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During fibroproliferation, protein-associated extracellular aldehydes are formed by the oxidation of lysine residues on extracellular matrix proteins to form the aldehyde allysine. Here we report three Mn(II)-based, small molecule magnetic resonance (MR) probes that contain α-effect nucleophiles to target allysine in vivo and report on tissue fibrogenesis. We used a rational design approach to develop turn-on probes with a 4-fold increase in relaxivity upon targeting. The effects of aldehyde condensation rate and hydrolysis kinetics on the performance of the probes to detect tissue fibrogenesis noninvasively in mouse models were evaluated by a systemic aldehyde tracking approach. We showed that for highly reversible ligations, off-rate was a stronger predictor of in vivo efficiency, enabling histologically validated, three-dimensional characterization of pulmonary fibrogenesis throughout the entire lung. The exclusive renal elimination of these probes allowed for rapid imaging of liver fibrosis. Reducing the hydrolysis rate by forming an oxime bond with allysine enabled delayed phase imaging of kidney fibrogenesis. The imaging efficacy of these probes, coupled with their rapid and complete elimination from the body, make them strong candidates for clinical translation.

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Purpose:To evaluate the prognostic value of posttreatment fibrosis in human PDAC patients, and to compare a type I collagen targeted MRI probe, CM-101, to the standard contrast agent, Gd-DOTA, for their abilities to identify FOLFIRINOX-induced fibrosis in a murine model of PDAC.Experimental Design:Ninety-three chemoradiation-treated human PDAC samples were stained for fibrosis and outcomes evaluated. For imaging, C57BL/6 and FVB mice were orthotopically implanted with PDAC cells and FOLFIRINOX was administered. Mice were imaged with Gd-DOTA and CM-101.Results:In humans, post-chemoradiation PDAC tumor fibrosis was associated with longer overall survival (OS) and disease-free survival (DFS) on multivariable analysis (OS P = 0.028, DFS P = 0.047). CPA increased the prognostic accuracy of a multivariable logistic regression model comprised of previously established PDAC risk factors [AUC CPA (−) = 0.76, AUC CPA (+) = 0.82]. In multiple murine orthotopic PDAC models, FOLFIRINOX therapy reduced tumor weight (P < 0.05) and increased tumor fibrosis by collagen staining (P < 0.05). CM-101 MR signal was significantly increased in fibrotic tumor regions. CM-101 signal retention was also increased in the more fibrotic FOLFIRINOX-treated tumors compared with untreated controls (P = 0.027), consistent with selective probe binding to collagen. No treatment-related differences were observed with Gd-DOTA imaging.Conclusions:In humans, post-chemoradiation tumor fibrosis is associated with OS and DFS. In mice, our MR findings indicate that translation of collagen molecular MRI with CM-101 to humans might provide a novel imaging technique to monitor fibrotic response to therapy to assist with prognostication and disease management.

Both exercise-induced molecular mechanisms and physiological cardiac remodeling have been previously studied on a whole heart level. However, the regional microstructural tissue effects of these molecular mechanisms in the heart have yet to be spatially linked and further elucidated. We show in exercised mice that the expression of CITED4, a transcriptional co-regulator necessary for cardioprotection, is regionally heterogenous in the heart with preferential significant increases in the lateral wall compared with sedentary mice. Concordantly in this same region, the heart's local microstructural tissue helicity is also selectively increased in exercised mice. Quantification of CITED4 expression and microstructural tissue helicity reveals a significant correlation across both sedentary and exercise mouse cohorts. Furthermore, genetic deletion of CITED4 in the heart prohibits regional exercise-induced microstructural helicity remodeling. Taken together, CITED4 expression is necessary for exercise-induced regional remodeling of the heart's microstructural helicity revealing how a key molecular regulator of cardiac remodeling manifests into downstream local tissue-level changes.Expression of transcription factor CITED4 is necessary for exercise-induced regional remodeling of the heart's microstructural helicity, revealing how a key molecular regulator of cardiac remodeling mediates local tissue-level changes.

