Amoxicillin was prescribed in 23% (95% CI 18-30%), azithromycin was prescribed in 47% (95% CI 41-54%), and cephalosporins were prescribed in 26% (95% CI 21-31%) of antibiotic visits for CAP. There were no significant differences in annual CAP visits or prescribing by antibiotic class since guideline publication. Amoxicillin prescribing was significantly less likely in visits by older children, aged 5-18 years, [adjusted odds ratio (aOR) 0.22, 95% CI 0.10-0.49] compared to visits by younger children aged 90 days-4 years with CAP. Compared with the Northeast, amoxicillin prescribing was significantly lower in the Midwest (aOR 0.35, 95% CI 0.13-0.98) and South (aOR 0.23, 95% CI 0.08-0.63). Azithromycin prescribing was significantly more likely in visits to EDs (aOR 1.46, 95% CI 1.07-1.98) compared to physician offices., Conclusion: Despite national guideline recommendations, amoxicillin prescribing for CAP in outpatient settings is low and azithromycin remains the predominant antibiotic prescribed, highlighting the need for dedicated antibiotic stewardship efforts in ambulatory settings.

The oncofetal mRNA-binding protein, IMP1 or insulin-like growth factor-2 mRNA-binding protein 1 (IGF2BP1), promotes the overexpression of several oncogenic proteins by binding to and stabilizing their mRNAs. IMP1 is frequently overexpressed in melanoma and is associated with a poor prognosis, but the full spectrum of IMP1 target transcripts remains unknown. Here, we report the identification of protein kinase C-α (PKCα), as a novel molecular target of IMP1. Overexpression of IMP1 resulted in increased levels of PKCα, while RNAi knockdown of IMP1 resulted in decreased PKCα mRNA stability, PKCα protein levels, and MAPK/ERK activation. In addition to IMP1 acting as a positive regulator of PKCα mRNA, we also report the identification of miR-340 as a negative regulator of PKCα mRNA. In melanoma cancer cells, inhibition of miR-340 led to increased PKCα protein levels. PKCα plays important roles in numerous signaling pathways including the MAPK/ERK signaling pathway. PKCα activates RAF1, which in turn activates MEK1, and activates downstream transcriptional targets of MAPK through activation of JNK signaling. Together, these pathways provide a way to activate MAPK signaling downstream of BRAF and MEK1 inhibitors, which are commonly used to treat melanoma. Analysis of 117 melanoma tumors samples showed that overexpression of PKCα is associated with poorer overall survival. In patients harboring BRAF or NRAS mutations, PKCα overexpression is associated with an 11-fold increased risk of death. Thus, PKCα mRNA is a novel target of IMP1, which is commonly overexpressed in melanoma and is linked to poorer overall survival.

Study Objective: The frequency of antibiotic prescribing and types of antibiotics prescribed for dental conditions presenting to the emergency department (ED) is not well known. The objective of this study is to quantify how often and which dental diagnoses made in the ED resulted in an antibiotic prescription., Methods: From 2011 to 2015, there were an estimated 2.2 million (95% confidence interval [CI] 1.9 to 2.5 million) ED visits per year for dental-related conditions, which accounted for 1.6% (95% CI 1.5% to 1.7%) of ED visits. This is based on an unweighted 2,125 observations from the National Hospital Ambulatory Medical Care Survey in which a dental-related diagnosis was made., Results: An antibiotic, most often a narrow-spectrum penicillin or clindamycin, was prescribed in 65% (95% CI 61% to 68%) of ED visits with any dental diagnosis. The most common dental diagnoses for all ages were unspecified disorder of the teeth and supporting structures (44%; 95% CI 41% to 48%; International Classification of Diseases, Ninth Revision, Clinical Modification[ICD-9-CM] code 525.9), periapical abscess without sinus (21%; 95% CI 18% to 25%; ICD-9-CM code 522.5), and dental caries (18%; 95% CI 15% to 22%; ICD-9-CM code 521.0). Recommended treatments for these conditions are usually dental procedures rather than antibiotics., Conclusion: The common use of antibiotics for dental conditions in the ED may indicate the need for greater access to both preventive and urgent care from dentists and other related specialists as well as the need for clearer clinical guidance and provider education related to oral infections., (Copyright © 2018 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

: media-1vid110.1542/5972296744001PEDS-VA&#95;2018-1056 Video Abstract OBJECTIVES: To characterize and compare ambulatory antibiotic prescribing for children in US pediatric and nonpediatric emergency departments (EDs)., Methods: A cross-sectional retrospective study of patients aged 0 to 17 years discharged from EDs in the United States was conducted by using the 2009-2014 National Hospital Ambulatory Medical Care Survey ED data. We estimated the proportion of ED visits resulting in antibiotic prescriptions, stratified by antibiotic spectrum, class, diagnosis, and ED type ("pediatric" defined as >75% of visits by patients aged 0-17 years, versus "nonpediatric"). Multivariable logistic regression was used to determine factors independently associated with first-line, guideline-concordant prescribing for acute otitis media, pharyngitis, and sinusitis., Results: In 2009-2014, of the 29 million mean annual ED visits by children, 14% (95% confidence interval [CI]: 10%-20%) occurred at pediatric EDs. Antibiotics overall were prescribed more frequently in nonpediatric than pediatric ED visits (24% vs 20%, P < .01). Antibiotic prescribing frequencies were stable over time. Of all antibiotics prescribed, 44% (95% CI: 42%-45%) were broad spectrum, and 32% (95% CI: 30%-34%, 2.1 million per year) were generally not indicated. Compared with pediatric EDs, nonpediatric EDs had a higher frequency of prescribing macrolides (18% vs 8%, P < .0001) and a lower frequency of first-line, guideline-concordant prescribing for the respiratory conditions studied (77% vs 87%, P < .001)., Conclusions: Children are prescribed almost 7 million antibiotic prescriptions in EDs annually, primarily in nonpediatric EDs. Pediatric antibiotic stewardship efforts should expand to nonpediatric EDs nationwide, particularly regarding avoidance of antibiotic prescribing for conditions for which antibiotics are not indicated, reducing macrolide prescriptions, and increasing first-line, guideline-concordant prescribing., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2019 by the American Academy of Pediatrics.)

