OBJECTIVES::
Measurements of extravascular lung water (EVLW) correlate to the degree of pulmonary edema and have substantial prognostic information in critically ill patients. Prior studies using single indicator thermodilution have reported that 21% to 35% of patients with clinical acute respiratory distress syndrome (ARDS) have normal EVLW (<10 mL/kg). Given that lung size is independent of actual body weight, we sought to determine whether indexing EVLW to predicted or adjusted body weight affects the frequency of increased EVLW in patients with ARDS. DESIGN:: Prospective, observational cohort study. SETTING:: Medical and surgical intensive care units at two academic hospitals. PATIENTS:: Thirty patients within 72 hrs of meeting American-European Consensus Conference definition of ARDS and 14 severe sepsis patients without ARDS. INTERVENTIONS:: None. MEASUREMENT AND MAIN RESULTS:: EVLW was measured for 7 days by PiCCO transpulmonary thermodilution; 225 measurements of EVLW indexed to actual body weight (ActBW) were compared with EVLW indexed to predicted body weight (PBW) and adjusted body weight (AdjBW). Mean EVLW indexed to ActBW was 12.7 mg/kg for ARDS patients and 7.8 mg/kg for non-ARDS sepsis patients (p < .0001). In all patients, EVLW increased an average of 1.1 ± 2.1 mL/kg when indexed to AdjBW and 2.0 ± 4.1 mL/kg when indexed to PBW. Indexing EVLW to PBW or AdjBW increased the proportion of ARDS patients with elevated EVLW (each p < .05) without increasing the frequency of elevated EVLW in non-ARDS patients. EVLW indexed to PBW had a stronger correlation to Lung Injury Score (r = .39 vs. r = .17) and Pao2/Fio2 ratio (r = .25 vs. r = .10) than did EVLW indexed to ActBW. CONCLUSIONS:: Indexing EVLW to PBW or AdjBW reduces the number of ARDS patients with normal EVLW and correlates better to Lung Injury Score and oxygenation than using ActBW. Studies are needed to confirm the presumed superiority of this method for diagnosing ARDS and to determine the clinical treatment implications.
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Danica K. Knight;
Steven Belenko;
Tisha Wiley;
Angela A. Robertson;
Nancy Arrigona;
Michael Dennis;
John P. Bartkowski;
Larkin S. McReynolds;
Jennifer E. Becan;
Hannah K. Knudsen;
Gail A. Wasserman;
Eve Rose;
Ralph Diclemente;
Carl Leukefeld
Background: The purpose of this paper is to describe the Juvenile Justice-Translational Research on Interventions for Adolescents in the Legal System (JJ-TRIALS) study, a cooperative implementation science initiative involving the National Institute on Drug Abuse, six research centers, a coordinating center, and Juvenile Justice Partners representing seven US states. While the pooling of resources across centers enables a robust implementation study design involving 36 juvenile justice agencies and their behavioral health partner agencies, co-producing a study protocol that has potential to advance implementation science, meets the needs of all constituencies (funding agency, researchers, partners, study sites), and can be implemented with fidelity across the cooperative can be challenging. This paper describes (a) the study background and rationale, including the juvenile justice context and best practices for substance use disorders, (b) the selection and use of an implementation science framework to guide study design and inform selection of implementation components, and (c) the specific study design elements, including research questions, implementation interventions, measurement, and analytic plan.
Methods/design: The JJ-TRIALS primary study uses a head-to-head cluster randomized trial with a phased rollout to evaluate the differential effectiveness of two conditions (Core and Enhanced) in 36 sites located in seven states. A Core strategy for promoting change is compared to an Enhanced strategy that incorporates all core strategies plus active facilitation. Target outcomes include improvements in evidence-based screening, assessment, and linkage to substance use treatment.
Discussion: Contributions to implementation science are discussed as well as challenges associated with designing and deploying a complex, collaborative project.
