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Factors associated with mortality in patients with COVID-19 requiring mechanical ventilation: An international cohort study from 139 intensive care unit across 6 continents [Meeting Abstract]

Li, Bassi G; Suen, J; Dalton, H J; White, N; Barnett, A; Corley, A; Hinton, S; Forsyth, S; Laffey, J G; Brodie, D; Burrell, A; Fan, E; Bartlett, R; Torres, A; Chiumello, D; Elhazmi, A; Hodgson, C L; Ichiba, S; Luna, C; Murthy, S; Nichol, A D; Yeung, Ng P; Ogino, M; Fraser, J
Rationale: Patients with COVID-19 commonly develop severe hypoxemic respiratory failure and require invasive mechanical ventilation (MV). The disease burden and predictors of mortality in this population remain uncertain.
Method(s): Prospective observational cohort study from 139 intensive care units of the international COVID-19 Critical Care Consortium. Patients enrolled from January 14th through November 31st 2020 were included in the analysis. Patient's characteristics and clinical data were assessed. Multivariable Cox proportional hazards analysis was conducted to identify indipendent predictors of mortality within 28 days from commencement of MV.
Result(s): 1578 patients on MV were included into the analysis. Mean+/-SD age was 59 years+/-13 and patients were predominantly males (66%). 542 Patients (34.4%) died within 28 days from commencement of MV. Nonsurvivors were slightly older (mean age+/-SD 62+/-13 vs. 59+/-13) and presented more frequently hypertension, chronic cardiac disease and diabetes. Median (IQR) PaO2/FiO2 upon commencement of MV was 96 (68-135) and 111 (81-173) in patients who did not survive vs. survivors, respectively (p=0.04). ECMO (13% vs 25%, p<0.01), inhaled nitric oxide (11% vs 15%, p=0.02) and recruitment manoeauvres (26% vs 31%, p<0.01) were used less frequently in patients who did not survive. Independent risk factors associated with 28-day mortality included age older than 70 years (hazard ratio [HR], 2.83; 95% CI, 1.32-6.07), higher creatinine levels upon ICU admission (HR, 1.20; 95% CI, 1.03-1.40), and lower pH within 24h from commencement of MV (HR, 0.12; 95% CI, 0.02-0.62), while a shorter period (day) from early symptoms to hospitalisation reduced mortality risks (HR, 0.96; 95% CI, 0.93-0.99).
Conclusion(s): Our findings from a large international cohort of critically-ill COVID-19 patients on mechanical ventilation emphasises that elderly patients, not promptly admitted to the hospital, and who present higher creatinine levels and acidosis are at higher risk of mortality
EMBASE:635309835
ISSN: 1535-4970
CID: 4915462

A role for triglyceride lipase brummer in the regulation of sex differences in Drosophila fat storage and breakdown

Wat, Lianna W; Chao, Chien; Bartlett, Rachael; Buchanan, Justin L; Millington, Jason W; Chih, Hui Ju; Chowdhury, Zahid S; Biswas, Puja; Huang, Vivian; Shin, Leah J; Wang, Lin Chuan; Gauthier, Marie-Pierre L; Barone, Maria C; Montooth, Kristi L; Welte, Michael A; Rideout, Elizabeth J
Triglycerides are the major form of stored fat in all animals. One important determinant of whole-body fat storage is whether an animal is male or female. Here, we use Drosophila, an established model for studies on triglyceride metabolism, to gain insight into the genes and physiological mechanisms that contribute to sex differences in fat storage. Our analysis of triglyceride storage and breakdown in both sexes identified a role for triglyceride lipase brummer (bmm) in the regulation of sex differences in triglyceride homeostasis. Normally, male flies have higher levels of bmm mRNA both under normal culture conditions and in response to starvation, a lipolytic stimulus. We find that loss of bmm largely eliminates the sex difference in triglyceride storage and abolishes the sex difference in triglyceride breakdown via strongly male-biased effects. Although we show that bmm function in the fat body affects whole-body triglyceride levels in both sexes, in males, we identify an additional role for bmm function in the somatic cells of the gonad and in neurons in the regulation of whole-body triglyceride homeostasis. Furthermore, we demonstrate that lipid droplets are normally present in both the somatic cells of the male gonad and in neurons, revealing a previously unrecognized role for bmm function, and possibly lipid droplets, in these cell types in the regulation of whole-body triglyceride homeostasis. Taken together, our data reveal a role for bmm function in the somatic cells of the gonad and in neurons in the regulation of male-female differences in fat storage and breakdown and identify bmm as a link between the regulation of triglyceride homeostasis and biological sex.
PMID: 31961851
ISSN: 1545-7885
CID: 4281822

