Publications by authors named "Adam Lucas"

26 Publications

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Imaging Hallmarks of the Tumor Microenvironment in Glioblastoma Progression.

Front Oncol 2021 26;11:692650. Epub 2021 Aug 26.

Department of Biomedical Engineering, Yale University, New Haven, CT, United States.

Glioblastoma progression involves multifaceted changes in vascularity, cellularity, and metabolism. Capturing such complexities of the tumor niche, from the tumor core to the periphery, by magnetic resonance imaging (MRI) and spectroscopic imaging (MRSI) methods has translational impact. In human-derived glioblastoma models (U87, U251) we made simultaneous and longitudinal measurements of tumor perfusion (F), permeability (K), and volume fractions of extracellular (v) and blood (v) spaces from dynamic contrast enhanced (DCE) MRI, cellularity from apparent diffusion coefficient (ADC) MRI, and extracellular pH (pH) from an MRSI method called Biosensor Imaging of Redundant Deviation in Shifts (BIRDS). Spatiotemporal patterns of these parameters during tumorigenesis were unique for each tumor. While U87 tumors grew faster, F, K, and v increased with tumor growth in both tumors but these trends were more pronounced for U251 tumors. Perfused regions between tumor periphery and core with U87 tumors exhibited higher F, but K of U251 tumors remained lowest at the tumor margin, suggesting primitive vascularization. Tumor growth was uncorrelated with v, ADC, and pH. U87 tumors showed correlated regions of reduced v and lower ADC (higher cellularity), suggesting ongoing proliferation. U251 tumors revealed that the tumor core had higher v and elevated ADC (lower cellularity), suggesting necrosis development. The entire tumor was uniformly acidic (pH 6.1-6.8) early and throughout progression, but U251 tumors were more acidic, suggesting lower aerobic glycolysis in U87 tumors. Characterizing these cancer hallmarks with DCE-MRI, ADC-MRI, and BIRDS-MRSI will be useful for exploring tumorigenesis as well as timely therapies targeted to specific vascular and metabolic aspects of the tumor microenvironment.
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http://dx.doi.org/10.3389/fonc.2021.692650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426346PMC
August 2021

Evaluation of area under the concentration curve adjusted by the terminal-phase as a metric to reduce the impact of variability in bioequivalence testing.

Br J Clin Pharmacol 2021 Jul 16. Epub 2021 Jul 16.

Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Brentford, Middlesex, UK.

Aim: To quantify the utility of a terminal-phase adjusted area under the concentration curve method in increasing the probability of a correct and conclusive outcome of a bioequivalence (BE) trial for highly variable drugs when clearance (CL) varies more than the volume of distribution (V).

Methods: Data from a large population of subjects were generated with variability in CL and V, and used to simulate a two-period, two-sequence crossover BE trial. The 90% confidence interval for formulation comparison was determined following BE assessment using the area under the concentration curve (AUC) ratio test, and the proposed terminal-phase adjusted AUC ratio test. An outcome of bioequivalent, nonbioequivalent or inconclusive was then assigned according to predefined BE limits.

Results: When CL varied more than V, the proposed approach enhanced the probability of correctly assigning bioequivalent or nonbioequivalent and reduced the risk of an inconclusive trial. For a hypothetical drug with between-subject variability of 35% for CL and 10% for V, when the true test-reference ratio of bioavailability was 1.15, a crossover study of n = 14 subjects analysed by the proposed method would have 80% or 20% probability of claiming bioequivalent or nonbioequivalent, compared to 22%, 46% or 32% probability of claiming bioequivalent, nonbioequivalent or inconclusive using the standard AUC ratio test.

Conclusions: The terminal-phase adjusted AUC ratio test represents a simple and readily applicable approach to enhance the BE assessment of drug products when CL varies more than V.
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http://dx.doi.org/10.1111/bcp.14986DOI Listing
July 2021

A high-throughput imaging platform to characterize extracellular pH in organotypic three-dimensional in vitro models of liver cancer.

NMR Biomed 2021 03 22;34(3):e4465. Epub 2020 Dec 22.

Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA.

Given the extraordinary nature of tumor metabolism in hepatocellular carcinoma and its impact on oncologic treatment response, this study introduces a novel high-throughput extracellular pH (pH ) mapping platform using magnetic resonance spectroscopic imaging in a three-dimensional (3D) in vitro model of liver cancer. pH mapping was performed using biosensor imaging of redundant deviation in shifts (BIRDS) on 9.4 T and 11.7 T MR scanners for validation purposes. 3D cultures of four liver cancer (HepG2, Huh7, SNU475, VX2) and one hepatocyte (THLE2) cell line were simultaneously analyzed (a) without treatment, (b) supplemented with 4.5 g/L d-glucose, and (c) treated with anti-glycolytic 3-bromopyruvate (6.25, 25, 50, 75, and 100 μM). The MR results were correlated with immunohistochemistry (GLUT-1, LAMP-2) and luminescence-based viability assays. Statistics included the unpaired t-test and ANOVA test. High-throughput pH imaging with BIRDS for in vitro 3D liver cancer models proved feasible. Compared with non-tumorous hepatocytes (pH = 7.1 ± 0.1), acidic pH was revealed in liver cancer (VX2, pH = 6.7 ± 0.1; HuH7, pH = 6.8 ± 0.1; HepG2, pH = 6.9 ± 0.1; SNU475, pH = 6.9 ± 0.1), in agreement with GLUT-1 upregulation. Glucose addition significantly further decreased pH in hyperglycolytic cell lines (VX2, HepG2, and Huh7, by 0.28, 0.06, and 0.11, respectively, all p < 0.001), whereas 3-bromopyruvate normalized tumor pH in a dose-dependent manner without affecting viability. In summary, this study introduces a non-invasive pH imaging platform for high-yield screening using a translational 3D liver cancer model, which may help reveal and target mechanisms of therapy resistance and inform personalized treatment of patients with hepatocellular carcinoma.
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http://dx.doi.org/10.1002/nbm.4465DOI Listing
March 2021

Protocol for a systematic review on tertiary prevention interventions for patients with stroke in African countries.