Terbinafine N-dealkylation pathways result in formation of 6,6-dimethyl-2-hepten-4-ynal (TBF-A), a reactive allylic aldehyde, that may initiate idiosyncratic drug-induced liver toxicity. Previously, we reported on the importance of CYP2C19 and 3A4 as major contributors to TBF-A formation. In this study, we expanded on those efforts to assess individual contributions of CYP1A2, 2B6, 2C8, 2C9, and 2D6 in terbinafine metabolism. The combined knowledge gained from these studies allowed us to scale the relative roles of the P450 isozymes in hepatic clearance of terbinafine including pathways leading to TBF-A, and hence, provide a foundation for assessing their significance in terbinafine-induced hepatotoxicity. We used in vitro terbinafine reactions with recombinant P450s to measure kinetics for multiple metabolic pathways and calculated contributions of all individual P450 isozymes to in vivo hepatic clearance for the average human adult. The findings confirmed that CYP3A4 was a major contributor (at least 30% total metabolism) to all three of the possible N-dealkylation pathways; however, CYP2C9, and not CYP2C19, played a critical role in terbinafine metabolism and even exceeded CYP3A4 contributions for terbinafine N-demethylation. A combination of their metabolic capacities accounted for at least 80% of the conversion of terbinafine to TBF-A, while CYP1A2, 2B6, 2C8, and 2D6 made minor contributions. Computational approaches provide a more rapid, less resource-intensive strategy for assessing metabolism, and thus, we additionally predicted terbinafine metabolism using deep neural network models for individual P450 isozymes. Cytochrome P450 isozyme models accurately predicted the likelihood for terbinafine N-demethylation, but overestimated the likelihood for a minor N-denaphthylation pathway. Moreover, the models were not able to differentiate the varying roles of the individual P450 isozymes for specific reactions with this particular drug. Taken together, the significance of CYP2C9 and 3A4 and to a lesser extent, CYP2C19, in terbinafine metabolism is consistent with reported drug interactions. This finding suggests that variations in individual P450 contributions due to other factors like polymorphisms may similarly contribute to terbinafine-related adverse health outcomes. Nevertheless, the impact of their metabolic capacities on formation of reactive TBF-A and consequent idiosyncratic hepatotoxicity will be mitigated by competing detoxification pathways, TBF-A decay, and TBF-A adduction to glutathione that remain understudied.
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Shireen Parsai;
Richard L. J. Qiu;
Peng Qi;
Juan C. L. Alfonso;
Jeremy Donaghue;
Eric Murray;
David Majkszak;
Nicole Dorio;
Clifton D. Fuller;
Kristy Brock;
Shlomo Koyfman;
Neil Woody;
Nikhil Joshi;
Jacob G. Scott
Purpose
Prior in silico simulations propose that Temporally Feathered Radiation Therapy (TFRT) may reduce toxicity related to head and neck radiation therapy. In this study we demonstrate a step‐by‐step guide to TFRT planning with modern treatment planning systems.
Methods
One patient with oropharyngeal cancer planned for definitive radiation therapy using intensity‐modulated radiation therapy (IMRT) techniques was replanned using the TFRT technique. Five organs at risk (OAR) were identified to be feathered. A “base plan” was first created based on desired planning target volumes (PTV) coverage, plan conformality, and OAR constraints. The base plan was then re‐optimized by modifying planning objectives, to generate five subplans. All beams from each subplan were imported onto one trial to create the composite TFRT plan. The composite TFRT plan was directly compared with the non‐TFRT IMRT plan. During plan assessment, the composite TFRT was first evaluated followed by each subplan to meet preset compliance criteria.
Results
The following organs were feathered: oral cavity, right submandibular gland, left submandibular gland, supraglottis, and OAR Pharynx. Prescription dose PTV coverage (>95%) was met in each subplan and the composite TFRT plan. Expected small variations in dose were observed among the plans. The percent variation between the high fractional dose and average low fractional dose was 29%, 28%, 24%, 19%, and 10% for the oral cavity, right submandibular, left submandibular, supraglottis, and OAR pharynx nonoverlapping with the PTV.
Conclusions
Temporally Feathered Radiation Therapy planning is possible with modern treatment planning systems. Modest dosimetric changes are observed with TFRT planning compared with non‐TFRT IMRT planning. We await the results of the current prospective trial to seeking to demonstrate the feasibility of TFRT in the modern clinical workflow (NCT03768856). Further studies will be required to demonstrate the potential benefit of TFRT over non‐TFRT IMRT Planning.