Undergraduate students participating in the UCLA Undergraduate Research Consortium for Functional Genomics (URCFG) have conducted a two-phased screen using RNA interference (RNAi) in combination with fluorescent reporter proteins to identify genes important for hematopoiesis in Drosophila. This screen disrupted the function of approximately 3500 genes and identified 137 candidate genes for which loss of function leads to observable changes in the hematopoietic development. Targeting RNAi to maturing, progenitor, and regulatory cell types identified key subsets that either limit or promote blood cell maturation. Bioinformatic analysis reveals gene enrichment in several previously uncharacterized areas, including RNA processing and export and vesicular trafficking. Lastly, the participation of students in this course-based undergraduate research experience (CURE) correlated with increased learning gains across several areas, as well as increased STEM retention, indicating that authentic, student-driven research in the form of a CURE represents an impactful and enriching pedagogical approach.

Background: Despite considerable research on exercise-induced neuroplasticity in the brain, a major ongoing challenge in translating findings from animal studies to humans is that clinical and preclinical settings employ very different techniques. Objective: Here we aim to bridge this divide by using diffusion tensor imaging MRI (DTI), an advanced imaging technique commonly applied in human studies, in a longitudinal exercise study with mice. Methods: Wild-type mice were exercised using voluntary free-wheel running, and MRI scans were at baseline and after four weeks and nine weeks of running. Results: Both hippocampal volume and fractional anisotropy, a surrogate for microstructural directionality, significantly increased with exercise. In addition, exercise levels correlated with effect size. Histological analysis showed more PDGFRα+ oligodendrocyte precursor cells in the corpus callosum of running mice. Conclusions: These results provide compelling in vivo support for the concept that similar adaptive changes occur in the brains of mice and humans in response to exercise.

Background: Familial chylomicronemia syndrome (FCS) is an ultrarare condition caused by biallelic pathogenic DNA variants in lipolysis-associated genes, resulting in severe hypertriglyceridemia (HTG) and associated with high risk of acute pancreatitis with few therapeutic options. In a 16-week Phase 1 study (NCT03783377), subcutaneously administered ARO-APOC3 reduced serum apolipoprotein C3 (APOC3) and TG in healthy volunteers and participants (pts) with HTG and was well tolerated. Purpose: To report on the safety/pharmacodynamic (PD) effects of ARO-APOC3 in both FCS pts with biallelic pathogenic variants and pts with severely elevated TG at screening (>880 mg/dL) but without biallelic pathogenic variants (chylomicronemia (MCM)). Methods: Four genetically confirmed FCS pts received 50 mg ARO-APOC3 and 26 MCM pts received 10, 25, 50, or 100 mg ARO-APOC3 on Days 1 and 29. Since similar PD responses were observed among MCM pts, results were pooled across dose levels. Safety and PD responses were examined. Maximal mean/median changes from baseline for APOC3, TG, non-HDL-C, and HDL-C were reported. Results: Baseline/demographics were comparable between groups, except for mean BMI (22.1 [FCS] and 30.5 [MCM] kg/m 2 ), and mean baseline HDL-C , which were lower in FCS pts (Table 1) (p Conclusions: In patients with severe HTG, ARO-APOC3 was safe, and consistently decreased APOC3, TG, and non-HDL-C, and increased HDL-C, regardless of underlying genetic cause of HTG, and may represent a promising RNAi therapeutic for the treatment of severe HTG.

Inappropriate daily lab testing can have adverse effects on patients, including anemia, pain, and interruption of sleep. We implemented a student-led, multifaceted intervention featuring clinician education, publicity campaign, gamification, and system changes, including a novel nurse-driven protocol to reduce unnecessary daily lab testing in a teaching hospital. We applied a quasi-experimental interrupted time series design with a segmented regression analysis to estimate changes before and after our 14-month intervention with a comparison to a control surgical unit. There was an increasing trend in the baseline period, which was mitigated by the intervention (postintervention effect estimate -0.04 labs per patient day/month, p < .05), which was not seen in the control unit. Estimated cost savings was $94,269 ($6,734/month). A student-led, multidisciplinary campaign involving nurse-driven pathway, education, publicity, gamification, and system changes was effective in reducing daily lab testing.

