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BACKGROUND: The capability of bronchoscopy in the diagnosis of peripheral pulmonary nodules (PPNs) remains limited. Despite decades of effort, evidence suggests that the diagnostic accuracy for electromagnetic navigational bronchoscopy (EMN) and radial endobronchial ultrasound (EBUS) approach only 50%. New developments in robotic bronchoscopy (RB) may offer improvements in the assessment of PPNs. METHODS: A prospective single-blinded randomized controlled comparative study to assess success in localization and puncture of PPNs, using an ultrathin bronchoscope with radial EBUS (UTB-rEBUS) vs EMN vs RB in a human cadaver model of PPNs < 2 cm, was performed. The primary end point was the ability to successfully localize and puncture the target nodule, verified by cone-beam CT comparing RB and EMN. Secondary end points included needle to target position “miss” distance, and UTB-rEBUS comparisons. RESULTS: Sixty procedures were performed to target 20 PPNs over the study period. Implanted PPNs were distributed across all lobes, with 80% located within the lung periphery. The target PPN mean diameter was 16.5 ± 1.5 mm, with 50% noted to have a CT bronchus sign. The rate of successful PPN localization and puncture was superior when using RB, compared with EMN (80% vs 45%; P = .02). Among unsuccessful needle passes, the median needle to target “miss” distance was significantly different when comparing UTB-rEBUS, EMN, and RB (P = .0014). CONCLUSIONS: In a cadaver model, use of RB significantly increased the ability to localize and successfully puncture small PPNs when compared with existing technologies. This study demonstrates the potential of RB to precisely reach, localize, and puncture small nodules in the periphery of the lung.

Objective:To evaluate the clinical impact of an antimicrobial stewardship program (ASP) on high-risk pediatric patients.Design:Retrospective cohort study.Setting:Free-standing pediatric hospital.Patients:This study included patients who received an ASP review between March 3, 2008, and March 2, 2017, and were considered high-risk, including patients receiving care by the neonatal intensive care (NICU), hematology/oncology (H/O), or pediatric intensive care (PICU) medical teams.Methods:The ASP recommendations included stopping antibiotics; modifying antibiotic type, dose, or duration; or obtaining an infectious diseases consultation. The outcomes evaluated in all high-risk patients with ASP recommendations were (1) hospital-acquired Clostridium difficile infection, (2) mortality, and (3) 30-day readmission. Subanalyses were conducted to evaluate hospital length of stay (LOS) and tracheitis treatment failure. Multivariable generalized linear models were performed to examine the relationship between ASP recommendations and each outcome after adjusting for clinical service and indication for treatment.Results:The ASP made 2,088 recommendations, and 50% of these recommendations were to stop antibiotics. Recommendation agreement occurred in 70% of these cases. Agreement with an ASP recommendation was not associated with higher odds of mortality or hospital readmission. Patients with a single ASP review and agreed upon recommendation had a shorter median LOS (10.2 days vs 13.2 days; P < .05). The ASP recommendations were not associated with high rates of tracheitis treatment failure.Conclusions:ASP recommendations do not result in worse clinical outcomes among high-risk pediatric patients. Most ASP recommendations are to stop or to narrow antimicrobial therapy. Further work is needed to enhance stewardship efforts in high-risk pediatric patients.

We performed a retrospective chart review on severe adverse drug reactions (ADRs) detected by a pharmacovigilance program at a free-standing pediatric hospital from January 2011 through September 2014. The pharmacist-led program identifies ADRs using electronic medical record triggers. A systematic approach was used to classify ADR type and severity and assure accurate documentation. Data collection included demographics, implicated medication, type of ADR, Naranjo probability scale, ADR-associated International Classification of Diseases, 9th Revision E codes, 30-day mortality, and health care visit cost. One hundred sixty-six severe pediatric ADRs were included, occurring in 163 unique patients. Severe ADRs were commonly associated with antimicrobials (48%), antineoplastics (10%), and antiepileptics (10%). The majority of ADRs were classified by the Naranjo probability scale as probable (59%). One hundred fifty-four patients were admitted to the hospital, with a median length of stay of 3 days; 22 of these patients required admission to the pediatric intensive care unit for a median of 3 days. The median estimated health care cost associated with severe ADRs was $4055.52. No deaths occurred. Nearly 40% of severe ADRs would have gone unidentified using ADR-associated International Classification of Diseases, 9th Revision E codes alone. The impact of pediatric ADRs on the health care system is underestimated. Strategies such as active pharmacovigilance programs enhance the identification, characterization, and documentation of these otherwise unrecognized ADRs.