The city of Clarkston (Georgia) is home to many refugees and immigrants, including Bhutanese and Burmese populations. Use of gutka and paan masala is common in these populations. While gutka and paan masala contain toxic ingredients including carcinogens, little research has examined general use, perceptions of risk, cultural norms, and access to these products among Bhutanese and Burmese populations in the southern U.S. This study uses focus groups and key informant interviews to develop an understanding of gutka and paan masala use among Bhutanese and Burmese refugee populations residing in Clarkston, focusing in particular on knowledge and perceptions of harm, patterns of and reasons for use, access to gutka and paan masala, and resources for cessation and prevention of gutka and paan masala use. We conducted 21 focus groups with Bhutanese and Burmese youths and adults and 11 key informant interviews. We analyzed data using MAXQDA and a grounded theory approach. Emerging themes included mixed understandings of ingredients and harms associated with gutka and paan masala use. The continued use of paan masala was perceived to be due to cultural traditions. Youths, particularly Bhutanese, were perceived as a rising group of users of gutka and paan masala. Widespread availability and accessibility in Clarkston made it easy for both adults and youths to acquire and use gutka and paan masala. Few participants knew about prevention efforts or resources in their communities. In conclusion, culturally-relevant awareness and education programs as well as health promotion materials regarding gutka and paan masala are much needed in Bhutanese and Burmese communities. More regulatory actions are needed, such as better warning signs in businesses to inform customers of ingredients in these products and their health risks, age restrictions on gutka and paan masala purchase, and compliance checks.
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Nima Kokabi;
Linzi Arndt-Webster;
Bernard Chen;
David Brandon;
Ila Sethi;
Amir Davarpanah;
James Galt;
Mohammad Elsayed;
Zachary Bercu;
Mircea Cristescu;
S. Cheenu Kappadath;
David Schuster
Background: There is an increasing body of evidence indicating Y90 dose thresholds for tumor response and treatment-related toxicity. These thresholds are poorly studied in resin Y90, particularly in hepatocellular carcinoma (HCC). Purpose: To evaluate the efficacy of prospective voxel-based dosimetry for predicting treatment response and adverse events (AEs) in patients with HCC undergoing resin-based Y90 radioembolization. Materials and methods: This correlative study was based on a prospective single-arm clinical trial (NCT04172714), which evaluated the efficacy of low/scout (555 MBq) activity of resin-based Y90 for treatment planning. Partition model was used with goal of tumor dose (TD) > 200 Gy and non-tumoral liver dose (NTLD) < 70 Gy for non-segmental therapies. Single compartment dose of 200 Gy was used for segmentectomies. Prescribed Y90 activity minus scout activity was administered for therapeutic Y90 followed by Y90-PET/CT. Sureplan® (MIM Software, Cleveland, OH) was used for dosimetry analysis. Treatment response was evaluated at 3 and 6 months. Receiver operating characteristic curve determined TD response threshold for objective response (OR) and complete response (CR) as well as non-tumor liver dose (NTLD) threshold that predicted AEs. Results: N = 30 patients were treated with 33 tumors (19 segmental and 14 non-segmental). One patient died before the first imaging, and clinical follow-up was excluded from this analysis. Overall, 26 (81%) of the tumors had an OR and 23 (72%) had a CR. A mean TD of 253 Gy predicted an OR with 92% sensitivity and 83% specificity (area under the curve (AUC = 0.929, p < 0.001). A mean TD of 337 Gy predicted a CR with 83% sensitivity and 89% specificity (AUC = 0.845, p < 0.001). A mean NTLD of 81 and 87 Gy predicted grade 3 AEs with 100% sensitivity and 100% specificity in the non-segmental cohort at 3- and 6-month post Y90, respectively. Conclusion: In patients with HCC undergoing resin-based Y90, there are dose response and dose toxicity thresholds directly affecting outcomes. Clinical trial number: NCT04172714.
The northern cardinal (Cardinalis cardinalis) is a good indicator species for environmental contaminants because it does not migrate and its range covers a diversity of habitats, including metropolitan Atlanta, GA and the geographically isolated Hawaiian Islands. In addition, the cardinal is often found near people's homes, making it likely to be exposed to the same outdoor elements, including soil, groundwater, and air, that surrounding humans experience. In this study, blood serum concentrations of 12 per- and polyfluoroalkyl substances (PFASs) were measured in 40 cardinals from Atlanta and 17 cardinals from the Big Island (Hawaii), HI. We observed significantly higher median concentrations of four PFASs and significantly higher detection frequencies of seven PFASs in the cardinals from Atlanta, relative to the PFAS median concentrations and detection frequencies observed in the cardinals from Hawaii (α = 0.05). Among the PFASs measured, perfluorooctane sulfonate (PFOS) was observed in the highest concentrations. A linear regression model controlling for sex, age, and airport distance did not explain PFOS variation within the Atlanta samples, but a similar model explained 90% of PFOS variation within the Hawaii samples. To our knowledge, these are the first measurements of PFASs in northern cardinals.
