Higher Dietary Polyphenol Intake Is Associated With Lower Blood Inflammatory Markers.

BACKGROUND: Evidence suggests a link between polyphenol intake and reduced incidence of several chronic diseases. This could arise through associations between polyphenol intake and reduced systemic oxidative stress and subsequent inflammation. However, confirming this association is difficult, as few large cohorts allow for comprehensive assessments of both polyphenol intake and markers of systemic inflammation. OBJECTIVES: To address this, polyphenol intake was assessed in the UK-based Airwave cohort using 7-d diet diaries and data from Phenol-Explorer to test for associations between polyphenol intake and blood biomarkers of inflammation. METHODS: Participants included 9008 males and females aged 17-74 y (median age: 42 y) whose data was included in a cross-sectional analysis. Phenol-Explorer was used to estimate individuals' polyphenol intake from diet data describing the consumption of 4104 unique food items. C-reactive protein (CRP) and fibrinogen were used as blood biomarkers of inflammation. RESULTS: There were 448 polyphenols found in reported diet items. Median total polyphenol intake was 1536 mg/d (1058-2092 mg/d). Phenolic acids and flavonoids were the main types of polyphenols, and nonalcoholic beverages, vegetables, and fruit were the primary sources. Variation in energy-adjusted polyphenol intake was explained by age, sex, salary, body mass index, education level, smoking, and alcohol consumption. Linear regressions showed inverse associations between total daily intake and both CRP (ß: -0.00702; P < 0.001) and fibrinogen (ß: -0.00221; P = 0.038). Associations with specific polyphenol compound groups were also found. Logistic regressions using total polyphenol intake quartiles showed stepwise reductions in the odds of elevated CRP with higher intake (6%, 23%, and 24% compared with quartile 1; P = 0.003), alongside 3% and 7% lower odds per unit of polyphenol consumption equivalent to 1 cup of tea or coffee per day. CONCLUSIONS: This study describes polyphenol intake in a large, contemporary UK cohort. We observed associations between higher intake and lower CRP and fibrinogen. This contributes to evidence supporting the health benefits of dietary polyphenols.

Protocol optimization for functional cardiac CT imaging using noise emulation in the raw data domain.

BACKGROUND: Four-dimensional (4D) wide coverage computed tomography (CT) is an effective imaging modality for measuring the mechanical function of the myocardium. However, repeated CT measurement across a number of heartbeats is still a concern. PURPOSE: A projection-domain noise emulation method is presented to generate accurate low-dose (mA modulated) 4D cardiac CT scans from high-dose scans, enabling protocol optimization to deliver sufficient image quality for functional cardiac analysis while using a dose level that is as low as reasonably achievable (ALARA). METHODS: Given a targeted low-dose mA modulation curve, the proposed noise emulation method injects both quantum and electronic noise of proper magnitude and correlation to the high-dose data in projection domain. A spatially varying (i.e., channel-dependent) detector gain term as well as its calibration method were proposed to further improve the noise emulation accuracy. To determine the ALARA dose threshold, a straightforward projection domain image quality (IQ) metric was proposed that is based on the number of projection rays that do not fall under the non-linear region of the detector response. Experiments were performed to validate the noise emulation method with both phantom and clinical data in terms of visual similarity, contrast-to-noise ratio (CNR), and noise-power spectrum (NPS). RESULTS: For both phantom and clinical data, the low-dose emulated images exhibited similar noise magnitude (CNR difference within 2%), artifacts, and texture to that of the real low-dose images. The proposed channel-dependent detector gain term resulted in additional increase in emulation accuracy. Using the proposed IQ metric, recommended kVp and mA settings were calculated for low dose 4D Cardiac CT acquisitions for patients of different sizes. CONCLUSIONS: A detailed method to estimate system-dependent parameters for a raw-data based low dose emulation framework was described. The method produced realistic noise levels, artifacts, and texture with phantom and clinical studies. The proposed low-dose emulation method can be used to prospectively select patient-specific minimal-dose protocols for functional cardiac CT.

Protocol Optimization for Functional Cardiac CT Imaging Using Noise Emulation in the Raw Data Domain.