BMJ Open 2020 09 13;10(9):e038459. Epub 2020 Sep 13.

Center of Health Sciences, Institute of General Practice and Family Medicine, Martin-Luther-Universitat Halle-Wittenberg, Halle, Sachsen-Anhalt, Germany

Introduction: Stroke is one of the common causes of mortality, morbidity and years of life lost worldwide. Baseline research on stroke epidemiology, prevention, acute and rehabilitative interventions in Africa is necessary to approach specific contexts and regional circumstances. Most studies on stroke have been conducted in high-income countries. This protocol describes the methodology to summarise the best available evidence on tertiary preventive strategies like rehabilitation interventions for patients with stroke in African contexts.

Methods And Analysis: We will include experimental studies and prospective cohort studies conducted in African countries. A protocol has been registered in PROSPERO. Systematic search will include eight electronic databases (MEDLINE, Embase, the Cochrane Library, CINAHL, Cab-Direct, Physiotherapy Evidence Database (PEDro), African Journals Online and African Index Medicus) and the International Clinical Trials Register Platform and base on predefined search terms. We will search from inception of each database and repeat this strategy 3 months prior to review submission. Details of all eligible studies will be extracted and risk of bias for outcomes on global disability or dependence in daily living will be assessed. Main aim of this systematic review is to provide a narrative description of evidence on tertiary prevention strategies (including rehabilitation) for stroke. This description will be visualised in structured tables to aid interpretation of study characteristics, intervention effects and certainty of the evidence.

Ethics And Dissemination: No ethical approval is necessary. Results will be presented in national and international conferences and published in a peer-reviewed journal.

Prospero Registration Number: CRD42020159125.
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http://dx.doi.org/10.1136/bmjopen-2020-038459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488840PMC
September 2020

Idarubicin-Loaded ONCOZENE Drug-Eluting Bead Chemoembolization in a Rabbit Liver Tumor Model: Investigating Safety, Therapeutic Efficacy, and Effects on Tumor Microenvironment.

J Vasc Interv Radiol 2020 10 17;31(10):1706-1716.e1. Epub 2020 Jul 17.

Department of Radiology and Biomedical Imaging, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06510. Electronic address:

Purpose: To investigate toxicity, efficacy, and microenvironmental effects of idarubicin-loaded 40-μm and 100-μm drug-eluting embolic (DEE) transarterial chemoembolization in a rabbit liver tumor model.

Materials And Methods: Twelve male New Zealand White rabbits with orthotopically implanted VX2 liver tumors were assigned to DEE chemoembolization with 40-μm (n = 5) or 100-μm (n = 4) ONCOZENE microspheres or no treatment (control; n = 3). At 24-72 hours postprocedurally, multiparametric magnetic resonance (MR) imaging including dynamic contrast-enhanced (DCE), diffusion-weighted imaging (DWI), and biosensor imaging of redundant deviation in shifts (BIRDS) was performed to assess extracellular pH (pHe), followed by immediate euthanasia. Laboratory parameters and histopathologic ex vivo analysis included fluorescence confocal microscopy and immunohistochemistry.

Results: DCE MR imaging demonstrated a similar degree of devascularization of embolized tumors for both microsphere sizes (mean arterial enhancement, 8% ± 12 vs 36% ± 51 in controls; P = .07). Similarly, DWI showed postprocedural increases in diffusion across the entire lesion (apparent diffusion coefficient, 1.89 × 10 mm/s ± 0.18 vs 2.34 × 10 mm/s ± 0.18 in liver; P = .002). BIRDS demonstrated profound tumor acidosis at baseline (mean pHe, 6.79 ± 0.08 in tumor vs 7.13 ± 0.08 in liver; P = .02) and after chemoembolization (6.8 ± 0.06 in tumor vs 7.1 ± 0.04 in liver; P = .007). Laboratory and ex vivo analyses showed central tumor core penetration and greater increase in liver enzymes for 40-μm vs 100-μm microspheres. Inhibition of cell proliferation, intratumoral hypoxia, and limited idarubicin elution were equally observed with both sphere sizes.

Conclusions: Noninvasive multiparametric MR imaging visualized chemoembolic effects in tumor and tumor microenvironment following DEE chemoembolization. Devascularization, increased hypoxia, coagulative necrosis, tumor acidosis, and limited idarubicin elution suggest ischemia as the predominant therapeutic mechanism. Substantial size-dependent differences indicate greater toxicity with the smaller microsphere diameter.
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http://dx.doi.org/10.1016/j.jvir.2020.04.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541537PMC
October 2020

Molecular MRI of the Immuno-Metabolic Interplay in a Rabbit Liver Tumor Model: A Biomarker for Resistance Mechanisms in Tumor-targeted Therapy?

Radiology 2020 09 7;296(3):575-583. Epub 2020 Jul 7.