Background and Purpose: Accurate estimation of ischemic core on baseline imaging has treatment implications in patients with acute ischemic stroke (AIS). Machine learning (ML) algorithms have shown promising results in estimating ischemic core using routine non-contrast CT (NCCT). We used a ML-trained algorithm to quantify ischemic core volume on NCCT and compared the results to concurrent diffusion MRI as the reference standard in patients with AIS. Methods: We analyzed consecutive anterior circulation AIS patients who had baseline (pretreatment) NCCT and MRI (DWI). Ischemic lesion volume was calculated on MRI-DWI using an automated software (Olea Medical SAS, La Ciotat, France). An automatic segmentation approach using a combination of traditional 3D graphics and statistical methods, and ML classification techniques (Brainomix, Oxford, United Kingdom) was used to identify ischemic core voxels on NCCT. Total ischemic core volumes on ML-NCCT and DWI-MR were quantitatively compared by Bland-Altman plots and Pearson correlation. Results: A total of 50 patients (27 female, 23 male, mean age 72.6 years) were included. Baseline imaging was performed within 173 ± 143 minutes (mean ± SD) from symptom onset. The mean time difference between MRI and NCCT was 72 min. The baseline NIHSS was 14, 8-21 (Median, IQR). Algorithm-segmented ischemic core volume detected on NCCT was median 12.7 mL, IQR 3.5-26.0 mL. Ischemic core volume on DWI MRI was median 8.8 mL, IQR 3.2-34.0 mL. ML-NCCT core volumes significantly correlated with DWI MRI core volumes, r =0.61, p p =0.81. For the reperfusion treatment threshold of an ischemic core volume within 70 mL, while no patients would have been excluded using our algorithm, five patients would have been incorrectly dichotomized as having an ischemic volume of Conclusion: This ML-approach accurately quantifies ischemic core volume on NCCT compared to the reference standard of diffusion MRI in patients with AIS.

Background and Purpose: In acute ischemic stroke (AIS), perfusion imaging, while not directly visualizing collateral vessels, can provide important insight into collateral robustness, indexed by perfusion lesion volume and by perfusion lesion heterogeneity. Two proposed perfusion lesion heterogeneity measures indexing collateral status are the Perfusion Collateral Index (PCI) and Hypoperfusion Intensity Ratio (HIR), but their accuracy compared with direct collateral assessment on DSA has been incompletely characterized. Methods: Consecutive AIS patients with anterior circulation large vessel occlusion who underwent pre-endovascular thrombectomy MRI perfusion imaging were included. MRI measures analyzed were: 1) Perfusion Collateral Index ( PCI) - the volume of moderately hypoperfused tissue (arterial tissue delay time between 2 and 6 seconds: ATD 2-6sec ) multiplied by its corresponding relative cerebral blood volume using Olea software; 2) Hypoperfusion Intensity Ratio (HIR) ratio of moderate TMax >6 s lesion volume versus severe Tmax >10 s lesion volume with the RAPID software program. DSA collateral scores were evaluated by ASITN grading and dichotomized to inadequate (ASTIN Results: Among 48 patients meeting entry criteria, age (mean ± SD) was 70 (± 15.2), 54% were female, and NIHSS (median, IQR) was 15 (10-19). For HIR, there was no significant difference in score values in patients with adequate vs inadequate collaterals: 0.35 ± 0.20 vs 0.39 ± 0.25, p=0.68. ROC analysis using previously described cut-off of 0.4 resulted in an AUC of 0.52 and sensitivity/specificity of 71% / 33%. For PCI, score values were significantly higher in patients with adequate vs inadequate collaterals, 117 ± 61 vs. 57 ± 41, p=0.002. ROC analysis using previously described cut-off of 62 resulted in an AUC of 0.8 and sensitivity/specificity of 84% / 78%. Conclusion: Collateral status can be accurately assessed on perfusion MRI with the Perfusion Collateral Index, which outperformed the Hypoperfusion Intensity Ratio. MRI-PCI is an informative imaging biomarker of collateral status in patients with AIS.