Background For marginally operable stage IIIA non–small-cell lung cancer (NSCLC), surgery might not be done as planned after neoadjuvant concurrent chemoradiotherapy (CCRT) for reasons (unresectable or medically inoperable conditions, or patient refusal). This study aims to investigate the outcomes of a phased CCRT protocol established to maximize the operability of marginally operable stage IIIA NSCLC and to care for reassessed inoperable patients, in comparison with continuous-course definitive CCRT. Materials and Methods Forty-seven patients with marginally operable stage IIIA NSCLC receiving CCRT were included. Twenty-eight patients were treated with our phased CCRT protocol, including neoadjuvant CCRT followed by surgery (group A, n = 16) or, for reassessed inoperable patients, maintenance chemotherapy and split-course CCRT boost (group B, n = 12). The other 19 were treated with continuous-course definitive CCRT (group C). Overall survival (OS) and progression-free survival (PFS) were analyzed. Results Among all, median OS and PFS were 35.6 and 12.8 months, respectively (median follow-up, 22.3 months). The median OS of group A (not reached) was better than that of group B (34.4 months) and group C (15.2 months) ( P = .009). On multivariate analysis, performance status 0 to 1 (hazard ratio [HR], 0.026; P P = .003), and group A (HR, 0.199; P = .033) were independent prognostic factors. The OS of group B (HR, 0.450; 95% confidence interval, 0.118-1.717; P = .243) was not statistically different from that of group C. Conclusions For marginally operable stage IIIA NSCLC, our phased CCRT strategy may optimize survival by maximizing operability and maintain an acceptable survival for reassessed inoperable patients by split-course CCRT boost following maintenance chemotherapy.

Purpose Systemic therapy has improved rhabdomyosarcoma event-free and overall survival; however, approximately 40 % of patients will have progressive or recurrent disease which is difficult to cure and remains a considerable challenge. Minimal progress has been made in improving outcomes for metastatic or relapsed RMS due to a lack of effective therapeutic agents. Targeted therapies are likely to be incorporated into regimens which rely on conventional cytotoxic chemotherapy. A system to evaluate novel combinations of interest is needed. Methods In this study, we explored 8 agents, 5 that are routinely used or similar to agents used in the clinical management of RMS and 3 biologically targeted agents with novel mechanisms of action, the Wee1 inhibitor AZD1775, the tyrosine kinase inhibitor cabozantinib, and the proteasome inhibitor bortezomib. All were tested individually at clinically achievable concentrations for activity in 4 RMS cell lines and then for potential synergy in two-drug combinations. Results We found single-agent activity in five of the agents (or their active metabolites) that constitute the standard of care in RMS and for AZD1775 with mean IC50 values of 207 ng/ml, well below clinically achievable levels. In addition, the combination of individual cytotoxic chemotherapeutics currently used for RMS demonstrated largely synergistic activity with higher, but clinically achievable concentrations of AZD1775 in our assays. Conclusions Prioritization of chemotherapeutics in RMS is possible using an in vitro system that can define novel drug combinations worthy of future investigation. AZD1775 exhibits single-agent activity, as well as synergy with conventional cytotoxic chemotherapy, and is a novel targeted agent that warrants further study in RMS. Electronic supplementary material The online version of this article (doi:10.1007/s00280-016-3077-8) contains supplementary material, which is available to authorized users.