Fillable 3d printed hollow sphere sets for resolution and contrast measurement in nuclear medicine [Meeting Abstract]

Bartlett, R; Barbee, D
Purpose: Nuclear medicine imaging tests frequently require use of multiple hollow spheres of various size filled with radioactivity in order to measure resolution, contrast, and recovery coefficient. Certain vendor tests can require scans using identical spheres, requiring purchase of multiple sphere sets or specific spheres. Additionally, once filled for testing, spheres become unavailable for other scanners. Therefore, this work sets out to develop 3D printed, fillable spheres for resolution and contrast quality assurance tests of PET and SPECT scanners as customizable, disposable, and low-cost alternatives to those available on the market. Methods: Hollow sphere sets were designed in 123D (Autodesk) with various stem and wall thickness configurations for inner diameter spheres of 5.0, 7.5, and 10 mm. Each sphere and stem were combined and printed as one piece with -20 threads and hollow inner diameter for filling. Spheres were 3D printed using a Makerbot Replicator 2 (Makerbot Industries) using a variety of layer thicknesses, infill and outer shells. All spheres were vacuum tested and leak tested using blue dye in a water bath. Results: The optimal 3D printing parameters were found to be 0.1 mm layer thickness, 100% infill, 1 shell, and transparent filament. Wall thicknesses were successfully reduced to as small as 1 mm while maintaining seal. Spheres printed in 30-45 min for less than $1. MicroCT of each sphere demonstrated that sphere inner diameter was reproducible to within 0.2 mm of the desired diameter. Spheres successfully performed as well as marketed products in PET and cardiac SPECT QA testing. Conclusion: 3D printing of hollow spheres can be an alternative to perform regulatory quality assurance tests on nuclear medicine SPECT and PET cameras. Printed spheres are inexpensive, quick to manufacture, disposable, and configurable for on-demand testing requirements
EMBASE:622804786
ISSN: 0094-2405
CID: 3187992

Quantitative impact of Dixon mumap variability in dual-time-point brain PET/MR

Jackson, Kimberly; Bartlett, Rachel; Friedman, Kent; Shepherd, Timothy; Koesters, Thomas; Teruel, Jose; Fenchel, Mathias; Hermosillova-Valadez, Gerardo; Faul, David; Boada, Fernando
PMCID:4798694
PMID: 26956335
ISSN: 2197-7364
CID: 2023522

Quantitative Graphical Analysis of Simultaneous Dynamic PET/MRI For Assessment of Prostate Cancer

Rosenkrantz, Andrew B; Koesters, Thomas; Vahle, Anne-Kristin; Friedman, Kent; Bartlett, Rachel M; Taneja, Samir S; Ding, Yu-Shin; Logan, Jean
PURPOSE: Dynamic FDG imaging for prostate cancer characterization is limited by generally small size and low uptake in prostate tumors. Our aim in this pilot study was to explore feasibility of simultaneous PET/MRI to guide localization of prostate lesions for dynamic FDG analysis using a graphical approach. METHODS: Three patients with biopsy-proven prostate cancer underwent simultaneous FDG PET/MRI, incorporating dynamic prostate imaging. Histology and multiparametric MRI findings were used to localize tumors, which in turn guided identification of tumors on FDG images. Regions of interest were manually placed on tumor and benign prostate tissue. Blood activity was extracted from a region of interest placed on the femoral artery on PET images. FDG data were analyzed by graphical analysis using the influx constant Ki (Patlak analysis) when FDG binding seemed irreversible and distribution volume VT (reversible graphical analysis) when FDG binding seemed reversible given the presence of washout. RESULTS: Given inherent coregistration, simultaneous acquisition facilitated use of MRI data to localize small lesions on PET and subsequent graphical analysis in all cases. In 2 cases with irreversible binding, tumor had higher Ki than benign using Patlak analysis (0.023 vs 0.006 and 0.019 vs 0.008 mL/cm per minute). In 1 case appearing reversible, tumor had higher VT than benign using reversible graphical analysis (0.68 vs 0.52 mL/cm). CONCLUSIONS: Simultaneous PET/MRI allows localization of small prostate tumors for dynamic PET analysis. By taking advantage of inclusion of the femoral arteries in the FOV, we applied advanced PET data analysis methods beyond conventional static measures and without blood sampling.
PMCID:4352122
PMID: 25608166
ISSN: 0363-9762
CID: 1440332

Copper-64-diacetyl-bis(N(4)-methylthiosemicarbazone) Pharmacokinetics in FaDu Xenograft Tumors and Correlation With Microscopic Markers of Hypoxia

