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Introduction: As aggregation underpins Tau toxicity, aggregation inhibitor peptides may have disease-modifying potential. They are therefore currently being designed and target either the 306 VQIVYK 311 aggregation-promoting hotspot found in all Tau isoforms or the 275 VQIINK 280 aggregation-promoting hotspot found in 4R isoforms. However, for any Tau aggregation inhibitor to potentially be clinically relevant for other tauopathies, it should target both hotspots to suppress aggregation of Tau isoforms, be stable, cross the blood-brain barrier, and rescue aggregation-dependent Tau phenotypes in vivo., Methods: We developed a retro-inverso, stable D-amino peptide, RI-AG03 [Ac-rrrrrrrrGpkyk(ac)iqvGr-NH2], based on the 306 VQIVYK 311 hotspots which exhibit these disease-relevant attributes., Results: Unlike other aggregation inhibitors, RI-AG03 effectively suppresses aggregation of multiple Tau species containing both hotspots in vitro and in vivo, is non-toxic, and suppresses aggregation-dependent neurodegenerative and behavioral phenotypes., Discussion: RI-AG03 therefore meets many clinically relevant requirements for an anti-aggregation Tau therapeutic and should be explored further for its disease-modifying potential for Tauopathies., Highlights: Our manuscript describes the development of a novel peptide inhibitor of Tau aggregation, a retro-inverso, stable D-amino peptide called RI-AG03 that displays many clinically relevant attributes. We show its efficacy in preventing Tau aggregation in both in vitro and in vivo experimental models while being non-toxic to cells. RI-AG03 also rescues a biosensor cell line that stably expresses Tau repeat domains with the P301S mutation fused to Cer/Clo and rescues aggregation-dependent phenotypes in vivo, suppressing neurodegeneration and extending lifespan. Collectively our data describe several properties and attributes of RI-AG03 that make it a promising disease-modifying candidate to explore for reducing pathogenic Tau aggregation in Tauopathies such as Alzheimer's disease. Given the real interest in reducing Tau aggregation and the potential clinical benefit of using such agents in clinical practice, RI-AG03 should be investigated further for the treatment of Tauopathies after validation in mammalian models. Tau aggregation inhibitors are the obvious first choice as Tau-based therapies as much of Tau-mediated toxicity is aggregation dependent. Indeed, there are many research efforts focusing on this therapeutic strategy with aggregation inhibitors being designed against one of the two aggregation-promoting hotspots of the Tau protein. To our knowledge, RI-AG03 is the only peptide aggregation inhibitor that inhibits aggregation of Tau by targeting both aggregation-promoting hotspot motifs simultaneously. As such, we believe that our study will have a significant impact on drug discovery efforts in this arena., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The dietary consumption of extra virgin olive oil (EVOO) is believed to slow the progression of Alzheimer's disease (AD) symptoms. Its protective mechanisms are unclear, but specific EVOO phenolic compounds can individually impede the aggregation of amyloid-β (Aβ) peptides and the microtubule-associated protein tau, two important pathological manifestations of AD. It is unknown, however, whether the numerous and variable phenolic compounds that are consumed in dietary EVOO can collectively alter tau and Aβ aggregation as effectively as the individual compounds. The activity of these complex mixtures against Aβ and tau may be moderated by competition between active and nonactive phenolic components and by extensive derivatizations and isomerization. Here, phenolic mixtures extracted from two different EVOO sources are characterized and tested for how they modulate the aggregation of Aβ40 peptide and tau peptides in vitro . The chromatographic and NMR analysis of Greek and Saudi Arabian EVOO phenolic extracts reveals that they have different concentration profiles, and over 30 compounds are identified. Thioflavin T fluorescence and circular dichroism measurements show that relatively low concentrations (<20 μg/mL) of the Greek and Saudi extracts reduce the rate of Aβ40 aggregation and fibril mass, despite the extracts having different phenolic profiles. By contrast, the Greek extract reduces the rate of tau aggregation only at very high phenolic concentrations (>100 μg/mL). Most compounds in the extracts bind to preformed Aβ40 fibrils and release soluble Aβ oligomers that are mildly toxic to SH-SY5Y cells. Much higher (500 μg/mL) extract concentrations are required to remodel tau filaments into oligomers, and a minimal binding of phenolic compounds to the preformed filaments is observed. It is concluded that EVOO extracts having different phenol profiles are similarly capable of modulating Aβ40 aggregation and fibril morphology in vitro at relatively low concentrations but are less efficient at modulating tau aggregation. Over 2 M tonnes of EVOO are consumed globally each year as part of the Mediterranean diet, and the results here provide motivation for further clinical interrogation of the antiaggregation properties of EVOO as a potential protective mechanism against AD., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Background: Tuberculosis (TB) incidence is decreasing in the Northern Territory (NT) but still exceeds rates elsewhere in Australia. Deaths and morbidity from advanced TB continue, with delay in diagnosis a contributor to adverse outcomes., Aims: We aimed to describe the delay in diagnosis of TB, identify risk factors for delay and examine the associations between delay and clinical outcomes., Methods: We conducted a historical cohort analysis which included adult inpatients diagnosed with TB at the Royal Darwin Hospital from 2010 to 2020. Patient delay was measured as time from symptom onset to first seeking care, and health system delay was quantified as time from first relevant clinical contact to diagnosis. The sum of these two periods was the total delay. Ethics approval was granted by NT HREC (2020-3852)., Results: Eighty-four cases were included; the median total delay was 90 days (interquartile range (IQR): 60-121), patient delay was 53 days (IQR: 30-90), and health system delay was 21 days (IQR: 12-45). Patient delay was longer among patients with extrapulmonary (median: 100 days (IQR: 90-105) compared with pulmonary TB patients (39 days (IQR: 27-54), P < 0.0001). Health system delay was longer in those aged ≥45 years (30 days (IQR: 16-51) vs younger patients (14 days (IQR: 8-30), P = 0.007) and among non-smokers (31 days (IQR: 21-55) vs 21 days (IQR: 10-40), P = 0.048). Median delay was longer among patients with non-drug-related complications of disease (P < 0.0001), those admitted to critical care (P < 0.0001), and those with respiratory failure (P = 0.001)., Conclusion: The patient delays we report are longer than reported elsewhere in Australia. The next steps will require concerted efforts to improve community awareness of TB and strategies to strengthen health systems through better resourcing and healthcare provider support., (© 2023 The Authors. Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians.)