Osteosarcoma is an orphan disease with only 900 patients diagnosed each year in US. Most patients are adolescents with small number of older patients. The 5-survival rates for those with metastatic disease is only 30%. Frustratingly, there has been little change in treatment options (chemotherapy, surgery and radiotherapy) due to the difficulty of conducting clinical trials in this rare but deadly cancer. To address this, strong pre-clinical trial information is required to motivate clinical trial design. In vitro and in vivo, we identified that the pan-HDAC inhibitor, panobinostat is highly effective in limiting osteosarcoma growth and metastasis. Panobinostat is approved for the treatment of other malignancies but has noted toxicities. Therefore, to identify therapeutic targets, we explored the HDACs responsible for driving osteosarcoma metastasis and the specific genes through which those HDACs mediated their effects. Our data shows that HDAC1 and HDAC2 are key for osteosarcoma survival using siRNA approaches. Use of the HDAC1/2 selective inhibitor romidepsin in vitro and in vivo supported this finding. To identify targets being regulated by HDAC1/2, we performed microarray and proteomics analyses on romidepsin treated osteosarcoma cells. We found and validated independently that, SLC17A7, a metabolic vesicular glutamate transporter to be highly induced in response to romidepsin treatment; >100 fold more than base line in multiple osteosarcoma cell lines. Functionally, SLC17A7 allows entry of glutamate into the synaptic vesicles from cytoplasm and releases the glutamate from the cells via exocytosis. In our studies, we have seen that romidepsin treatment leads to reduced glutamate levels in the conditioned media and cell death indicating key roles for SLC17A7 in driving osteosarcoma progression and metastasis. In conclusion, our data shows that HDAC1/2 suppression of SLC17A7 is a novel means of promoting osteosarcoma progression and metastasis. Citation Format: Niveditha Nerlakanti, Jeremy McGuire, Diana Yu, Damon R. Reed, Conor C. Lynch. Epigenetic silencing of SLC17A7 promotes osteosarcoma growth [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-044.

Gliomas are the most common primary central nervous system tumor but the molecular mechanisms responsible for their development and progression are not completely understood. Isocitrate dehydrogenase 1 (IDH1) is the most commonly mutated gene in grade II-III glioma and secondary glioblastoma (GBM) but functional validation of this alteration has been hampered by difficulties generating autochthonous mouse models harboring mutant IDH. In this study, we used the RCAS/TVA glioma mouse model to assess the role of IDH1(R132H) in glioma development in the context of clinically-relevant cooperating genetic alterations in vitro and in vivo. Immortal Cdkn2a, Pten, and Atrx-deficient astrocytes expressing IDH1(R132H) exhibited elevated (R)-2-hydroxyglutarate (2-HG) levels, reduced NADPH, increased proliferation, and anchorage-independent growth. Cell proliferation and soft agar growth was significantly enhanced by co-expression of PDGFA. Substitution of IDH1(R132H) with a cell membrane-permeable [tri-fluoromethyl benzyl (TFMB)-esterified] version of (R)-2HG mimicked the phenotype observed in cells expressing IDH1(R132H). Interestingly, addition of TFMB-(R)-2HG further enhanced colony formation in cells expressing IDH1(R132H) while treatment with the mutant IDH1 inhibitor AG-120 reduced anchorage independent growth. These data suggest that the effects of IDH1(R132H) are mediated by 2-HG and not loss of native IDH1 activity. Although not sufficient on its own, IDH1(R132H) cooperated with PDGFA and loss of Cdkn2a, Atrx, and Pten to promote glioma development in vivo. These tumors resembled proneural human mutant IDH1 GBM genetically, histologically, and functionally. Our findings support the hypothesis that IDH1(R132H) promotes glioma development through production of 2-HG. This model validates a role for IDH1(R132H) in glioma development, permits mechanistic studies that further our understanding of oncogenesis in this context, and enables rapid testing of rationale therapeutic strategies designed to combat this deadly disease.

BACKGROUND AND OBJECTIVES: Hospitalists increasingly serve as the primary physicians for children hospitalized with infections. Consequently, hospitalists frequently interact with institutional antimicrobial stewardship programs (ASPs). Understanding how these services interact can inform ongoing practice improvement efforts. The objectives of this study were to identify factors associated with ASP recommendations among hospitalist-managed children, and to determine the association of ASP interventions with clinical outcomes for hospitalist-managed patients. METHODS: We retrospectively analyzed ASP reviews of hospitalist patients from a children’s hospital from March 2008 to June 2013. Clinical factors associated with an ASP recommendation were determined. Length of stay and 30-day readmission were compared between cases of agreement and disagreement with ASP recommendations. RESULTS: The ASP reviewed 2163 hospitalist patients, resulting in 350 recommendations (16.2% of reviews). Hospitalists agreed with ASP recommendations in 86.9% of cases. The odds of an ASP recommendation decreased during the study period. Ceftriaxone was the most common antibiotic associated with a recommendation (154/350, 44.0%); community-acquired pneumonia was the most common diagnosis (105/350, 30.0%). Antibiotic discontinuation was the most often recommendation; hospitalists most often disagreed with consulting infectious diseases. Disagreement with ASP recommendations was associated with a decreased length of stay of 15.4 (95% confidence interval –33.2 to 1.1) hours but not 30-day readmission prevalence. CONCLUSIONS: Pediatric hospitalists and ASPs can form an effective collaboration that improves antibiotic use while providing safe care. Better characterization of the areas of disagreement between hospitalists and ASPs is needed. Future studies are needed to identify ASP strategies that will be beneficial in other hospitalist settings.