Background: Four-dimensional (4D) wide coverage computed tomography (CT) is an effective imaging modality for measuring the mechanical function of the myocardium. However, repeated CT measurement across a number of heartbeats is still a concern. Purpose: A projection-domain noise emulation method is presented to generate accurate low-dose (mA modulated) 4D cardiac CT scans from high-dose scans, enabling protocol optimization to deliver sufficient image quality for functional cardiac analysis while using a dose level that is as low as reasonably achievable (ALARA). Methods: Given a targeted low-dose mA modulation curve, the proposed noise emulation method injects both quantum and electronic noise of proper magnitude and correlation to the high-dose data in projection domain. A spatially varying (i.e., channel-dependent) detector gain term as well as its calibration method were proposed to further improve the noise emulation accuracy. To determine the ALARA dose threshold, a straightforward projection domain image quality (IQ) metric was proposed that is based on the number of projection rays that do not fall under the non-linear region of the detector response. Experiments were performed to validate the noise emulation method with both phantom and clinical data in terms of visual similarity, contrast-to-noise ratio (CNR), and noise-power spectrum (NPS). Results: For both phantom and clinical data, the low-dose emulated images exhibited similar noise magnitude (CNR difference within 2%), artifacts, and texture to that of the real low-dose images. The proposed channel-dependent detector gain term resulted in additional increase in emulation accuracy. Using the proposed IQ metric, recommended kVp and mA settings were calculated for low dose 4D Cardiac CT acquisitions for patients of different sizes. Conclusions: A detailed method to estimate system-dependent parameters for a raw-data based low dose emulation framework was described. The method produced realistic noise levels, artifacts, and texture with phantom and clinical studies. The proposed low-dose emulation method can be used to prospectively select patient-specific minimal-dose protocols for functional cardiac CT.

Motion correction of wide-detector 4DCT images for cardiac resynchronization therapy planning.

BACKGROUND: Lead placement at the latest mechanically activated left ventricle (LV) segments is strongly correlated with response to cardiac resynchronization therapy (CRT). We demonstrate the feasibility of a cardiac 4DCT motion correction algorithm (ResyncCT) in estimating LV mechanical activation for guiding lead placement in CRT. METHODS: Subjects with full cardiac cycle 4DCT images acquired using a wide-detector CT scanner for CRT planning/upgrade were included. 4DCT images exhibited motion artifact-induced false-dyssynchrony, hindering LV mechanical activation time estimation. Motion-corrupted images were processed with ResyncCT to yield motion-corrected images. Time to onset of shortening (TOS) was estimated in each of 72 endocardial segments. A false-dyssynchrony index (FDI) was used to quantify the extent of motion artifacts in the uncorrected and the ResyncCT images. After motion correction, the change in classification of LV free-wall segments as optimal target sites for lead placement was investigated. RESULTS: Twenty subjects (70.7 â€‹± â€‹13.9 years, 6 female) were analyzed. Motion artifacts in the ResyncCT-processed images were significantly reduced (FDI: 28.9 â€‹± â€‹9.3 â€‹% vs 47.0 â€‹± â€‹6.0 â€‹%, p â€‹< â€‹0.001). In 10 (50 â€‹%) subjects, ResyncCT motion correction yielded statistically different TOS estimates (p â€‹< â€‹0.05). Additionally, 43 â€‹% of LV free-wall segments were reclassified as optimal target sites for lead placement after motion correction. CONCLUSIONS: ResyncCT significantly reduced motion artifacts in wide-detector cardiac 4DCT images, yielded statistically different time to onset of shortening estimates, and changed the location of optimal target sites for lead placement. These results highlight the potential utility of ResyncCT motion correction in CRT planning when using wide-detector 4DCT imaging.

Quantitative analysis of small coronary artery calcium detectability with an accurate simulation and validation on a clinical CT scanner.