From the Department of Radiology and Biomedical Imaging (L.J.S., L.A.D., I.T.S., J.J.W., J.S., M.D.L., L.A., A.B., J.D., F.H., D.C., J.C.), Department of Internal Medicine, Section of Rheumatology (R.R.M., L.L., R.J.B.), Department of Immunobiology (N.J.), and Department of Pathology (V.P., X.Z.), Yale University School of Medicine, 300 Cedar St, New Haven, CT 06520; Institute of Radiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, Berlin, Germany (L.J.S., L.A.D., I.T.S., L.A.); Visage Imaging, San Diego, Calif (M.D.L.); Department of Biomedical Engineering, Yale School of Engineering and Applied Science, New Haven, Conn (J.D.); and Department of Radiology, Hadassah Hebrew University Medical Center, Jerusalem, Israel (S.N.G.).

Background The immuno-metabolic interplay has gained interest for determining and targeting immunosuppressive tumor micro-environments that remain a barrier to current immuno-oncologic therapies in hepatocellular carcinoma. Purpose To develop molecular MRI tools to reveal resistance mechanisms to immuno-oncologic therapies caused by the immuno-metabolic interplay in a translational liver cancer model. Materials and Methods A total of 21 VX2 liver tumor-bearing New Zealand white rabbits were used between October 2018 and February 2020. Rabbits were divided into three groups. Group A ( = 3) underwent intra-arterial infusion of gadolinium 160 (Gd)-labeled anti-human leukocyte antigen-DR isotope (HLA-DR) antibodies to detect antigen-presenting immune cells. Group B ( = 3) received rhodamine-conjugated superparamagnetic iron oxide nanoparticles (SPIONs) intravenously to detect macrophages. These six rabbits underwent 3-T MRI, including T1- and T2-weighted imaging, before and 24 hours after contrast material administration. Group C ( = 15) underwent extracellular pH mapping with use of MR spectroscopy. Of those 15 rabbits, six underwent conventional transarterial chemoembolization (TACE), four underwent conventional TACE with extracellular pH-buffering bicarbonate, and five served as untreated controls. MRI signal intensity distribution was validated by using immunohistochemistry staining of HLA-DR and CD11b, Prussian blue iron staining, fluorescence microscopy of rhodamine, and imaging mass cytometry (IMC) of gadolinium. Statistical analysis included Mann-Whitney and Kruskal-Wallis tests. Results T1-weighted MRI with Gd-labeled antibodies revealed localized peritumoral ring enhancement, which corresponded to gadolinium distribution detected with IMC. T2-weighted MRI with SPIONs showed curvilinear signal intensity representing selective peritumoral deposition in macrophages. Extracellular pH-specific MR spectroscopy of untreated liver tumors showed acidosis (mean extracellular pH, 6.78 ± 0.09) compared with liver parenchyma (mean extracellular pH, 7.18 ± 0.03) ( = .008) and peritumoral immune cell exclusion. Normalization of tumor extracellular pH (mean, 6.96 ± 0.05; = .02) using bicarbonate during TACE increased peri- and intratumoral immune cell infiltration ( = .002). Conclusion MRI in a rabbit liver tumor model was used to visualize resistance mechanisms mediated by the immuno-metabolic interplay that inform susceptibility and response to immuno-oncologic therapies, providing a therapeutic strategy to restore immune permissiveness in liver cancer. © RSNA, 2020
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http://dx.doi.org/10.1148/radiol.2020200373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434651PMC
September 2020

Estimating human ADME properties, pharmacokinetic parameters and likely clinical dose in drug discovery.

Expert Opin Drug Discov 2019 12 20;14(12):1313-1327. Epub 2019 Sep 20.

Drug Metabolism and Pharmacokinetics, Evotec , Abingdon , UK.

: Prediction of human absorption, distribution, metabolism, and excretion (ADME) properties, therapeutic dose and exposure has become an integral part of compound optimization in discovery. Incorporation of drug metabolism and pharmacokinetics into discovery projects has largely tempered historical drug failure due to sub-optimal ADME. In the current era, inadequate safety and efficacy are leading culprits for attrition; both of which are dependent upon drug exposure. Therefore, prediction of human pharmacokinetics (PK) and dose are core components of de-risking strategies in discovery. : The authors provide an overview of human dose prediction methods and present a toolbox of PK parameter prediction models with a proposed framework for a consensus approach valid throughout the discovery value chain. Mechanistic considerations and indicators for their application are discussed which may impact the dose prediction approach. Examples are provided to illustrate how implementation of the proposed strategy throughout discovery can assist project progression. : Anticipation of human ADME, therapeutic dose and exposure must be deliberated throughout drug discovery from virtual/initial synthesis where key properties are considered and similar molecules ranked, into development where advanced compounds can be subject to prediction with greater mechanistic understanding and data-driven model selection.
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http://dx.doi.org/10.1080/17460441.2019.1660642DOI Listing
December 2019

Cryotherapy for nodal metastasis in NSCLC with acquired resistance to immunotherapy.

J Immunother Cancer 2018 12 12;6(1):147. Epub 2018 Dec 12.

Division of Interventional Radiology, Department of Radiology and Biomedical Imaging, Yale School of Medicine, 330 Cedar Street, New Haven, CT, 06510, USA.