© 2015 American Chemical Society. Continuing developments in the elucidation techniques of complex catalytic processes is of foremost importance to modern synthetic chemistry, and the identification of efficient synthetic techniques relies on precise, reliable, and adaptable methods to dissect the mechanism of a given transformation. Currently, methods of reaction development are grounded upon the systematic modification of specific variables - such as temperature, time, concentration, etc. - to account for and control the dynamic series of coupled equilibria within a catalytic environment. On the other hand, tandem reaction analytical methods that involve the concomitant use of different instruments to probe a reaction can provide time-resolved information regarding active chemical species and facilitate the interrogation and optimization of the system. Herein, we report our study applying tandem in situ ReactIR and HPLC-MS monitoring to the dysprosium(III) triflate-catalyzed aza-Piancatelli rearrangement of 2-furylcarbinols, a reaction that grants access to trans-4,5-disubstituted cyclopentenones - common motifs in important biologically relevant and natural compounds. With a prototype automated sampling apparatus, information was obtained about the intrinsic chemoselectivity of the reaction, and previously unseen intermediates were observed, allowing for a more detailed reaction mechanism to be substantiated. The advantages of applying this type of tandem measurement to study these types of systems are also discussed. (Figure Presented).

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is the standard therapy for advanced lung adenocarcinomas with common EGFR mutations. Preclinical studies have suggested that uncommon G719X, L861Q, and S768I mutations are also sensitive to EGFR-TKIs. However, the efficacy of EGFR-TKIs in patients with these uncommon mutations remains unclear.A nationwide survey was performed to collect data from gefitinib and erlotinib treatment outcomes of patients with stage IIIB/IV lung adenocarcinoma bearing EGFR G719X/L861Q/S768I mutations. The results were compared with those regarding patients with exon 19 deletions or L858R mutations.One hundred and sixty-one patients with uncommon EGFR mutations were enrolled from 18 institutes throughout Taiwan. Mutations of G719X, L861Q, S768I, G719X + L861Q, and G719X + S768I were observed in 78, 57, 7, 9, and 10 patients, respectively. After receiving EGFR-TKI treatment, patients with uncommon mutations exhibited a significantly inferior tumor response rate (41.6% vs. 66.5%; p0.001) and progression-free survival (median, 7.7 vs. 11.4 months; p0.001) than patients with common mutations. Among the patients who used EGFR-TKIs as first-line treatment, there was a significant difference in overall survival between these two groups of patients (median, 24.0 vs. 29.7 months; p = 0.005).Gefitinib and erlotinib are active in patients with G719X/L861Q/S768I mutations; however, less effective than in those with common mutations.

BACKGROUNDThe number of pediatric antimicrobial stewardship programs (ASPs) is increasing and program evaluation is a key component to improve efficiency and enhance stewardship strategies.OBJECTIVETo determine the antimicrobials and diagnoses most strongly associated with a recommendation provided by a well-established pediatric ASP.DESIGN AND SETTINGRetrospective cohort study from March 3, 2008, to March 2, 2013, of all ASP reviews performed at a free-standing pediatric hospital.METHODSASP recommendations were classified as follows: stop therapy, modify therapy, optimize therapy, or consult infectious diseases. A multinomial distribution model to determine the probability of each ASP recommendation category was performed on the basis of the specific antimicrobial agent or disease category. A logistic model was used to determine the odds of recommendation disagreement by the prescribing clinician.RESULTSThe ASP made 2,317 recommendations: stop therapy (45%), modify therapy (26%), optimize therapy (19%), or consult infectious diseases (10%). Third-generation cephalosporins (0.20) were the antimicrobials with the highest predictive probability of an ASP recommendation whereas linezolid (0.05) had the lowest probability. Community-acquired pneumonia (0.26) was the diagnosis with the highest predictive probability of an ASP recommendation whereas fever/neutropenia (0.04) had the lowest probability. Disagreement with ASP recommendations by the prescribing clinician occurred 22% of the time, most commonly involving community-acquired pneumonia and ear/nose/throat infections.CONCLUSIONSEvaluation of our pediatric ASP identified specific clinical diagnoses and antimicrobials associated with an increased likelihood of an ASP recommendation. Focused interventions targeting these high-yield areas may result in increased program efficiency and efficacy.Infect Control Hosp Epidemiol2015;00(0): 1–8