The detection of thrombus in the left atrial appendage (LAA) is vital in the prevention of stroke. We present a novel technique to detect and characterize LAA thrombus in humans using positron emission tomography (PET) of a fibrin-binding radiotracer, [64Cu]FBP8. Initial testing in healthy volunteers (n = 8) revealed that [64Cu]FBP8 was stable to metabolism and was rapidly eliminated with a blood half-life of one hour. Patients with atrial fibrillation (AF) and recent transesophageal echocardiograms (TEEs) of the LAA (positive n = 12, negative n = 12) were studied. PET, integrated with magnetic resonance (PET-MR), of the thorax was performed one hour after [64Cu]FBP8 injection. The maximum standardized uptake value (SUVMax) in the LAA was significantly higher in the TEE positive than negative subjects, median [interquartile range] of 4.0 [3.0–6.0] vs. 2.3 [2.1–2.5]; p < 0.001. A SUVMax threshold of 2.6 correctly identified 12/12 positive TEEs and 10/12 negative ones, yielding an area-under-the-receiver operating characteristic curve of 0.97. The minimum longitudinal magnetic relaxation time (T1Min) in the LAA was significantly shorter in the TEE positive than TEE negative group 970 [780–1080] vs. 1380 [1120–1620], p < 0.05, with some overlap between the groups. Logistic regression using SUVMax and T1Min allowed all TEE positive and negative subjects to be classified with 100% accuracy. A strong correlation was seen between fibrin (SUVMax) and methemoglobin (T1Min) content in the LAA. In conclusion, the detection of LAA thrombus in humans with PET-MR of [64Cu]FBP8 is highly accurate and provides useful information on the biological properties of cardiac thrombus.One Sentence SummaryFirst-in-human fibrin-targeted PET-MR of thrombus

Purpose: To evaluate the prognostic value of posttreatment fibrosis in human PDAC patients, and to compare a type I collagen targeted MRI probe, CM-101, to the standard contrast agent, Gd-DOTA, for their abilities to identify FOLFIRINOX-induced fibrosis in a murine model of PDAC. Experimental Design: Ninety-three chemoradiation-treated human PDAC samples were stained for fibrosis and outcomes evaluated. For imaging, C57BL/6 and FVB mice were orthotopically implanted with PDAC cells and FOLFIRINOX was administered. Mice were imaged with Gd-DOTA and CM-101. Results: In humans, post-chemoradiation PDAC tumor fibrosis was associated with longer overall survival (OS) and disease-free survival (DFS) on multivariable analysis (OS P = 0.028, DFS P = 0.047). CPA increased the prognostic accuracy of a multivariable logistic regression model comprised of previously established PDAC risk factors [AUC CPA (−) = 0.76, AUC CPA (+) = 0.82]. In multiple murine orthotopic PDAC models, FOLFIRINOX therapy reduced tumor weight (P < 0.05) and increased tumor fibrosis by collagen staining (P < 0.05). CM-101 MR signal was significantly increased in fibrotic tumor regions. CM-101 signal retention was also increased in the more fibrotic FOLFIRINOX-treated tumors compared with untreated controls (P = 0.027), consistent with selective probe binding to collagen. No treatment-related differences were observed with Gd-DOTA imaging. Conclusions: In humans, post-chemoradiation tumor fibrosis is associated with OS and DFS. In mice, our MR findings indicate that translation of collagen molecular MRI with CM-101 to humans might provide a novel imaging technique to monitor fibrotic response to therapy to assist with prognostication and disease management.

The aim of this exploratory study was to investigate the level of skills and training needs reported by special educators and teaching associates in functional behavioral assessment (FBA) and behavioral interventions within special education (SPED) schools in Singapore. The Skills and Needs Inventories in Functional Behavior Assessments and Interventions (SNI-FBAI), a self-report inventory, was administered to 378 special educators and 38 teaching support staff across seven SPED schools in Singapore. Perceived ratings across both groups were obtained across 13 items for skills and six items for training needs in FBA and behavioral interventions. The results suggested that special educators and teaching associates indicated relatively lower ratings on their perceived skill in more items related to conducting an FBA when compared with items related to behavioral interventions. In terms of training needs, both groups rated developing skills in FBA and behavioral interventions for managing severe challenging behaviors as a priority area for training.

Resistance to reverse transcriptase and protease inhibitors was frequently detected in HIV from black men who have sex with men (MSM) enrolled in the HIV prevention trials network (HPTN) 061 study. In this study, integrase strand transfer inhibitor (INSTI) resistance was analyzed in black MSM enrolled in HPTN 061 (134 infected at enrollment and 23 seroconverters) and a follow-up study, HPTN 073 (eight seroconverters). The ViroSeq HIV-1 Integrase Genotyping Kit (Abbott Molecular) was used for analysis. Major INSTI resistance mutations were not detected in any of the samples. HIV from 14 (8.4%) of the 165 men, including 4 (12.9%) of 31 seroconverters, had accessory or polymorphic INSTI-associated mutations. The most frequently detected mutation was E157Q. These findings are promising because INSTI-based regimens are now recommended for first-line antiretroviral treatment and because long-acting cabotegravir is being evaluated for pre-exposure prophylaxis.