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Galina Gritsina;
Ka-wing Fong;
Xiaodong Lu;
Zhuoyuan Lin;
Wanqing Xie;
Shivani Agarwal;
Dong Lin;
Gary E Schiltz;
Himisha Beltran;
Eva Corey;
Colm Morrissey;
Yuzhuo Wang;
Jonathan C Zhao;
Maha Hussain;
Jindan Yu
CXCR7 is an atypical chemokine receptor that recruits β-arrestin (ARRB2) and internalizes into clathrin-coated intracellular vesicles where the complex acts as a scaffold for cytoplasmic kinase assembly and signal transduction. Here, we report that CXCR7 was elevated in the majority of prostate cancer (PCa) cases with neuroendocrine features (NEPC). CXCR7 markedly induced mitotic spindle and cell cycle gene expression. Mechanistically, we identified Aurora Kinase A (AURKA), a key regulator of mitosis, as a novel target that was bound and activated by the CXCR7-ARRB2 complex. CXCR7 interacted with proteins associated with microtubules and golgi, and, as such, the CXCR7-ARRB2-containing vesicles trafficked along the microtubules to the pericentrosomal golgi apparatus, where the complex interacted with AURKA. Accordingly, CXCR7 promoted PCa cell proliferation and tumor growth, which was mitigated by AURKA inhibition. In summary, our study reveals a critical role of CXCR7-ARRB2 in interacting and activating AURKA, which can be targeted by AURKA inhibitors to benefit a subset of patients with NEPC.
Introduction: Poisoning is an increasingly important cause of injury in the United States. In 2009 poison centers received 2,479,355 exposure reports, underscoring the role of poison centers in intentional and unintentional injury prevention. Antiretroviral (ARV) agents are commonly prescribed drugs known to cause toxicity, yet the frequency of these incidents is unknown. The objectives of this study were to quantify the number of reported cases of toxicity secondary to ARV agents at a regional poison center, and to describe the circumstances and clinical manifestations of these poisonings. Methods: We conducted a retrospective review of poison center records between December 1, 2001, and January 7, 2010. Results: One hundred sixty-two exposures to ARV agents were reported to the poison center, of which 30% were intentional and 70% were unintentional. Three patients developed major toxicity and no deaths occurred. The remaining patients developed moderate and minor effects as defined by poison center guidelines. Conclusion: ARV drug toxicity appears to be infrequently reported to the poison center. Fatal and major toxicities are uncommon, and intentional overdoses are associated with a more serious toxicity. Educational efforts should encourage clinicians to report toxicities related to the use of ARV agents to poison centers in order to better study this problem.
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Thomas H. Thatcher;
Collynn F. Woeller;
Juilee Thakar;
Atif Khan;
Philip Hopke;
Matthew Smith;
Karan Uppal;
Douglas Walker;
Young-Mi Go;
Dean Jones;
Pamela L. Krahl;
Timothy M. Mallon;
Patricia J. Sime;
Richard P. Phipps;
Mark J. Utell
Objective:The potential health risks of deployment to sites with open burn pits remain poorly understood, in part, because personal exposure monitoring was not performed. Here, we investigated whether postdeployment serum samples contain biomarkers associated with exposure to burn pits.Methods:A total of 237 biomarkers were measured in 800 serum samples from deployed and never-deployed subjects. We used a regression model and a supervised vector machine to identify serum biomarkers with significant associations with exposures and deployment.Results:We identified 101 serum biomarkers associated with polycyclic aromatic hydrocarbons, dioxins or furans, and 54 biomarkers associated with deployment. Twenty-six of these biomarkers were shared in common by the exposure and deployment groups.Conclusions:We identify a potential signature of exposure to open burn pits, and provide a framework for using postexposure sera to identify exposures when contemporaneous monitoring was inadequate.