Novel approaches with checkpoint inhibitors in immunotherapy continue to be essential in the treatment of non-small cell lung cancer (NSCLC). However, the low rate of primary response and the development of acquired resistance during the immunotherapy limit their long-term effectiveness. The underlying cause of acquired resistance is poorly understood; potential management strategies for patients with acquired resistance are even less clear. Here, we report the case of a 75-year-old female smoker with cough, fatigue, and weight loss that was found to have an 8.6 cm right upper lobe lung lesion with local invasion, adenopathy, and a malignant pericardial effusion. This lesion was biopsied and identified to be cT3N3M1b squamous cell cancer of the lung without any recognizable PD-L1 expression on tumor cells. For her metastatic NSCLC, the patient underwent two lines of conventional chemotherapy before initiation of combination immunotherapy with an anti-PD-L1 and anti-CTLA-4 antibody. Though she initially achieved a response, she thereafter progressed and developed immunotherapy resistant lymph nodal metastasis. While cervical lymph nodes could be surgically removed, another metastasis in an aortocaval area required a more sensitive therapy like thermal ablation. The aortocaval node was partially treated with a single treatment of cryotherapy and demonstrated durable complete response. Cryotherapy for checkpoint immunotherapy resistant metastasis appears to be a safe and feasible treatment for treating metastatic disease in non-small cell lung cancer. The prospect of cryotherapy adjuvancy may enable local control of metastatic disease after initial response to immune checkpoint immunotherapy and may impact on overall outcomes.
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http://dx.doi.org/10.1186/s40425-018-0468-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292083PMC
December 2018

What Imaging-Detected Pathologies Are Associated With Shoulder Symptoms and Their Persistence? A Systematic Literature Review.

Arthritis Care Res (Hoboken) 2018 08 6;70(8):1169-1184. Epub 2018 Jun 6.

University of Leeds, Leeds, and Arthritis Research UK Centre for Sport, Exercise, and Osteoarthritis, Nottingham, UK.

Objective: Shoulder symptoms are common, and imaging is being increasingly used to help with management. However, the relationship between imaging and symptoms remains unclear. This review aims to understand the relationship between imaging-detected pathologies, symptoms, and their persistence.

Methods: A systematic review using Medline, EMBASE, Cochrane, and grey literature was conducted to April 2017. The cross-sectional and longitudinal relationships between imaging-detected abnormalities and symptoms were analyzed and associations qualitatively characterized by a best-evidence synthesis based on study design, covariate adjustment, and the Grade of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. Modalities included ultrasound, magnetic resonance imaging (MRI), radiographs, positron emission tomography (PET), bone scintigraphy, and computed tomography.

Results: A total of 6,569 abstracts was screened and 56 articles were included. In total, 50 studies did not adjust for covariates and 36 analyzed individual pathologies only. The majority of studies showed conflicting results. There was no significant association between most imaging features and symptoms among high-quality, cross-sectional studies. There was low-quality evidence that enhancement of the joint capsule on MRI and increased uptake on PET were associated with symptoms in adhesive capsulitis. Based on high-quality longitudinal studies, enlarging rotator cuff tears were associated with an increased incidence of symptoms.

Conclusion: There were conflicting results on the association of imaging features with shoulder symptoms and their persistence. The existing evidence was very low in quality, based on the GRADE methodology. Further high-quality studies are required to understand the relationship between imaging and shoulder symptoms and to determine the appropriate role of imaging in care pathways.
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http://dx.doi.org/10.1002/acr.23554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099421PMC
August 2018

A multi-institutional analysis of children on long-term non-invasive respiratory support and their outcomes.

Pediatr Pulmonol 2018 04 17;53(4):498-504. Epub 2018 Jan 17.

Division of Pediatric Critical Care Medicine, Department of Pediatrics, Columbia University College of Physician and Surgeons, New York, New York.

Objectives: To characterize a multi-institutional cohort of children with chronic respiratory failure that use long-term, non-invasive respiratory support, perform a time-to-event analysis of transitions to transtracheal ventilation and identify factors associated with earlier transition to transtracheal ventilation.

Study Design: A retrospective cohort study of patients less than 21 years of age with diagnoses associated with chronic respiratory failure and discharged on non-invasive respiratory support was performed using data from the Pediatric Health Information System (PHIS) between 2007 and 2015. Demographic and clinical characteristics, as well as times from index discharge on non-invasive support to transtracheal ventilation were presented. A competing risk regression model was fitted to estimate factors associated with earlier transition to transtracheal ventilation.

Results: A total of 3802 patients were identified. Their median age at index discharge was 10.4 years (interquartile range [IQR] 4.1-14.9). Of these patients, 337 (8.9%) transitioned to transtracheal ventilation and transitioned at a median of 11.5 months (IQR 4.6-26) post-index discharge, or a median age of 9.3 years (IQR 4.2-14.5). Competing risk modeling demonstrated that patients who were older or whose discharge occurred later in the study period had lower hazards of earlier transition to transtracheal ventilation, whereas patients with anoxia/encephalopathy and quadriplegia had higher hazards of earlier transitioning.

Conclusions: Most patients on long-term, non-invasive respiratory support who progress to transtracheal ventilation transition do so within a few years of support initiation. Various characteristics were associated with earlier risk of transitioning to transtracheal ventilation. This information may enhance anticipatory guidance for this population.
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http://dx.doi.org/10.1002/ppul.23925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5898633PMC
April 2018

Science to Practice: Molecular-targeted Drug Delivery in Combination with Radiofrequency Ablation of Liver Cancer: A Magic Bullet?