BACKGROUND: The absence of coronary artery calcium (CAC) measured via CT is associated with very favorable prognosis, and current guidelines recommend low-density lipoprotein cholesterol (LDL-c) lowering therapy for individuals with any CAC. This motivates early detection of small granules of CAC; however, calcium scan sensitivity for detecting very low levels of calcium has not been quantified. PURPOSE: In this work, the size limit of detectability of small calcium hydroxyapatite (CaHA) granules with clinical CAC scanning was assessed using validated simulations. METHODS: CT projections of digital 3D mathematical phantoms containing small CaHA granules were simulated analytically; images were reconstructed using a filter designed to reproduce the point spread function of a specific commercial scanner, and a relationship of HU number versus diameter was derived. These simulation results were validated with experimental measurements of HU versus diameter from phantoms containing small granules of CaHA on a GE Revolution CT scanner in the clinic; ground truth measurements of the CaHA granule diameters were obtained using a Zeiss Xradia 510 Versa high-resolution 3D micro-CT imaging system. Using experimental measurements on the clinical CT scanner, detectability was quantified with a detectability index (d') using a non-prewhitened matched filter. The effect of changes to reconstruction slice thickness and reconstruction kernel on granule detectability was evaluated. RESULTS: Under typical clinical calcium scanning and reconstruction conditions, the minimum detectable diameter of a simulated spherical calcium granule with a clinically relevant CaHA density was 0.76 mm. The minimum detectable volume was 2.4 times smaller on images reconstructed at a slice thickness of 0.625 mm compared to 2.5 mm. The detectability index d' increased by a factor of 1.7 when images were reconstructed with 0.625 mm slices compared to 2.5 mm slices. d' did not change when images were reconstructed with the high-resolution BONE filter compared to the less sharp STANDARD resolution filter on the GE Revolution CT. CONCLUSIONS: We have quantified detectability versus size of small calcium granules at the resolution limit of a widely available clinical CT scanner. Detectability increased significantly with reduced slice thickness and did not change with a sharper reconstruction kernel. The simulation can be used to calculate the trade-off between dose and CAC detectability.

Dural sinus narrowing in patients with spontaneous anterior skull base cerebrospinal fluid leak.

Objectives: Current evidence suggests a link between idiopathic intracranial hypertension (IIH) and spontaneous cerebrospinal fluid (sCSF) leak, as well as between IIH and dural venous sinus (DVS) narrowing. However, there are limited data linking DVS narrowing and sCSF leak. This study aims to determine the prevalence of DVS narrowing in patients with sCSF leak. Methods: A retrospective review of all patients with sCSF leak that presented to a tertiary academic center from 2008 to 2019. Preoperative imaging was independently reviewed by two neuroradiologists to evaluate for DVS narrowing. Available literature was used to estimate the prevalence of DVS narrowing in the general population to allow for comparison. Data were analyzed using Exact binomial test. Results: Analysis of 25 patients with appropriate imaging revealed the majority were women (21/25, 84%) with a mean age of 51.89 years (SD 13.96). The majority of these patients were found to have narrowing of the DVS (20/25, 80%). In patient with sCSF leaks, there was a significantly higher proportion of patients with DVS narrowing compared with published literature examining this condition in the general population (80% vs. 40%, CI 0.59-0.93, p < .001). Conclusion: The prevalence of DVS narrowing in patients with sCSF leaks is substantial and likely greater than the general population. Moreover, there appears to be narrowing in most patients with sCSF leak. Preoperative radiological evaluation of the DVS using MR venography may be useful in patients with sCSF leaks as DVS stenosis may be an underdiagnosed etiology. Further study is needed to evaluate this. Level of Evidence: IV.

Target cell-specific synaptic dynamics of excitatory to inhibitory neuron connections in supragranular layers of human neocortex.

Rodent studies have demonstrated that synaptic dynamics from excitatory to inhibitory neuron types are often dependent on the target cell type. However, these target cell-specific properties have not been well investigated in human cortex, where there are major technical challenges in reliably obtaining healthy tissue, conducting multiple patch-clamp recordings on inhibitory cell types, and identifying those cell types. Here, we take advantage of newly developed methods for human neurosurgical tissue analysis with multiple patch-clamp recordings, post-hoc fluorescent in situ hybridization (FISH), machine learning-based cell type classification and prospective GABAergic AAV-based labeling to investigate synaptic properties between pyramidal neurons and PVALB- vs. SST-positive interneurons. We find that there are robust molecular differences in synapse-associated genes between these neuron types, and that individual presynaptic pyramidal neurons evoke postsynaptic responses with heterogeneous synaptic dynamics in different postsynaptic cell types. Using molecular identification with FISH and classifiers based on transcriptomically identified PVALB neurons analyzed by Patch-seq, we find that PVALB neurons typically show depressing synaptic characteristics, whereas other interneuron types including SST-positive neurons show facilitating characteristics. Together, these data support the existence of target cell-specific synaptic properties in human cortex that are similar to rodent, thereby indicating evolutionary conservation of local circuit connectivity motifs from excitatory to inhibitory neurons and their synaptic dynamics.

Room-temperature crystallography reveals altered binding of small-molecule fragments to PTP1B.