The development of complex, multi-step methods in molecular biology is a laborious, costly, iterative and often intuition-bound process where an optimum is sought in a multidimensional parameter space through step-by-step optimisations. The difficulty of miniaturising reactions under the microliter volumes usually handled in multiwell plates by robots, plus the cost of the experiments, limit the number of parameters and the dynamic ranges that can be explored. Nevertheless, because of non-linearities of the response of biochemical systems to their reagent concentrations, broad dynamic ranges are necessary. Here we use a high-performance nanoliter handling platform and computer generation of liquid transfer programs to explore in quadruplicates more than 600 combinations of 4 parameters of a biochemical reaction, the reverse-transcription, which lead us to uncover non-linear responses, parameter interactions and novel mechanistic insights. With the increased availability of computer-driven laboratory platforms for biotechnology, our results demonstrate the feasibility and advantage of methods development based on reproducible, computer-aided exhaustive characterisation of biochemical systems.

Background: Lifestyle modification is an important component of clinical encounters, particularly in student-run free clinics that provide care for uninsured patients with a high burden of chronic disease. This study aimed to evaluate the effect of two interventions on the rates of documentation of patient diet, exercise, and health goals at East Harlem Health Outreach Partnership (EHHOP), a student-run free clinic affiliated with the Icahn School of Medicine at Mount Sinai.Methods: A quasi-experimental study was performed at EHHOP over 12 weeks from September to November 2015. Rates of documentation of lifestyle modification and health goals discussions were assessed at baseline and following two periods of intervention. Intervention 1 used electronic medical record (EMR) templates for documenting discussions, and Intervention 2 used focused student teaching to prioritize discussion and documentation of lifestyle modification and health goals. Patient characteristics and documentation rates were compared between each of the three time periods.Results: A total of 161 patient visits were included. There were no significant differences in patient characteristics between Baseline (n=54), Intervention 1 (n=50), and Intervention 2 (n=57) time periods. Rates of documentation increased from 48% (Baseline) to 56% (Intervention 1) to 68% (Intervention 2) for diet, 25% to 42% to 53% for exercise, and 22% to 34% to 39% for health goals. EMR-based Intervention 1 was more effective in improving documentation rates for clinicians caring for patients without diabetes, and student teaching-based Intervention 2 was more effective in improving documentation rates for clinicians caring for patients with diabetes.Conclusions: Systemic efforts that incorporate targeted EMR templates and teaching can help promote documentation rates of lifestyle modification discussions in student clinicians.

Analysis of viral genetic linkage can reveal generalized transmission patterns within a population. The HIV Prevention Trials Network 061 study evaluated HIV incidence among black men who have sex with men. HIV genotypes from 169 men who were HIV infected at enrollment and 23 men who seroconverted during the study were analyzed for genetic linkage. This analysis showed some associations of viral linkage with income, study site, and timing of infection.

Depression is linked to a range of poor HIV-related health outcomes. Minorities and men who have sex with men (MSM), suffer from high rates of depression. The current study examined the relationship between depressive symptoms and social network characteristics among community-recruited Black MSM in HPTN 061 from 6 US cities. A social network inventory was administer at baseline and depression was assessed with the CES-D at baseline, 6, and 12-months. At baseline, which included 1167 HIV negative and 348 HIV positive participants, size of emotional, financial, and medical support networks were significantly associated with fewer depressive symptoms. In longitudinal mixed models, size of emotional, financial, and medical support networks were significantly associated with fewer depressive symptoms as was the number of network members seen weekly. In the multivariate analyses, size of medical appointment network remained statistically significant (aOR= 0.89, CI=0.81-0.98). These findings highlight the importance of network support of medical care on depression and suggest the value of support mobilization.