Radiology 2017 11;285(2):333-335

Department of Radiology and Biomedical Imaging Yale University School of Medicine 300 Cedar St New Haven, CT 06520.

In an effort to improve the technical success rates and clinical outcomes of radiofrequency (RF) ablation, Yan et al validated the use of a tumor-penetrating peptide and thermosensitive doxorubicin (DOX)-loaded nanoparticles in combination with RF ablation in a hepatocellular carcinoma mouse model. By achieving higher chemotherapeutic drug concentrations in target lesions, fewer toxic effects, and improved survival end points in an animal tumor model, the authors conclude that superior tumor treatment with RF ablation is possible when combined with molecular-targeted drug delivery systems.
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http://dx.doi.org/10.1148/radiol.2017171527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5673055PMC
November 2017

Repeated Critical Illness and Unplanned Readmissions Within 1 Year to PICUs.

Crit Care Med 2017 Aug;45(8):1276-1284

1Division of Pediatric Critical Care, Department of Pediatrics, Columbia University College of Physician and Surgeons, New York, NY.2Department of Statistics, University of California, Berkeley, CA.3Department of Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, CA.4Department of Medicine, University of California, San Francisco, San Francisco, CA.5Division of Pulmonary and Critical Care, Department of Medicine, University of California, San Francisco, San Francisco, CA.6Philip R. Lee Institute for Health Policy Studies, University of California, San Francisco, San Francisco, CA.

Objectives: To determine the occurrence rate of unplanned readmissions to PICUs within 1 year and examine risk factors associated with repeated readmission.

Design: Retrospective cohort analysis.

Setting: Seventy-six North American PICUs that participated in the Virtual Pediatric Systems, LLC (VPS, LLC, Los Angeles, CA).

Patients: Ninety-three thousand three hundred seventy-nine PICU patients discharged between 2009 and 2010.

Interventions: None.

Measurements And Main Results: Index admissions and unplanned readmissions were characterized and their outcomes compared. Time-to-event analyses were performed to examine factors associated with readmission within 1 year. Eleven percent (10,233) of patients had 15,625 unplanned readmissions within 1 year to the same PICU; 3.4% had two or more readmissions. Readmissions had significantly higher PICU mortality and longer PICU length of stay, compared with index admissions (4.0% vs 2.5% and 2.5 vs 1.6 d; all p < 0.001). Median time to readmission was 30 days for all readmissions, 3.5 days for readmissions during the same hospitalization, and 66 days for different hospitalizations. Having more complex chronic conditions was associated with earlier readmission (adjusted hazard ratio, 2.9 for one complex chronic condition; hazard ratio, 4.8 for two complex chronic conditions; hazard ratio, 9.6 for three or more complex chronic conditions; all p < 0.001 compared no complex chronic condition). Most specific complex chronic condition conferred a greater risk of readmission, and some had considerably higher risk than others.

Conclusions: Unplanned readmissions occurred in a sizable minority of PICU patients. Patients with complex chronic conditions and particular conditions were at much higher risk for readmission.
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http://dx.doi.org/10.1097/CCM.0000000000002439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5541898PMC
August 2017

Pediatric intermediate care and pediatric intensive care units: PICU metrics and an analysis of patients that use both.

J Crit Care 2017 10 26;41:268-274. Epub 2017 May 26.

Division of Pediatric Critical Care Medicine, Department of Pediatrics, Columbia University College of Physicians and Surgeons, Morgan Stanley Children's Hospital, 3959 Broadway, New York, NY 10032, United States. Electronic address:

Purpose: To examine how intermediate care units (IMCUs) are used in relation to pediatric intensive care units (PICUs), characterize PICU patients that utilize IMCUs, and estimate the impact of IMCUs on PICU metrics.

Materials & Methods: Retrospective study of PICU patients discharged from 108 hospitals from 2009 to 2011. Patients admitted from or discharged to IMCUs were characterized. We explored the relationships between having an IMCU and several PICU metrics: physical length-of-stay (LOS), medical LOS, discharge wait time, admission severity of illness, unplanned PICU admissions from wards, and early PICU readmissions.

Results: Thirty-three percent of sites had an IMCU. After adjusting for known confounders, there was no association between having an IMCU and PICU LOS, mean severity of illness of PICU patients admitted from general wards, or proportion of PICU readmissions or unplanned ward admissions. At sites with an IMCU, patients waited 3.1h longer for transfer from the PICU once medically cleared (p<0.001).

Conclusions: There was no association between having an IMCU and most measures of PICU efficiency. At hospitals with an IMCU, patients spent more time in the PICU once they were cleared for discharge. Other ways that IMCUs might affect PICU efficiency or particular patient populations should be investigated.
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http://dx.doi.org/10.1016/j.jcrc.2017.05.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5633493PMC
October 2017

Children and Young Adults Who Received Tracheostomies or Were Initiated on Long-Term Ventilation in PICUs.

Pediatr Crit Care Med 2016 08;17(8):e324-34

1Division of Pediatric Critical Care, Department of Pediatrics, Columbia University College of Physician and Surgeons, New York, NY. 2Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA. 3Department of Statistics, University of California, Berkeley, CA. 4Division of Pulmonary, Allergy and Critical Care Medicine, Department of Pediatrics, Columbia University College of Physician and Surgeons, New York, NY. 5Division of Pediatric Allergy, Immunology and Rheumatology, Department of Pediatrics, Columbia University College of Physician and Surgeons, New York, NY. 6Division of Pediatric Pulmonology, Department of Pediatrics, Keck School of Medicine of University of Southern California, Los Angeles, CA. 7Division of Pulmonary Medicine, Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA. 8Division of Pulmonary and Critical Care, Department of Pediatrics, University of California, San Francisco, CA. 9Philip R. Lee Institute for Health Policy Studies, University of California, San Francisco, CA.