Much of our current understanding of how small-molecule ligands interact with proteins stems from X-ray crystal structures determined at cryogenic (cryo) temperature. For proteins alone, room-temperature (RT) crystallography can reveal previously hidden, biologically relevant alternate conformations. However, less is understood about how RT crystallography may impact the conformational landscapes of protein-ligand complexes. Previously, we showed that small-molecule fragments cluster in putative allosteric sites using a cryo crystallographic screen of the therapeutic target PTP1B (Keedy et al., 2018). Here, we have performed two RT crystallographic screens of PTP1B using many of the same fragments, representing the largest RT crystallographic screens of a diverse library of ligands to date, and enabling a direct interrogation of the effect of data collection temperature on protein-ligand interactions. We show that at RT, fewer ligands bind, and often more weakly - but with a variety of temperature-dependent differences, including unique binding poses, changes in solvation, new binding sites, and distinct protein allosteric conformational responses. Overall, this work suggests that the vast body of existing cryo-temperature protein-ligand structures may provide an incomplete picture, and highlights the potential of RT crystallography to help complete this picture by revealing distinct conformational modes of protein-ligand systems. Our results may inspire future use of RT crystallography to interrogate the roles of protein-ligand conformational ensembles in biological function.

Prediction of Cardiac Resynchronization Therapy Response Using a Lead Placement Score Derived From 4-Dimensional Computed Tomography.

BACKGROUND: Cardiac resynchronization therapy (CRT) is an effective treatment for patients with heart failure; however, 30% of patients do not respond to the treatment. We sought to derive patient-specific left ventricle maps of lead placement scores (LPS) that highlight target pacing lead sites for achieving a higher probability of CRT response. METHODS: Eighty-two subjects recruited for the ImagingCRT trial (Empiric Versus Imaging Guided Left Ventricular Lead Placement in Cardiac Resynchronization Therapy) were retrospectively analyzed. All 82 subjects had 2 contrast-enhanced full cardiac cycle 4-dimensional computed tomography scans: a baseline and a 6-month follow-up scan. CRT response was defined as a reduction in computed tomography-derived end-systolic volume ≥15%. Eight left ventricle features derived from the baseline scans were used to train a support vector machine via a bagging approach. An LPS map over the left ventricle was created for each subject as a linear combination of the support vector machine feature weights and the subject's own feature vector. Performance for distinguishing responders was performed on the original 82 subjects. RESULTS: Fifty-two (63%) subjects were responders. Subjects with an LPS≤Q1 (lower-quartile) had a posttest probability of responding of 14% (3/21), while subjects with an LPS≥ Q3 (upper-quartile) had a posttest probability of responding of 90% (19/21). Subjects with Q1

Combatting Planktonic and Biofilm Populations of Carbapenem-Resistant Acinetobacter baumannii with Polymyxin-Based Combinations.

Carbapenem-resistant Acinetobacter baumannii (CRAB) can cause serious infections that are associated with high mortality rates. During the course of an infection, many CRAB isolates are able to form biofilms, which are recalcitrant to several antibiotics and can be difficult to treat. Polymyxin-based regimens are a first-line treatment option for CRAB infections, but they have not been optimized against both planktonic and biofilm phases of growth. The objective of this study was to identify polymyxin-based combinations that are active against planktonic and biofilm populations of CRAB. Four CRAB isolates (meropenem MICs: 8-256 mg/L) capable of forming biofilms were used in each experiment. The activities of polymyxin B alone and in combination with ampicillin/sulbactam, meropenem, minocycline, and rifampin were assessed using time-kill assays, with the CRAB isolates grown in planktonic and biofilm phases. Viable colony counts were used to detect the bactericidal activity and synergy of the antibiotic combinations. Against the planktonic populations, polymyxin B combined with meropenem, minocycline, ampicillin/sulbactam, and rifampin caused 3.78, -0.15, 4.38, and 3.23 mean log10 CFU/mL reductions against all isolates at 24 h, respectively. Polymyxin B combined with meropenem, ampicillin/sulbactam, or rifampin was synergistic against 75-100% (3/4 or 4/4) of CRAB isolates. Against biofilms, polymyxin B combined with meropenem, minocycline, ampicillin/sulbactam, and rifampin caused 1.86, 1.01, 0.66, and 3.55 mean log10 CFU/mL reductions against all isolates at 24 h, respectively. Only the combination of polymyxin B and rifampin retained bactericidal activity or synergy against any of the isolates when grown as biofilms (50% of isolates). The combination of polymyxin B and rifampin may be promising for CRAB infections that have planktonic and biofilm populations present.