McCall, KC; Humm, JL; Bartlett, R; Reese, M; Carlin, S
PURPOSE: The behavior of copper-64-diacetyl-bis(N(4)-methylthiosemicarbazone) ((64)Cu-ATSM) in hypoxic tumors was examined through a combination of in vivo dynamic positron emission tomography (PET) and ex vivo autoradiographic and histologic evaluation using a xenograft model of head-and-neck squamous cell carcinoma. METHODS AND MATERIALS: (64)Cu-ATSM was administered during dynamic PET imaging, and temporal changes in (64)Cu-ATSM distribution within tumors were evaluated for at least 1 hour and up to 18 hours. Animals were sacrificed at either 1 hour (cohort A) or after 18 hours (cohort B) postinjection of radiotracer and autoradiography performed. Ex vivo analysis of microenvironment subregions was conducted by immunohistochemical staining for markers of hypoxia (pimonidazole hydrochloride) and blood flow (Hoechst-33342). RESULTS: Kinetic analysis revealed rapid uptake of radiotracer by tumors. The net influx (K(i)) constant was 12-fold that of muscle, whereas the distribution volume (V(d)) was 5-fold. PET images showed large tumor-to-muscle ratios, which continually increased over the entire 18-hour course of imaging. However, no spatial changes in (64)Cu-ATSM distribution occurred in PET imaging at 20 minutes postinjection. Microscopic intratumoral distribution of (64)Cu-ATSM and pimonidazole were not correlated at 1 hour or after 18 hours postinjection, nor was (64)Cu-ATSM and Hoechst-33342. CONCLUSIONS: The oxygen partial pressures at which (64)Cu-ATSM and pimonidazole are reduced and bound in cells are theorized to be distinct and separable. However, this study demonstrated that microscopic distributions of these tracers within tumors are independent. Researchers have shown (64)Cu-ATSM uptake to be specific to malignant expression, and this work has also demonstrated clear tumor targeting by the radiotracer.
PMCID:3522091
PMID: 22727887
ISSN: 0360-3016
CID: 169681

Image-guided PO2 probe measurements correlated with parametric images derived from 18F-fluoromisonidazole small-animal PET data in rats

Bartlett, Rachel M; Beattie, Bradley J; Naryanan, Manoj; Georgi, Jens-Christoph; Chen, Qing; Carlin, Sean D; Roble, Gordon; Zanzonico, Pat B; Gonen, Mithat; O'Donoghue, Joseph; Fischer, Alexander; Humm, John L
(18)F-fluoromisonidazole PET, a noninvasive means of identifying hypoxia in tumors, has been widely applied but with mixed results, raising concerns about its accuracy. The objective of this study was to determine whether kinetic analysis of dynamic (18)F-fluoromisonidazole data provides better discrimination of tumor hypoxia than methods based on a simple tissue-to-plasma ratio. METHODS: Eleven Dunning R3327-AT prostate tumor-bearing nude rats were immobilized in custom-fabricated whole-body molds, injected intravenously with (18)F-fluoromisonidazole, and imaged dynamically for 105 min. They were then transferred to a robotic system for image-guided measurement of intratumoral partial pressure of oxygen (Po(2)). The dynamic (18)F-fluoromisonidazole uptake data were fitted with 2 variants of a 2-compartment, 3-rate-constant model, one constrained to have K(1) equal to k(2) and the other unconstrained. Parametric images of the rate constants were generated. The Po(2) measurements were compared with spatially registered maps of kinetic rate constants and tumor-to-plasma ratios. RESULTS: The constrained pharmacokinetic model variant was shown to provide fits similar to that of the unconstrained model and did not introduce significant bias in the results. The trapping rate constant, k(3), of the constrained model provided a better discrimination of low Po(2) than the tissue-to-plasma ratio or the k(3) of the unconstrained model. CONCLUSION: The use of kinetic modeling on a voxelwise basis can identify tumor hypoxia with improved accuracy over simple tumor-to-plasma ratios. An effective means of controlling noise in the trapping rate constant, k(3), without introducing significant bias, is to constrain K(1) equal to k(2) during the fitting process.
PMCID:3784982
PMID: 22933821
ISSN: 0161-5505
CID: 834412

Positron lymphography: multimodal, high-resolution, dynamic mapping and resection of lymph nodes after intradermal injection of 18F-FDG