Objectives: To characterize patients who received tracheostomies for airway compromise or were initiated on long-term ventilation for chronic respiratory failure in PICUs and to examine variation in the incidence of initiation, patient characteristics, and modalities across sites.

Design: Retrospective cross-sectional analysis.

Settings: Seventy-three North American PICUs that participated in the Virtual Pediatric Systems, LLC.

Patients: PICU patients admitted between 2009 and 2011.

Interventions: None.

Measurements And Main Results: Among 115,437 PICU patients, 1.8% received a tracheostomy or were initiated on long-term ventilation; 1,034 received a tracheostomy only, 717 were initiated on invasive ventilation, and 381 were initiated on noninvasive ventilation. Ninety percent had substantial chronic conditions and comorbidities, including more than 50% with moderate or worse cerebral disability upon discharge. Seven percent were initiated after a catastrophic injury/event. Across sites, there was variation in incidence of tracheotomy and initiation of long-term ventilation, ranging from 0% to 4.6%. There also was variation in patient characteristics, time to tracheotomy, number of extubations prior to tracheostomy, and the use of invasive ventilation versus noninvasive ventilation.

Conclusions: Although the PICU incidence of initiation of tracheostomies and long-term ventilation was relatively uncommon, it suggests that thousands of children and young adults receive these interventions each year in North American PICUs. The majority of them have conditions and comorbidities that impose on-going care needs, beyond those required by artificial airways and long-term ventilation themselves.
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http://dx.doi.org/10.1097/PCC.0000000000000844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5113027PMC
August 2016

Frequency, risk factors, and outcomes of early unplanned readmissions to PICUs.

Crit Care Med 2013 Dec;41(12):2773-83

1Division of Pediatric Critical Care, Columbia University College of Physician and Surgeons, New York, NY. 2Department of Mathematics, Mills College, Oakland, CA. 3Columbia University School of Nursing, Columbia University, New York, NY. 4Center for Health Policy, Columbia University, New York, NY. 5Department of Epidemiology and Biostatistics, University of California, San Francisco, CA. 6Department of Medicine, University of California, San Francisco, CA. 7Division of Pulmonary and Critical Care, University of California, San Francisco, CA. 8Philip R. Lee Institute for Health Policy Studies, University of California, San Francisco, CA.

Objectives: To determine the rate of unplanned PICU readmissions, examine the characteristics of index admissions associated with readmission, and compare outcomes of readmissions versus index admissions.

Design: Retrospective cohort analysis.

Setting: Ninety North American PICUs that participated in the Virtual Pediatric Intensive Care Unit Systems.

Patients: One hundred five thousand four hundred thirty-seven admissions between July 2009 and March 2011.

Interventions: None.

Measurements And Main Results: Unplanned PICU readmission within 48 hours of index discharge was the primary outcome. Summary statistics, bivariate analyses, and mixed-effects logistic regression model with random effects for each hospital were performed.There were 1,161 readmissions (1.2%). The readmission rate varied among PICUs (0-3.3%), and acute respiratory (56%), infectious (35%), neurological (28%), and cardiovascular (20%) diagnoses were often present on readmission. Readmission risk increased in patients with two or more complex chronic conditions (adjusted odds ratio, 1.72; p < 0.001), unscheduled index admission (adjusted odds ratio, 1.37; p < 0.001), and transfer to an intermediate unit (adjusted odds ratio, 1.29; p = 0.004, compared with ward). Trauma patients had a decreased risk of readmission (adjusted odds ratio, 0.67; p = 0.003). Gender, race, insurance, age more than 6 months, perioperative status, and nighttime transfer were not associated with readmission. Compared with index admissions, readmissions had longer median PICU length of stay (3.1 vs 1.7 d, p < 0.001) and higher mortality (4% vs 2.5%, p = 0.002).

Conclusions: Unplanned PICU readmissions were relatively uncommon, but were associated with worse outcomes. Several patient and admission characteristics were associated with readmission. These data help identify high-risk patient groups and inform risk-adjustment for standardized readmission rates.
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http://dx.doi.org/10.1097/CCM.0b013e31829eb970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4327890PMC
December 2013

Novel N-Substituted Benzimidazolones as Potent, Selective, CNS-Penetrant, and Orally Active M1 mAChR Agonists.

ACS Med Chem Lett 2010 Sep 8;1(6):244-8. Epub 2010 Jun 8.

GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.

Virtual screening of the corporate compound collection yielded compound 1 as a subtype selective muscarinic M1 receptor agonist hit. Initial optimization of the N-capping group of the central piperidine ring resulted in compounds 2 and 3 with significantly improved potency and selectivity. Subsequent optimization of substituents on the phenyl ring of the benzimidazolone moiety led to the discovery of novel muscarinic M1 receptor agonists 4 and 5 with excellent potency, general and subtype selectivity, and pharmacokinetic (PK) properties including good central nervous system (CNS) penetration and oral bioavailability. Compound 5 showed robust in vivo activities in animal models of cognition enhancement. The combination of high potency, excellent selectivity, and good PK properties makes compounds 4 and 5 valuable tool compounds for investigating and validating potential therapeutic benefits resulting from selective M1 activation.
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http://dx.doi.org/10.1021/ml100105xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4007837PMC
September 2010

The discovery of a series of N-substituted 3-(4-piperidinyl)-1,3-benzoxazolinones and oxindoles as highly brain penetrant, selective muscarinic M1 agonists.