Approximately 30% of metastatic breast cancers harbor estrogen receptor α (ERα) mutations associated with resistance to endocrine therapy and reduced survival. Consistent with their constitutive proliferation, T47D and MCF7 cells in which wild-type ERα is replaced by the most common mutations, ERαY537S and ERαD538G, exhibit partially estrogen-independent gene expression. A novel invasion/dissociation/rebinding assay demonstrated that the mutant cells have a higher tendency to dissociate from invasion sites and rebind to a second site. Compared to ERαD538G breast tumors, ERαY537S tumors exhibited a dramatic increase in lung metastasis. Transcriptome analysis showed that the ERαY537S and ERαD538G mutations each elicit a unique gene expression profile. Gene set enrichment analysis showed Myc target pathways are highly induced in mutant cells. Moreover, chromatin immunoprecipitation showed constitutive, fulvestrant-resistant, recruitment of ERα mutants to the Myc enhancer region, resulting in estrogen-independent Myc overexpression in mutant cells and tumors. Knockdown and virus transduction showed Myc is necessary and sufficient for ligand-independent proliferation of the mutant cells but had no effect on metastasis-related phenotypes. Thus, Myc plays a key role in aggressive proliferation-related phenotypes exhibited by breast cancer cells expressing ERα mutations., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The endoplasmic reticulum stress sensor, the unfolded protein response (UPR), regulates intracellular protein homeostasis. While transient activation of the reactive UPR by unfolded protein is protective, prolonged and sustained activation of the reactive UPR triggers CHOP-mediated apoptosis. In the recently characterized, evolutionarily conserved anticipatory UPR, mitogenic hormones and other effectors pre-activate the UPR; how strong and sustained activation of the anticipatory UPR induces cell death was unknown. To characterize this cell death pathway, we used BHPI, a small molecule that activates the anticipatory UPR through estrogen receptor α (ERα) and induces death of ERα + cancer cells. We show that sustained activation of the anticipatory UPR by BHPI kills cells by inducing depletion of intracellular ATP, resulting in classical necrosis phenotypes, including plasma membrane disruption and leakage of intracellular contents. Unlike reactive UPR activation, BHPI-induced hyperactivation of the anticipatory UPR does not induce apoptosis or sustained autophagy. BHPI does not induce CHOP protein or PARP cleavage, and two pan-caspase inhibitors, or Bcl2 overexpression, have no effect on BHPI-induced cell death. Moreover, BHPI does not increase expression of autophagy markers, or work through recently identified programmed-necrosis pathways, such as necroptosis. Opening of endoplasmic reticulum IP 3 R calcium channels stimulates cell swelling, cPLA2 activation, and arachidonic acid release. Notably, cPLA2 activation requires ATP depletion. Importantly, blocking rapid cell swelling or production of arachidonic acid does not prevent necrotic cell death. Rapid cell death is upstream of PERK activation and protein synthesis inhibition, and results from strong and sustained activation of early steps in the anticipatory UPR. Supporting a central role for ATP depletion, reversing ATP depletion blocks rapid cell death, and the onset of necrotic cell death is correlated with ATP depletion. Necrotic cell death initiated by strong and sustained activation of the anticipatory UPR is a newly discovered role of the UPR.

Context: Limited data exist regarding uropathogen resistance in randomized controlled trials of urinary tract infection (UTI) prevention and antibiotic prophylaxis., Objective: To assess the effect of prophylaxis on developing a multidrug-resistant first recurrent UTI among children with vesicoureteral reflux., Data Sources: Cochrane Kidney and Transplant Specialized Register through May 25, 2017., Study Selection: Randomized controlled trials of patients ≤18 years of age with a history of vesicoureteral reflux being treated with continuous antibiotic prophylaxis compared with no treatment or placebo with available antibiotic sensitivity profiles., Data Extraction: Two independent observers abstracted data and assessed quality and validity per Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Adjusted meta-analyses were performed by using a mixed-effects logistic regression model., Results: One thousand two hundred and ninety-nine patients contributed 224 UTIs. Patients treated with prophylaxis were more likely to have a multidrug-resistant infection (33% vs 6%, P < .001) and were more likely to receive broad-spectrum antibiotics (68% vs 49%, P = .004). Those receiving prophylaxis had 6.4 times the odds (95% confidence interval: 2.7-15.6) of developing a multidrug-resistant infection. One multidrug-resistant infection would develop for every 21 reflux patients treated with prophylaxis., Limitations: Variables that may contribute to resistance such as medication adherence and antibiotic exposure for other illnesses could not be evaluated., Conclusions: Prophylaxis increases the risk of multidrug resistance among recurrent infections. This has important implications in the risk-benefit assessment of prophylaxis as a management strategy and in the selection of empirical treatment of breakthrough infections in prophylaxis patients., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)