Thorek, Daniel L J; Abou, Diane S; Beattie, Bradley J; Bartlett, Rachel M; Huang, Ruimin; Zanzonico, Pat B; Grimm, Jan
The lymphatic system plays a critical role in the maintenance of healthy tissues. Its function is an important indicator of the presence and extent of disease. In oncology, metastatic spread to local lymph nodes (LNs) is a strong predictor of poor outcome. Clinical methods for the visualization of LNs involve regional injection and tracking of (99m)Tc-sulfur colloid ((99m)Tc-SC) along with absorbent dyes. Intraoperatively, these techniques suffer from the requirement of administration of multiple contrast media ((99m)Tc-SC and isosulfan blue), unwieldy gamma-probes, and a short effective surgical window for dyes. Preclinically, imaging of transport through the lymphatics is further hindered by the resolution of lymphoscintigraphy and SPECT. We investigated multimodal imaging in animal models using intradermal administration of (18)F-FDG for combined diagnostic and intraoperative use. PET visualizes LNs with high sensitivity and resolution and low background. Cerenkov radiation (CR) from (18)F-FDG was evaluated to optically guide surgical resection of LNs. METHODS: Imaging of (18)F-FDG uptake used PET and sensitive luminescent imaging equipment (for CR). Dynamic PET was performed in both sexes and multiple strains (NCr Nude, C57BL/6, and Nu/Nu) of mice. Biodistribution confirmed the uptake of (18)F-FDG and was compared with that of (99m)Tc-SC. Verification of uptake and the ability to use (18)F-FDG CR to guide nodal removal were confirmed histologically. RESULTS: Intradermal injection of (18)F-FDG clearly revealed lymphatic vessels and LNs by PET. Dynamic imaging revealed rapid and sustained labeling of these structures. Biodistribution of the radiotracer confirmed the active transport of radioglucose in the lymphatics to the local LNs and over time into the general circulation. (18)F-FDG also enabled visualization of LNs through CR, even before surgically revealing the site, and guided LN resection. CONCLUSION: Intradermal (18)F-FDG can enhance the preclinical investigation of the lymphatics through dynamic, high-resolution, and quantitative tomographic imaging. Clinically, combined PET/Cerenkov imaging has significant potential as a single-dose, dual-modality tracer for diagnostics (PET/CT) and guided resection of LNs (Cerenkov optical).
PMCID:3537831
PMID: 22872741
ISSN: 0161-5505
CID: 985142

Assessment of fetal brain uptake of paraquat in utero using in vivo PET/CT imaging

Bartlett, Rachel M; Murali, Dhanabalan; Nickles, R Jerome; Barnhart, Todd E; Holden, James E; DeJesus, Onofre T
Prenatal in utero conditions are thought to play a role in the development of adult diseases including Parkinson's disease (PD). Paraquat is a common herbicide with chemical structure similar to 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine, a neurotoxin known to induce parkinsonism. In order to assess the role of in utero paraquat exposure in PD, uptake in maternal and fetal brains were measured using positron emission tomography (PET)/computed tomography (CT) imaging. Two anesthetized pregnant rhesus macaques in the late second trimester of pregnancy were given bolus iv injections of (1)(1)C-paraquat, and whole-body PET/CT imaging was performed. Using maternal ventricular blood pool as the input function, the unidirectional influx rate constants (K(i)s), a measure of the irreversible transport of paraquat from plasma to brain, were calculated for the maternal and fetal brains using Patlak graphical analysis. Results indicate minimal uptake of paraquat by both maternal and fetal brains with average K(i)s of 0.0009 and 0.0016 per minute, respectively. The highest regional cerebral uptake in the maternal brain (0.0009% injected dose) was seen in the pineal gland, a structure known to lack a blood brain barrier. The finding of minimal paraquat uptake in maternal and fetal brains is similar to previous findings in adult male macaques and extends the contention that a single acute paraquat exposure, prenatally or postnatally, is unlikely to play a role in PD.
PMCID:3155081
PMID: 21546347
ISSN: 1096-0929
CID: 162771

Fetal dopamine receptor characteristics assessed in utero

Bartlett, Rachel M; Dejesus, Onofre T; Barnhart, Todd E; Nickles, R Jerome; Christian, Bradley T; Graner, John L; Holden, James E
Any tracer in fetal tissue comes from maternal arterial blood. Provided steady state is achieved and intermediate compartments are reversible, the Logan graphical methods should be applicable to the assessment of binding parameters in the fetal brain. Two pregnant rhesus macaques were studied with fallypride and the Logan method was used to assess dopamine receptor distribution volume ratios (DVRs) in both maternal and fetal striatum. The agreement between fetal striatal DVRs using maternal arterial blood and maternal and fetal cerebellum as input functions strongly supports our hypothesis that the conditions necessary for graphical analysis have been met.
PMCID:2949247
PMID: 20531464
ISSN: 0271-678x
CID: 162772