Bioorg Med Chem Lett 2010 Sep 30;20(18):5434-8. Epub 2010 Jul 30.

GlaxoSmithKline, New Frontiers Science Park, 3rd Avenue, Harlow, Essex CM19 5AW, UK.

A series of N-substituted 3-(4-piperidinyl)-1,3-benzoxazolinones and oxindoles are reported which were found to be potent and selective muscarinic M1 agonists. By control of the physicochemical characteristics of the series, particularly the lipophilicity, compounds with good metabolic stability and excellent brain penetration were identified. An exemplar of the series was shown to be pro-cognitive in the novel object recognition rat model of temporal induced memory deficit.
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http://dx.doi.org/10.1016/j.bmcl.2010.07.097DOI Listing
September 2010

2' biaryl amides as novel and subtype selective M1 agonists. Part II: Further optimization and profiling.

Bioorg Med Chem Lett 2010 Jun 17;20(12):3545-9. Epub 2010 May 17.

Discovery Research and Centers of Excellence for Drug Discovery, GlaxoSmithKline, Collegeville, PA 19426, USA.

Further optimization of the biaryl amide series via extensively exploring structure-activity relationships resulted in potent and subtype selective M(1) agonists exemplified by compounds 9a and 9j with good rat PK properties including CNS penetration. Synthesis, structure-activity relationships, subtype selectivity for M(1) over M(2-5), and DMPK properties of these novel compounds are described.
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http://dx.doi.org/10.1016/j.bmcl.2010.04.127DOI Listing
June 2010

Taenia serialis in a domestic rabbit.

Authors:
Adam Lloyd Lucas

Vet Rec 2010 Mar;166(13):407

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http://dx.doi.org/10.1136/vr.c1656DOI Listing
March 2010

Potentiation of the anticonvulsant efficacy of sodium channel inhibitors by an NK1-receptor antagonist in the rat.

Epilepsia 2010 Aug 7;51(8):1543-51. Epub 2010 Jan 7.

New Frontiers Science Park, GlaxoSmithKline plc, Harlow, Essex, UK.

Purpose: Many patients with epilepsy are refractory to anticonvulsant drugs or do not tolerate side effects associated with the high doses required to fully prevent seizures. Antagonists of neurokinin-1 (NK1) receptors have the potential to reduce seizure severity, although this potential has not been fully explored in animals or humans. The present study was designed to evaluate the efficacy of the NK1-receptor antagonist, vofopitant, alone and in combination with different anticonvulsant drugs.

Methods: Studies were conducted in rats using a model of generalized seizure induced by electroshock. Drug concentrations in blood and brain were determined in parallel to distinguish pharmacodynamic from pharmacokinetic interactions.

Results: The NK1-receptor antagonist, GR205171 (vofopitant) had no anticonvulsant efficacy by itself, but could potentiate the anticonvulsant efficacy of lamotrigine and other sodium channel blockers. However, GR205171 had no effect on the anticonvulsant potency of either valproate or gabapentin. GR205171 did not produce central nervous system (CNS) side effects at the doses tested, and it did not potentiate side effects induced by high doses of lamotrigine. The NK1-receptor inactive enantiomer of GR205171, GR226206 did not potentiate the efficacy of lamotrigine, suggesting that effects observed with GR205171 were mediated by NK1 receptors. Analysis of the dose-effect relationship for GR205171 indicated that a high (>99%) occupancy of NK1 receptors is required for effect, consistent with previous behavioral and human clinical studies with this pharmacologic class.

Discussion: These results suggest that there may be benefit in adding treatment with a suitable NK1-receptor antagonist to treatment with a sodium channel blocker in patients with refractory epilepsy.
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http://dx.doi.org/10.1111/j.1528-1167.2009.02482.xDOI Listing
August 2010

The relationship between sodium channel inhibition and anticonvulsant activity in a model of generalised seizure in the rat.

Epilepsy Res 2009 Jul 28;85(1):96-106. Epub 2009 Mar 28.

epartment of Molecular and Cellular Biology, Neuroscience Centre of Excellence for Drug Discovery, Medicines Research Centre, GlaxoSmithKline S.p.A., Via Fleming 4, Verona 37135, Italy.

The development of novel anticonvulsant drugs with improved efficacy for the treatment of epilepsy is hindered by a lack of information regarding the quantitative relationship between target mechanism and in vivo efficacy. In the present study we have examined the correlation between the potency of structurally diverse compounds at voltage-gated sodium channels in vitro and their efficacy in a rodent model of acute generalised seizures induced by electroshock. We observed a significant correlation between the estimated affinity (Ki) of the compounds for the inactivated state of human recombinant Na(V)1.2 channels and the unbound brain concentration required for anticonvulsant efficacy. Furthermore, the data suggest that an unbound concentration equivalent to less than 50% of the Ki is sufficient for anticonvulsant effect. We noted that increasing sodium channel blocking potency was associated with increasing brain tissue binding and lipophilicity. These data suggest that there is a balance between sodium channel blocking potency in vitro and good pharmacokinetic characteristics necessary for anticonvulsant efficacy in vivo. Finally, we examined the sodium channel blocking potency of sodium valproate in relation to its anticonvulsant efficacy in vivo. We found that a higher unbound concentration of the drug in the brain was required for anticonvulsant efficacy than would be expected given its sodium channel blocking potency.
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http://dx.doi.org/10.1016/j.eplepsyres.2009.02.018DOI Listing
July 2009

Receptor occupancy and brain free fraction.