Eosinophilic pneumonia (EP) is a disease characterized by prominent infiltration of lung structures by eosinophils. The lung interstitium is infiltrated by eosinophils, and essentially the alveolar spaces are filled with eosinophils and a fibrinous exudate, with conservation of the global architecture of the lung. Diagnosis of EP relies on pathological demonstration of alveolar eosinophilia along with characteristic clinical manifestations of nonproductive cough, dyspnea, chest pain and/or unique imaging features. EP may be categorized according to the origin: EP of undetermined origin may overlap with well-individualized syndromes, while EP with a definite cause are mainly due to infections or drug abuse. Here, we report a case of an amphetamine abuser who developed acute EP and acute respiratory distress syndrome after amphetamine inhalation. Related studies on the pathogenesis of stimulant-related lung injury and treatment strategies are also discussed.

Background Antibiotics are commonly overused in the treatment of ventilator-associated tracheitis (VAT). Antimicrobial stewardship programs (ASP) optimize antibiotic prescribing and decrease unnecessary antibiotic use. At our institution, clinicians who have initiated antibiotics for the treatment of tracheitis do not agree with ASP recommendations in 35% of cases. The goal of this study was to compare antibiotic duration and treatment failure in children treated for VAT who did and did not receive an ASP recommendation. Methods We performed a retrospective cohort study to evaluate VAT treatment courses and subsequent treatment failures. For this study, we included all children who were hospitalized from January 2009 to February 2013 and reviewed by ASP for receiving a monitored drug with an indication of VAT. Treatment failure was defined as a patient requiring a repeat course of antibiotics with an indication of VAT within 14 days of completing a previous antibiotic course. Results A total of 220 VAT cases were included. ASP provided recommendations to optimize antibiotics in 44 cases (20%) and stop antibiotics in 53 cases (24%). The shortest duration of treatment (days) was prescribed when ASP recommended stop therapy (median 4.7, IQR 3.0–6.5) when compared with no intervention (6.0, 4.3–7.0; P = 0.01). Treatment failure occurred in 33 (15%) cases. No difference in antibiotic duration was observed between those who did or did not fail (6.3 vs. 5.9, respectively; P = 0.11). Additionally, treatment failure rates did not differ by ASP recommendation status (no recommendation 15%; optimize 18%; stop 11%; ID involved 20%; P = 0.78). Conclusion ASP recommendations for the treatment of pediatric VAT were not associated with an increased likelihood of treatment failure. Further work is needed to standardize the diagnosis and treatment of VAT to avoid unnecessary antibiotic use in these children. Disclosures All authors: No reported disclosures.