Regional left ventricular endocardial strains estimated from low-dose 4DCT: Comparison with cardiac magnetic resonance feature tracking.

BACKGROUND: Estimates of regional left ventricular (LV) strains provide additional information to global function parameters such as ejection fraction (EF) and global longitudinal strain (GLS) and are more sensitive in detecting abnormal regional cardiac function. The accurate and reproducible assessment of regional cardiac function has implications in the management of various cardiac diseases such as heart failure, myocardial ischemia, and dyssynchrony. PURPOSE: To develop a method that yields highly reproducible, high-resolution estimates of regional endocardial strains from 4DCT images. METHODS: A method for estimating regional LV endocardial circumferential ( ε c c ) $( {{\epsilon }_{cc}} )$ and longitudinal ( ε l l ${\epsilon }_{ll}$ ) strains from 4DCT was developed. Point clouds representing the LV endocardial surface were extracted for each time frame of the cardiac cycle from 4DCT images. 3D deformation fields across the cardiac cycle were obtained by registering the end diastolic point cloud to each subsequent point cloud in time across the cardiac cycle using a 3D point-set registration technique. From these deformation fields, ε c c and ε l l ${\epsilon }_{cc}\ {\rm{and\ }}{\epsilon }_{ll}$ were estimated over the entire LV endocardial surface by fitting an affine transformation with maximum likelihood estimation. The 4DCT-derived strains were compared with strains estimated in the same subjects by cardiac magnetic resonance (CMR); twenty-four subjects had CMR scans followed by 4DCT scans acquired within a few hours. Regional LV circumferential and longitudinal strains were estimated from the CMR images using a commercially available feature tracking software (cvi42). Global circumferential strain (GCS) and global longitudinal strain (GLS) were calculated as the mean of the regional strains across the entire LV for both modalities. Pearson correlation coefficients and Bland-Altman analyses were used for comparisons. Intraclass correlation coefficients (ICC) were used to assess the inter- and intraobserver reproducibility of the 4DCT-derived strains. RESULTS: The 4DCT-derived regional strains correlated well with the CMR-derived regional strains ( ε c c ${\epsilon }_{cc}$ : r = 0.76, p < 0.001; ε l l ${\epsilon }_{ll}$ : r = 0.64, p < 0.001). A very strong correlation was found between 4DCT-derived GCS and 4DCT-derived EF (r = -0.96; p < 0.001). The 4DCT-derived strains were also highly reproducible, with very low inter- and intraobserver variability (intraclass correlation coefficients in the range of [0.92, 0.99]). CONCLUSIONS: We have developed a novel method to estimate high-resolution regional LV endocardial circumferential and longitudinal strains from 4DCT images. Except for the definition of the mitral valve and LV outflow tract planes, the method is completely user independent, thus yielding highly reproducible estimates of endocardial strain. The 4DCT-derived strains correlated well with those estimated using a commercial CMR feature tracking software. The promising results reported in this study highlight the potential utility of 4DCT in the precise assessment of regional cardiac function for the management of cardiac disease.

Four-dimensional computed tomography of the left ventricle, Part I: Motion artifact reduction.

PURPOSE: Standard four-dimensional computed tomography (4DCT) cardiac reconstructions typically include spiraling artifacts that depend not only on the motion of the heart but also on the gantry angle range over which the data was acquired. We seek to reduce these motion artifacts and, thereby, improve the accuracy of left ventricular wall positions in 4DCT image series. METHODS: We use a motion artifact reduction approach (ResyncCT) that is based largely on conjugate pairs of partial angle reconstruction (PAR) images. After identifying the key locations where motion artifacts exist in the uncorrected images, paired subvolumes within the PAR images are analyzed with a modified cross-correlation function in order to estimate 3D velocity and acceleration vectors at these locations. A subsequent motion compensation process (also based on PAR images) includes the creation of a dense motion field, followed by a backproject-and-warp style compensation. The algorithm was tested on a 3D printed phantom, which represents the left ventricle (LV) and on challenging clinical cases corrupted by severe artifacts. RESULTS: The results from our preliminary phantom test as well as from clinical cardiac scans show crisp endocardial edges and resolved double-wall artifacts. When viewed as a temporal series, the corrected images exhibit a much smoother motion of the LV endocardial boundary as compared to the uncorrected images. In addition, quantitative results from our phantom studies show that ResyncCT processing reduces endocardial surface distance errors from 0.9 ± 0.8 to 0.2 ± 0.1 mm. CONCLUSIONS: The ResyncCT algorithm was shown to be effective in reducing motion artifacts and restoring accurate wall positions. Some perspectives on the use of conjugate-PAR images and on techniques for CT motion artifact reduction more generally are also given.