Drug Metab Dispos 2009 Apr 21;37(4):753-60. Epub 2009 Jan 21.

Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, DD1 5EH, Scotland, UK.

This study was designed to investigate whether brain unbound concentration (C(u,brain)) is a better predictor of dopamine D(2) receptor occupancy than total brain concentration, cerebrospinal fluid concentration (C(CSF)), or blood unbound concentration (C(u,blood)). The ex vivo D(2) receptor occupancy and concentration-time profiles in cerebrospinal fluid, blood, and brain of six marketed antipsychotic drugs were determined after oral administration in rats at a range of dose levels. The C(u,brain) was estimated from the product of total brain concentration and unbound fraction, which was determined using a brain homogenate method. In conclusion, the C(u,brain) of selected antipsychotic agents is a good predictor of D(2) receptor occupancy in rats. Furthermore, C(u,brain) seems to provide a better prediction of D(2) receptor occupancy than C(CSF) or C(u,blood) for those compounds whose mechanism of entry into brain tissue is influenced by factors other than simple passive diffusion.
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http://dx.doi.org/10.1124/dmd.108.022814DOI Listing
April 2009

Statistical mechanics of helix bundles using a dynamic programming approach.

J Am Chem Soc 2007 Apr 16;129(14):4272-81. Epub 2007 Mar 16.

Department of Mathematics, Saint Mary's College of California, Moraga, California 94575-3517, USA.

Despite much study, biomolecule folding cooperativity is not well understood. There are quantitative models for helix-coil transitions and for coil-to-globule transitions, but no accurate models yet treat both chain collapse and secondary structure formation together. We develop here a dynamic programming approach to statistical mechanical partition functions of foldamer chain molecules. We call it the ascending levels model. We apply it to helix-coil and helix-bundle folding and cooperativity. For 14- to 50-mer Baldwin peptides, the model gives good predictions for the heat capacity and helicity versus temperature and urea. The model also gives good fits for the denaturation of Oas's three-helix bundle B domain of protein A (F13W*) and synthetic protein alpha3C by temperature and guanidine. The model predicts the conformational distributions. It shows that these proteins fold with transitions that are two-state, although the transitions in the Baldwin helices are nearly higher order. The model shows that the recently developed three-helix bundle polypeptoids of Lee et al. fold anti-cooperatively, with a predicted value of DeltaHvH/DeltaHcal = 0.72. The model also predicts that two-helix bundles are unstable in proteins but stable in peptoids. Our dynamic programming approach provides a general way to explore cooperativity in complex foldable polymers.
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http://dx.doi.org/10.1021/ja067153sDOI Listing
April 2007

Homogeneous detection of unamplified genomic DNA sequences based on colorimetric scatter of gold nanoparticle probes.

Nat Biotechnol 2004 Jul 30;22(7):883-7. Epub 2004 May 30.

Department of Applied Science, Nanosphere, Inc., 4088 Commercial Avenue, Northbrook, Illinois 60062, USA.

Nucleic acid diagnostics is dominated by fluorescence-based assays that use complex and expensive enzyme-based target or signal-amplification procedures. Many clinical diagnostic applications will require simpler, inexpensive assays that can be done in a screening mode. We have developed a 'spot-and-read' colorimetric detection method for identifying nucleic acid sequences based on the distance-dependent optical properties of gold nanoparticles. In this assay, nucleic acid targets are recognized by DNA-modified gold probes, which undergo a color change that is visually detectable when the solutions are spotted onto an illuminated glass waveguide. This scatter-based method enables detection of zeptomole quantities of nucleic acid targets without target or signal amplification when coupled to an improved hybridization method that facilitates probe-target binding in a homogeneous format. In comparison to a previously reported absorbance-based method, this method increases detection sensitivity by over four orders of magnitude. We have applied this method to the rapid detection of mecA in methicillin-resistant Staphylococcus aureus genomic DNA samples.
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http://dx.doi.org/10.1038/nbt977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1201475PMC
July 2004

Gold nanoparticle-based detection of genomic DNA targets on microarrays using a novel optical detection system.

Biosens Bioelectron 2004 Mar;19(8):875-83

Nanosphere, Inc., Applied Research, 4088 Commercial Ave., Northbrook, IL 60062, USA.

The development of a nanoparticle-based detection methodology for sensitive and specific DNA-based diagnostic applications is described. The technology utilizes gold nanoparticles derivatized with thiol modified oligonucleotides that are designed to bind complementary DNA targets. A glass surface with arrays of immobilized oligonucleotide capture sequences is used to capture DNA targets, which are then detected via hybridization to the gold nanoparticle probes. Amplification with silver allows for detection and quantitation by measuring evanescent wave induced light scatter with low-cost optical detection systems. Compared to Cy3-based fluorescence, silver amplified gold nanoparticle probes provide for a approximately 1000-fold increase in sensitivity. Furthermore, direct detection of non-amplified genomic DNA from infectious agents is afforded through increased specificity and even identification of single nucleotide polymorphisms (SNP) in human genomic DNA appears feasible.
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http://dx.doi.org/10.1016/j.bios.2003.08.014DOI Listing
March 2004
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