Background Regulatory agencies strongly encourage the development of hospital-based antimicrobial stewardship (AS) programs (ASP) to support appropriate antimicrobial prescribing. One component of an ASP is a multidisciplinary team. While the initial conception centered on a physician and a pharmacist, including nurses in AS has been highlighted due to the nurse’s vital role in patient care. There are little data on nurses’ knowledge, attitudes, and practices in AS. The aim of this project was to determine ideas, concerns, and gaps in knowledge of bedside nurses at a local hospital level. Methods This project was conducted at an academic pediatric hospital in an urban setting. A survey was designed to obtain nurses’ attitudes and views of AS and to address their frequency and confidence of various AS activities, including triage/isolation, allergy history, obtainment of appropriate diagnostic studies, interpretation of microbiology results, antibiotic de-/escalation, intravenous-to-oral switches of antibiotics, patient/family education, and identification of antimicrobial-associated adverse events. Respondents were asked to identify barriers to AS participation and to propose educational topics of interest. The survey was sent out to nurses, with 3 weekly reminders. Results 155 of 513 respondents initiated the survey (response rate 30.2%); however, 112 participants completed the entire survey (completion rate 72.3%). Of the respondents, 67% believed that nurses should provide AS but only 32% themselves provided AS; furthermore, 26% of the respondents felt that nurses were equipped to provide AS. The most frequent AS activity reported was patient/family education while the least reported activity was the interpretation of microbiology reports. A correlation was identified between frequency and confidence of performing various AS-related tasks (R2 = 0.95). Barriers identified by respondents included antimicrobial knowledge, other timely priorities, and inclusion of nurses on bedside rounds. Conclusion Although few respondents felt prepared to provide antimicrobial stewardship, the majority (74%) were interested in learning more about how nurses could be involved. We are currently developing a nurse-centric educational curriculum based on the feedback from the survey. Disclosures All authors: No reported disclosures.

Background Assessing appropriateness of hospital antibiotic use is typically a labor-intensive task for antimicrobial stewardship teams and relies heavily on clinician judgement rather than a systematic process. Vancomycin is a frequently used agent that is a common stewardship target. We developed an algorithm to automatically classify the appropriateness of vancomycin days of therapy (DOTs) based upon electronic health record data. Methods We constructed a retrospective cohort of Oregon Health and Science University (OHSU) Hospital and Doernbecher Children’s Hospital patients admitted August 1, 2017 to July 31, 2018 receiving vancomycin. Data were collected on demographic, encounter, pharmacy, microbiology, and surgery data. An electronic algorithm was applied to classify vancomycin DOTs as appropriate, inappropriate, or indeterminate. Inappropriate use was defined as any case in which there was an opportunity for de-escalation as identified using microbiology data, ICD-10 codes, and procedure codes. Results We included 4,231 encounters; 493 (12%) were pediatric patients. Our algorithm automatically classified 59%, 3%, and 38% of encounters as having either appropriate, inappropriate, or indeterminate DOTs, respectively. Forty-four percent of all encounters received no more than a 24-hour course of vancomycin and were considered appropriate empiric therapy; half of these were attributed to surgical prophylaxis. Nine percent of all encounters had vancomycin administered within 3 days of a blood, sputum or tissue culture in which either a methicillin-resistant Staphylococcus species or an ampicillin-resistant, vancomycin-susceptible Enterococcus species was isolated and were classified as appropriate. Six percent of all encounters had cultures in which only Gram-negatives, fungi, or yeast were isolated and were therefore considered appropriate in the empiric period (≤48 hours) but inappropriate thereafter. Conclusion Automated assessments of antibiotic appropriateness could facilitate more informed antimicrobial stewardship initiatives and serve as a valuable stewardship metric. Characterization of indeterminate vancomycin use may inform increased automated classification. Further effort is needed to validate these assessments. Disclosures All authors: No reported disclosures.

Osteosarcoma (OS) is the most common bone malignancy in adolescents. At the time of initial diagnosis, approximately 15% of the patients present with metastatic disease in lungs. Prognosis for this cohort is grim with 5-year overall survival rates at 30%. Frustratingly, these statistics have changed little over the past three decades, in part due to the lack of progress in identifying effective therapies and difficulty in coordinating robust clinical trials in this relatively rare malignancy. To address this, we previously screened 54 FDA approved drugs against 5 different OS cell lines and identified the histone deacetylase inhibitor (HDAC), panobinostat (Pano) as having potent effects in vitro. Here, we explore whether Panobinostat is effective in preventing multiple stages of OS progression in vivo using the K7M2 and SAOS2LM7 pre-clinical models of the disease. Pano prevents the growth of primary OS and lung metastasis. Mice were intratibially inoculated with K7M2-Luc cells and then treated with vehicle (n=11) or panobinostat (n=10; 10 mg/kg for all in vivo studies). Tumor growth was measured by bioluminescence (RLU). The clinical endpoint was 1x106RLU (IVIS-200). Primary OS growth was significantly slower in the panobinostat treated group (p Citation Format: Niveditha Nerlakanti, Jeremy McGuire, Diana Yu, Damon R. Reed, Conor C. Lynch. HDAC inhibition significantly reduces primary and lung metastatic osteosarcoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2016.