Molecular architecture determines brain delivery of a transferrin receptor-targeted lysosomal enzyme.

Delivery of biotherapeutics across the blood-brain barrier (BBB) is a challenge. Many approaches fuse biotherapeutics to platforms that bind the transferrin receptor (TfR), a brain endothelial cell target, to facilitate receptor-mediated transcytosis across the BBB. Here, we characterized the pharmacological behavior of two distinct TfR-targeted platforms fused to iduronate 2-sulfatase (IDS), a lysosomal enzyme deficient in mucopolysaccharidosis type II (MPS II), and compared the relative brain exposures and functional activities of both approaches in mouse models. IDS fused to a moderate-affinity, monovalent TfR-binding enzyme transport vehicle (ETV:IDS) resulted in widespread brain exposure, internalization by parenchymal cells, and significant substrate reduction in the CNS of an MPS II mouse model. In contrast, IDS fused to a standard high-affinity bivalent antibody (IgG:IDS) resulted in lower brain uptake, limited biodistribution beyond brain endothelial cells, and reduced brain substrate reduction. These results highlight important features likely to impact the clinical development of TfR-targeting platforms in MPS II and potentially other CNS diseases.

Four-dimensional computed tomography of the left ventricle, Part II: Estimation of mechanical activation times.

PURPOSE: We demonstrate the viability of a four-dimensional X-ray computed tomography (4DCT) imaging system to accurately and precisely estimate mechanical activation times of left ventricular (LV) wall motion. Accurate and reproducible timing estimates of LV wall motion may be beneficial in the successful planning and management of cardiac resynchronization therapy (CRT). METHODS: We developed an anthropomorphically accurate in silico LV phantom based on human CT images with programmed septal-lateral wall dyssynchrony. Twenty-six temporal phases of the in silico phantom were used to sample the cardiac cycle of 1 s. For each of the 26 phases, 1 cm thick axial slabs emulating axial CT image volumes were extracted, 3D printed, and imaged using a commercially available CT scanner. A continuous dynamic sinogram was synthesized by blending sinograms from these static phases; the synthesized sinogram emulated the sinogram that would be acquired under true continuous phantom motion. Using the synthesized dynamic sinogram, images were reconstructed at 70 ms intervals spanning the full cardiac cycle; these images exhibited expected motion artifact characteristics seen in images reconstructed from real dynamic data. The motion corrupted images were then processed with a novel motion correction algorithm (ResyncCT) to yield motion corrected images. Five pairs of motion uncorrected and motion corrected images were generated, each corresponding to a different starting gantry angle (0 to 180 degrees in 45 degree increments). Two line profiles perpendicular to the endocardial surface were used to sample local myocardial motion trajectories at the septum and the lateral wall. The mechanical activation time of wall motion was defined as the time at which the endocardial boundary crossed a fixed position defined on either of the two line profiles while moving toward the center of the LV during systolic contraction. The mechanical activation times of these myocardial trajectories estimated from the motion uncorrected and the motion corrected images were then compared with those derived from the static images of the 3D printed phantoms (ground truth). The precision of the timing estimates was obtained from the five different starting gantry angle simulations. RESULTS: The range of estimated mechanical activation times observed across all starting gantry angles was significantly larger for the motion uncorrected images than for the motion corrected images (lateral wall: 58 ± 15 ms vs 12 ± 4 ms, p < 0.005; septal wall: 61 ± 13 ms vs 13 ± 9 ms, p < 0.005). CONCLUSIONS: 4DCT images processed with the ResyncCT motion correction algorithm yield estimates of mechanical activation times of LV wall motion with significantly improved accuracy and precision. The promising results reported in this study highlight the potential utility of 4DCT in estimating the timing of mechanical events of interest for CRT guidance.

Don Lindberg's Outreach Legacy at the National Library of Medicine.