To evaluate factors associated with HIV tropism among Black men who have sex with men (MSM) in the United States enrolled in a clinical study (HIV Prevention Trials Network 061).HIV tropism was analyzed using a phenotypic assay (Trofile assay, Monogram Biosciences). Samples were analyzed from 43 men who were HIV infected at enrollment and reported either exclusive insertive intercourse or exclusive receptive intercourse; samples were also analyzed from 20 men who were HIV uninfected at enrollment and seroconverted during the study. Clonal analysis of individual viral variants was performed for seroconverters who had dual/mixed (DM) viruses.DM viruses were detected in samples from 11 (26%) of the 43 HIV-infected men analyzed at the enrollment visit; HIV tropism did not differ between those reporting exclusive insertive vs receptive intercourse. DM viruses were also detected in five (25%) of the 20 seroconverters. DM viruses were associated with lower CD4 cell counts. Seroconverters with DM viruses had dual-tropic viruses only or mixed populations of CCR5- and dual-tropic viruses.DM viruses were frequently detected among Black MSM in this study, including seroconverters. Further studies are needed to understand factors driving transmission and selection of CXCR4- and dual-tropic viruses among Black MSM.

Purpose Although barriers to shared decision making in intensive care units are well documented, there are currently no easily scaled interventions to overcome these problems. We sought to assess stakeholders' perceptions of the acceptability, usefulness, and design suggestions for a tablet-based tool to support communication and shared decision making in ICUs. Methods We conducted in-depth semi-structured interviews with 58 key stakeholders (30 surrogates and 28 ICU care providers). Interviews explored stakeholders' perceptions about the acceptability of a tablet-based tool to support communication and shared decision making, including the usefulness of modules focused on orienting families to the ICU, educating them about the surrogate's role, completing a question prompt list, eliciting patient values, educating about treatment options, eliciting perceptions about prognosis, and providing psychosocial support resources. The interviewer also elicited stakeholders' design suggestions for such a tool. We used constant comparative methods to identify key themes that arose during the interviews. Results Overall, 95% (55/58) of participants perceived the proposed tool to be acceptable, with 98% (57/58) of interviewees finding six or more of the seven content domains acceptable. Stakeholders identified several potential benefits of the tool including that it would help families prepare for the surrogate role and for family meetings as well as give surrogates time and a framework to think about the patient's values and treatment options. Key design suggestions included: conceptualize the tool as a supplement to rather than a substitute for surrogate-clinician communication; make the tool flexible with respect to how, where, and when surrogates can access the tool; incorporate interactive exercises; use video and narration to minimize the cognitive load of the intervention; and build an extremely simple user interface to maximize usefulness for individuals with low computer literacy. Conclusion There is broad support among stakeholders for the use of a tablet-based tool to improve communication and shared decision making in ICUs. Eliciting the perspectives of key stakeholders early in the design process yielded important insights to create a tool tailored to the needs of surrogates and care providers in ICUs.

Recent studies have suggested that brown adipose tissue (BAT) plays an important role in obesity, insulin resistance and heart failure. The characterization of BAT in vivo, however, has been challenging. No technique to comprehensively image BAT anatomy and function has been described. Moreover, the impact on BAT of the neuroendocrine activation seen in heart failure has only recently begun to be evaluated in vivo. The aim of this study was to use MRI to characterize the impact of heart failure on the morphology and function of BAT. Mice subjected to permanent ligation of the left coronary artery were imaged with MRI 6 weeks later. T2 weighted MRI of BAT volume and blood oxygen level dependent MRI of BAT function were performed. T2 * maps of BAT were obtained at multiple time points before and after administration of the β3 adrenergic agonist CL 316 243 (CL). Blood flow to BAT was studied after CL injection using the flow alternating inversion recovery (FAIR) approach. Excised BAT tissue was analyzed for lipid droplet content and for uncoupling protein 1 (UCP1) mRNA expression. BAT volume was significantly lower in heart failure (51 ± 1 mm(3) versus 65 ± 3 mm(3) ; p

Background— Substrate utilization in tissues with high energetic requirements could play an important role in cardiometabolic disease. Current techniques to assess energetics are limited by high cost, low throughput, and the inability to resolve multiple readouts simultaneously. Consequently, we aimed to develop a multiplexed optical imaging platform to simultaneously assess energetics in multiple organs in a high throughput fashion. Methods and Results— The detection of 18F-Fluordeoxyglucose uptake via Cerenkov luminescence and free fatty acid uptake with a fluorescent C 16 free fatty acid was tested. Simultaneous uptake of these agents was measured in the myocardium, brown/white adipose tissue, and skeletal muscle in mice with/without thoracic aortic banding. Within 5 weeks of thoracic aortic banding, mice developed left ventricular hypertrophy and brown adipose tissue activation with upregulation of β 3 AR (β 3 adrenergic receptors) and increased natriuretic peptide receptor ratio. Imaging of brown adipose tissue 15 weeks post thoracic aortic banding revealed an increase in glucose ( P P P Conclusions— A multiplexed optical imaging technique is presented that allows substrate uptake to be simultaneously quantified in multiple tissues in a high throughput manner. The activation of brown adipose tissue occurs early in the onset of left ventricular hypertrophy, which produces tissue-specific changes in substrate uptake that may play a role in the systemic response to cardiac pressure overload.