The observed rate of reaction in the dysprosium triflate catalyzed aza-Piancatelli rearrangement is controlled by a key off-cycle binding between aniline and catalyst. Deconvoluting the role of these ancillary species greatly broadens our understanding of factors affecting the productive catalytic pathway. We demonstrate that the rate of reaction is controlled by initial competitive binding between the furylcarbinol and nitrogen nucleophile using either a Brønsted or Lewis acid catalyst and that the resulting rearrangement proceeds without involving the Brønsted and Lewis acid catalyst. This shows conclusively that the rate-controlling step and selectivity of reaction are decoupled. © 2013 American Chemical Society.

The article is devoted to the dynamics and status of agricultural lands of the Rostov Region. A detailed analysis of cultivated area decrease, changes in crop structure was carried out. The dynamics of land use and changing areas of natural and anthropogenic landscapes over the past 400 years has been studied. The main trend is established - the expansion of agricultural lands due to the reduction of pastures. A decrease in the area of arable land and crop areas in the late XX - early XXI centuries was revealed. Comparison of indicators of ecologically balanced anthropogenic load in the steppe zone with data for the Rostov Region is carried out. A differentiated assessment of the ecological and economic consequences of the crisis dynamics of land use is given.

A rapid test to detect methicillin resistance in Staphylococcus aureus through the penicillin-binding protein 2a antigen was introduced for pediatric patients hospitalized for purulent skin and soft tissue infections. Integration of this test with physician education and stewardship guidance improved targeted antibiotic use for infections caused by methicillin-susceptible S. aureus (44%-80%, P < 0.001), including when final culture results were not available.

Hospital-wide antibiograms provide general susceptibility patterns. Specific antibiograms were created for methicillin-resistant Staphylococcus aureus isolates based on infection process and epidemiology. Using clinical microbiology laboratory data and patient profiles, high clindamycin resistance rates were seen for nonskin and soft tissue infections and noncommunity-associated methicillin-resistant S. aureus isolates.

The association between spontaneous pneumothorax (SP) and stroke has not been reported, and this study aimed to explore this association. We used the National Health Insurance Research Database for conducting a nationwide, population-based, retrospective cohort study of patients newly hospitalized for SP from 2000 to 2010. A total of 2541 patients with newly diagnosed SP were included and compared with patients without SP. We observed that patients with SP were at higher risk for developing stroke, with an adjusted hazard ratio (HR) of 1.56. In addition, these patients had a significantly higher risk of hemorrhagic stroke (adjusted HR = 2.22) than of ischemic stroke (adjusted HR = 1.48). The risk of stroke was the highest in the initial 4 months after hospitalization for SP (adjusted HR = 3.41, 95% confidence interval = 1.98–5.87). In conclusion, our study revealed a correlation between stroke and a history of SP, and the risk of stroke after SP was time sensitive.

Schizophrenia (SCZD) is a debilitating neurological disorder with a world-wide prevalence of 1%; there is a strong genetic component, with an estimated heritability of 80-85%. Although post-mortem studies have revealed reduced brain volume, cell size, spine density and abnormal neural distribution in the prefrontal cortex and hippocampus of SCZD brain tissue and neuropharmacological studies have implicated dopaminergic, glutamatergic and GABAergic activity in SCZD, the cell types affected in SCZD and the molecular mechanisms underlying the disease state remain unclear. To elucidate the cellular and molecular defects of SCZD, we directly reprogrammed fibroblasts from SCZD patients into human induced pluripotent stem cells (hiPSCs) and subsequently differentiated these disorder-specific hiPSCs into neurons (Supplementary Fig. 1). SCZD hiPSC neurons showed diminished neuronal connectivity in conjunction with decreased neurite number, PSD95-protein levels and glutamate receptor expression. Gene expression profiles of SCZD hiPSC neurons identified altered expression of many components of the cyclic AMP and WNT signalling pathways. Key cellular and molecular elements of the SCZD phenotype were ameliorated following treatment of SCZD hiPSC neurons with the antipsychotic loxapine. To date, hiPSC neuronal pathology has only been demonstrated in diseases characterized by both the loss of function of a single gene product and rapid disease progression in early childhood. We now report hiPSC neuronal phenotypes and gene expression changes associated with SCZD, a complex genetic psychiatric disorder.