Friends and colleagues of Donald A.B. Lindberg M.D. came together to give tribute to his extraordinary contributions during his tenure (1984-2015) as Director of the U.S. National Library of Medicine (NLM). Dr. Lindberg died in 2019. The book, Transforming biomedical informatics and health information access: Don Lindberg and the U.S. National Library of Medicine. includes four sections. The ten edited chapters in section three (the Outreach section) are briefly summarized in this overview. As Associate Director for Health Information Programs Development, Elliot R. Siegel Ph.D. coordinated NLM's outreach programming under Dr. Lindberg's leadership from its inception in 1989 to his own retirement in 2010. Dr. Lindberg's legacy at NLM is one of new possibilities imagined, significant changes made in the mission and ethos of a venerable institution, and numerous successes achieved in a variety of settings and contexts. Like so much else Dr. Lindberg accomplished, these Outreach programs that profoundly changed the character of NLM would likely not have occurred without him. He made a difference.

Are We Making a Difference? Outreach Evaluation in Practice.

Donald A.B. Lindberg, M.D., brought with him when he joined NLM an inquisitive mind, tech savvy, and new ideas. He was an early advocate of both outreach and evaluation innovation at NLM. Dr. Lindberg initiated and supported multiple pilot test and implementation projects to strengthen NLM's health information outreach to healthcare providers, research scientists, health science and hospital librarians, and the general public, including minority and underserved populations. He helped steer NLM's transition to the Internet, and NLM's development of a robust framework for evaluating Internet and Web-based health information dissemination and outreach to its many audiences. Dr. Lindberg's leadership led to numerous landmark accomplishments, including the capacity-building "Measuring the Difference" outreach evaluation Guide, and a multidimensional approach to Internet and website evaluation that placed NLM at the forefront of federal agencies using these new and emerging technologies to support their missions.

Native Voices Exhibition: Stories of Health, Wellness, and Illness from American Indians, Alaska Natives, and Native Hawaiians.

The U.S. National Library of Medicine (NLM) exhibition known as Native Voices reflected Donald A.B. Lindberg M.D.'s keen and long-held desire to help improve public understanding of Native American health challenges and honor the culture, tradition, and healing ways of Native Peoples. A centerpiece of the exhibition was a large set of video interviews that Dr. Lindberg conducted with Native health and community leaders. Dr. Lindberg and his team engaged Native advisors in the exhibition development; sought Native input through Listening Circles, Tribal Consultations; and site visits, and made the video interviews accessible via interactive kiosks and iPads. For its time, this was state-of-the-art exhibition technology. The exhibition also included Native artifacts and art works to complement the videos, including a scale model of the iconic Hokule'a Native Hawaiian voyaging canoe, and a full-size Lummi Indian Healing Totem Pole. The totem journeyed across the U.S. prior to its installation next to the NLM herbal garden in Bethesda, MD. A traveling version of the exhibition visited more than 130 venues in 40 States across the U.S. The interview clips and other content are accessible on the exhibition website, and the full-length interviews are retained in the NLM permanent video collection.

Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells.

Recent studies have highlighted the potential role of 11oxygenated (keto or hydroxy) androgens in human reproductive function with 11keto androgens circulating at concentrations comparable with testosterone in women and children. However, the intrinsic androgenic bioactivities of 11 keto and hydroxy androgens are not fully characterized. We therefore investigated the full androgen dose-response curves using complementary in vitro yeast and mammalian (HEK293) host cell bioassays of 11 keto and hydroxy derivatives of the potent androgens, testosterone (T) and dihydrotestosterone (DHT), compared with their parent non-11 oxygenated steroids together with the pro-androgen precursor (androstenedione (A4)) and metabolites (androstanedione, androsterone). For potent androgens, the mammalian HEK293 host cell bioassay was 22-138 times more sensitive than the yeast host cell bioassay. In both androgen bioassays, 11keto derivatives displayed androgenic bioactivity but significantly lower molar potency than their parent non-keto steroids. By contrast, the 11hydroxy derivatives had minimal or no androgenic bioactivity. In both bioassays 5α-reduction increased androgenic potency. These findings confirm that that 11keto androgens may contribute directly to androgen status in women, children, and other conditions apart from healthy eugonadal men whereas 11hydroxy androgens have negligible androgenic potency although it cannot be excluded that they may be converted to more potent androgens in vivo.