The Skills and Needs Inventories in Functional Behavior Assessments and Intervention (SNI-FBAI) was developed and administered to 338 special educators and 28 teaching support staff across seven special education schools in Singapore. The SNI-FBAI was evaluated in terms of its content, face, and construct validity. Internal consistency was also established. Results of the study indicate that the SNI-FBAI is a reliable and valid measure. With the psychometric properties of the SNI-FBAI established, schools are encouraged to use this scale to assist with meeting professional development needs of their special educators and teaching support staff in functional behavior assessments and interventions.

We examined a novel farnesoid X receptor agonist, EDP-305, for its antifibrotic effect in bile duct ligation (BDL) and choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) models of hepatic injury. We used molecular magnetic resonance imaging with the type 1 collagen-binding probe EP-3533 and the oxidized collagen-specific probe gadolinium hydrazide to noninvasively measure treatment response. BDL rats (n = 8 for each group) were treated with either low or high doses of EDP-305 starting on day 4 after BDL and were imaged on day 18. CDAHFD mice (n = 8 for each group) were treated starting at 6 weeks after the diet and were imaged at 12 weeks. Liver tissue was subjected to pathologic and morphometric scoring of fibrosis, hydroxyproline quantitation, and determination of fibrogenic messenger RNA expression. High-dose EDP-305 (30 mg/kg) reduced liver fibrosis in both the BDL and CDAHFD models as measured by collagen proportional area, hydroxyproline analysis, and fibrogenic gene expression (all P < 0.05). Magnetic resonance signal intensity with both EP-3533 in the BDL model and gadolinium hydrazide in the CDAHFD model was reduced with EDP-305 30 mg/kg treatment (P < 0.01). Histologically, EDP-305 30 mg/kg halted fibrosis progression in the CDAHFD model. Conclusion: EDP-305 reduced fibrosis progression in rat BDL and mouse CDAHFD models. Molecular imaging of collagen and oxidized collagen is sensitive to changes in fibrosis and could be used to noninvasively measure treatment response in clinical trials. (Hepatology Communications 2018;2:821-835).

Little is known about HIV treatment optimism and risk behaviors among Black men who have sex with men (BMSM). Using longitudinal data from BMSM in the HPTN 061 study, we examined participants’ self-reported comfort with having condomless sex due to optimistic beliefs regarding HIV treatment. We assessed correlates of treatment optimism and its association with subsequent risk behaviors for HIV acquisition or transmission using multivariable logistic regression with generalized estimating equations. Independent correlates of treatment optimism included age ≥35 years, annual household income

Methamphetamine (meth), and other psychostimulants such as cocaine, present a persistent problem for society with chronic users being highly prone to relapse. We show, in a chronic methamphetamine administration model, that discontinuation of drug for more than a week produces much larger changes in overall meth-induced brain connectivity and cerebral blood volume (CBV) response than changes that occur immediately following meth administration. Areas showing the largest changes were hippocampal, limbic striatum and sensorimotor cortical regions as well as brain stem areas including the pedunculopontine tegmentum (PPTg) and pontine nuclei - regions known to be important in mediating reinstatement of drug-taking after abstinence. These changes occur concomitantly with behavioral sensitization and appear to be mediated through increases in dopamine D1 and D3 and decreases in D2 receptor protein and mRNA expression. We further identify a novel region of dorsal caudate/putamen, with a low density of calbindin neurons, that has an opposite hemodynamic response to meth than the rest of the caudate/putamen and accumbens and shows very strong correlation with dorsal CA1 and CA3 hippocampus. This correlation switches following meth abstinence from CA1/CA3 to strong connections with ventral hippocampus (ventral subiculum) and nucleus accumbens. These data provide novel evidence for temporal alterations in brain connectivity where chronic meth can subvert hippocampal - striatal interactions from cognitive control regions to regions that mediate drug reinstatement. Our results also demonstrate that the signs and magnitudes of the induced CBV changes following challenge with meth or a D3-preferring agonist are a complementary read out of the relative changes that occur in D1, D2 and D3 receptors using protein or mRNA levels.