Malawi is a sub-Saharan African nation with a severe HIV epidemic. The quality of life (QoL) has never been investigated among people living with HIV and AIDS (PLWHA) in Malawi. This study examines the QoL and associated factors including life needs among PLWHA at different stages of their illness in the northern region of Malawi.Survey analysis of consecutive outpatient participants receiving highly active antiretroviral therapy at the Rainbow Clinic and non-HIV patients receiving care at the affiliated Mzuzu Central Hospital during a one-month period was performed. Laboratory testing and clinical diagnosis were used to determine HIV status, determine CD4 count, and classify WHO clinical stage. A total of 267 HIV-infected patients and 598 non-HIV participants completed a needs assessment and a Short Form-36 (SF-36) questionnaire, which contained a QoL subscale. SF-36 subscales and needs assessment scores were analyzed using t-test, ANOVA test, and Generalized Linear Model-Tukey's test.HIV-positive patients had significantly lower physical functioning (p=0.0365), mental health (p=0.001), social functioning (p0.0001), and mental component summary (p=0.0069) scores than HIV-negative patients. Further, WHO Stage III HIV patients had significantly lower vitality (p=0.0439) and mental health (p=0.0022) scores than WHO Stages I and II patients; and WHO Stage IV patients had significantly lower vitality (p=0.0015), mental health (p=0.0006), and physical component summary (p=0.0443) scores than WHO Stages I and II patients. Finally, AIDS patients, as determined by CD4 count, had significantly lower bodily pain (p=0.0423) and physical component summary (p=0.0148) scores than non-AIDS, HIV-positive patients.HIV patients undergoing treatment in Malawi have a significantly lower QoL, both mentally and physically, than their non-HIV counterparts. Further, HIV patients at more advanced stages, both by the WHO definition and by CD4 count, have a significantly lower QoL than HIV patients at earlier stages of the disease.

We report a case of "rectangular (quadrangular) heart" seen on the chest X-ray. Full evaluation showed massive enlargement of right-sided chambers shadowing the left-sided chambers. Primary etiology of the right-sided failure was attributed to severe mitral and tricuspid regurgitation for which the patient underwent surgery. Learning objective: To understand that a cardiac chamber enlargement can result in massive increase in cardiac silhouette on a chest X-ray. Predominant right atrial and ventricular enlargement in comparison to left-sided chambers can give rise to a peculiar shape (rectangular/quadrangular) in the chest X-ray.>

Background While antibiotics frequently cause adverse drug reactions (ADR), the rate of antifungal (AF) ADR is unknown. The mechanisms of AF ADR and cross-reactivity among a drug class (i.e., azoles) are poorly understood. Given the use of AF therapy is on the rise, it is important to better understand the prevalence of AF ADR and how these reactions influence prescribing. Methods Thirty-two hospitals participated in a quarterly pediatric point prevalence survey that documented details on all admitted patients 0–17 years receiving any systemic antimicrobials, including drug, dose, and documented history of an antimicrobial ADR between June 2016 and December 2017. Patients who were recorded as receiving at least one systemic AF were included. A comparison of AF prescribing practices between those with and without an AF ADR was performed. Results Among 13,179 total patients, 2,213 AF were prescribed to 2,101 unique patients. The most common indications for AF included prophylaxis (64%), fever with neutropenia (4%), neonatal sepsis (3%), and catheter-related bloodstream infection (3%). The prevalence of patients with any documented AF ADR was 2.9%. Amphotericin was most commonly associated with an ADR. Fluconazole was the most commonly prescribed AF in those with no ADR (49%) when compared with those with an AF ADR (13%; P < .05). Patients with an amphotericin ADR were more likely to receive voriconazole (29%) when compared with those without (15%; P < .05). Interestingly, posaconazole use was highest in those with an azole ADR (22%) when compared with those with no azole ADR (4%; P < .05). Echinocandin ADR were infrequent, and those with a reported ADR still received an echinocandin 62% of the time. Conclusion Significant differences in antifungal prescribing exists based on ADR status. More work is needed to be able to effectively classify AF ADR, determine safe prescribing practices in those with an AF ADR, and evaluate outcomes associated with AF ADR status. Disclosures All authors: No reported disclosures.