The development of complex methods in molecular biology is a laborious, costly, iterative and often intuition-bound process where optima are sought in a multidimensional parameter space through step-by-step optimizations. The difficulty of miniaturizing reactions under the microliter volumes usually handled in multiwell plates by robots, plus the cost of the experiments, limit the number of parameters and the dynamic ranges that can be explored. Nevertheless, because of non-linearities of the response of biochemical systems to their reagent concentrations, broad dynamic ranges are necessary. Here we use a high-performance nanoliter handling platform and computer generation of liquid transfer programs to explore in quadruplicates 648 combinations of 4 parameters of a biochemical reaction, the reverse-transcription, which lead us to uncover non-linear responses, parameter interactions and novel mechanistic insights. With the increased availability of computer-driven laboratory platforms for biotechnology, our results demonstrate the feasibility and advantage of methods development based on reproducible, computer-aided exhaustive characterization of biochemical systems.

Background: Differentiating glioblastoma, brain metastasis, and central nervous system lymphoma (CNSL) on conventional magnetic resonance imaging (MRI) can present a diagnostic dilemma due to the potential for overlapping imaging features. We investigate whether machine learning evaluation of multimodal MRI can reliably differentiate these entities. Methods: Preoperative brain MRI including diffusion weighted imaging (DWI), dynamic contrast enhanced (DCE), and dynamic susceptibility contrast (DSC) perfusion in patients with glioblastoma, lymphoma, or metastasis were retrospectively reviewed. Perfusion maps (rCBV, rCBF), permeability maps (K-trans, Kep, Vp, Ve), ADC, T1C+ and T2/FLAIR images were coregistered and two separate volumes of interest (VOIs) were obtained from the enhancing tumor and non-enhancing T2 hyperintense (NET2) regions. The tumor volumes obtained from these VOIs were utilized for supervised training of support vector classifier (SVC) and multilayer perceptron (MLP) models. Validation of the trained models was performed on unlabeled cases using the leave-one-subject-out method. Head-to-head and multiclass models were created. Accuracies of the multiclass models were compared against two human interpreters reviewing conventional and diffusion-weighted MR images. Results: Twenty-six patients enrolled with histopathologically-proven glioblastoma (n=9), metastasis (n=9), and CNS lymphoma (n=8) were included. The trained multiclass ML models discriminated the three pathologic classes with a maximum accuracy of 69.2% accuracy (18 out of 26; kappa 0.540, P=0.01) using an MLP trained with the VpNET2 tumor volumes. Human readers achieved 65.4% (17 out of 26) and 80.8% (21 out of 26) accuracies, respectively. Using the MLP VpNET2 model as a computer-aided diagnosis (CADx) for cases in which the human reviewers disagreed with each other on the diagnosis resulted in correct diagnoses in 5 (19.2%) additional cases. Conclusions: Our trained multiclass MLP using VpNET2 can differentiate glioblastoma, brain metastasis, and CNS lymphoma with modest diagnostic accuracy and provides approximately 19% increase in diagnostic yield when added to routine human interpretation.

The aim of this study was to assess the volume and function of human brown adipose tissue (BAT) in vivo using MR imaging.BAT volumes under thermoneutral conditions in the cervical areas were assessed via water-fat contrast using the Dixon method and via water-saturation efficiency using fast spin-echo and T2-weighted images. The existence of cervical BAT was also assessed by (18)F-FDG PET/CT scans in the same subjects. BAT functionality was assessed via functional MR imaging (fMRI) blood oxygenation level-dependent (BOLD) signal changes in response to a mild cold challenge.Under thermoneutral conditions, we were able to distinguish BAT from white adipose tissue in the cervical and supraclavicular fat. BAT showed higher water-to-fat contrast and higher water-saturation efficiency in MR imaging scans. The location and volume of BAT assessed by MR imaging were comparable to the measurements by (18)F-FDG PET/CT scans. During mild cold challenge, BOLD fMRI signal increased in BAT by 10.7% ± 1.8% (P0.01).We demonstrated the feasibility of using MR imaging and fMRI to assess BAT volume and BAT responses to mild cold stimulation in the cervical areas of human subjects.