Electrospinning technique is well-known for the generation of different fibers. While it is a "simple" technique, it lies in the fact that the fibers are typically produced in the form of densely packed two-dimensional (2D) mats with limited thickness, shape, and porosity. The highly demanded three-dimensional (3D) fiber assemblies have been explored by time-consuming postprocessing and/or complex setup modifications. Here, we use a classic electrospinning setup to directly produce 3D fiber macrostructures only by modulating the spinning solution. Increasing solution conductivity modifies electrodynamic jet behavior and fiber assembling process; both are observed in situ using a high-speed camera. More viscous solutions render thicker fibers that own enhanced mechanical stiffness as examined by finite element analysis. We reveal the correlation between the universal solution parameters and the dimensionality of fiber assemblies, thereof, enlightening the design of more "3D spinnable" solutions that are compatible with any commercial electrospinning equipment. After a calcination step, ultralightweight ceramic fiber assemblies are generated. These inexpensive materials can clean up exceptionally large fractions of oil spillages and provide high-performance thermal insulation. This work would drive the development and scale-up production of next-generation 3D fiber materials for engineering, biomedical, and environmental applications.

The ESCRT machinery, comprising of multiple proteins and subcomplexes, is crucial for membrane remodelling in eukaryotic cells, in processes that include ubiquitin-mediated multivesicular body formation, membrane repair, cytokinetic abscission, and virus exit from host cells. This ESCRT system appears to have simpler, ancient origins, since many archaeal species possess homologues of ESCRT-III and Vps4, the components that execute the final membrane scission reaction, where they have been shown to play roles in cytokinesis, extracellular vesicle formation and viral egress. Remarkably, metagenome assemblies of Asgard archaea, the closest known living relatives of eukaryotes, were recently shown to encode homologues of the entire cascade involved in ubiquitin-mediated membrane remodelling, including ubiquitin itself, components of the ESCRT-I and ESCRT-II subcomplexes, and ESCRT-III and Vps4. Here, we explore the phylogeny, structure, and biochemistry of Asgard homologues of the ESCRT machinery and the associated ubiquitylation system. We provide evidence for the ESCRT-I and ESCRT-II subcomplexes being involved in ubiquitin-directed recruitment of ESCRT-III, as it is in eukaryotes. Taken together, our analyses suggest a pre-eukaryotic origin for the ubiquitin-coupled ESCRT system and a likely path of ESCRT evolution via a series of gene duplication and diversification events., (© 2022. The Author(s).)

Competing Interests: Dr. Kiser has provided consultancy services to Lucerno Dynamics in the past. Dr. Sullivan has provided manuscript editing services to Lucerno Dynamics in the past. All other authors declare no conflict of interest.

Human herpesvirus-6 (HHV-6) is a virus known for causing the highly contagious infection, roseola infantum, and has been associated with causing encephalitis in pediatric patients and less commonly in adult patients as well. Regardless of the patient's age, the primary HHV-6 infection could be complicated by neurological sequelae including encephalitis, acute encephalopathy with biphasic seizures syndrome, or demyelinating disease. HHV-6 encephalitis does occur in an adult as a primary infection or reactivation. However, immunocompromised, hematopoietic stem cell transplantation patients, and solid organ transplant recipients are the most affected population. Here we present a rare case of HHV-6 encephalitis in a 26-year-old healthy immunocompetent male. HHV-6 viral DNA was detected in the cerebrospinal fluid during the acute stage of the disease, and the diagnosis was confirmed by quantitative polymerase chain reaction (PCR). The patient was treated with ganciclovir and had a complete response to treatment without any further complication. The pathophysiology, clinical course, and treatment in otherwise immunocompetent adult patients are also discussed., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Mekheal et al.)

Ethylene-Vinyl Acetate (EVA) is the most popular material for manufacturing mouthguards. However, EVA mouthguards are problematic, for example inconsistent thicknesses across the mouthguard. Additive manufacturing provides a promising solution to this problem, as it can manufacture mouthguards with a greater precision. This paper compares the energy dissipation of EVA, the current material used for mouthguards, to various designs of a 3D printed material, some of which contain air cells. Impact testing was carried out at three different strain rates. The Split-Hopkinson bar was used for medium and high strain rate tests, and an Instron test rig was used for low strain rate testing. The best performing design dissipated 25% more energy than EVA in the medium and high strain rate testing respectively while the low strain rate testing was inconclusive. This research has shown that additive manufacturing provides a viable method of manufacturing mouthguards. This opens up the opportunity for embedding electronics/sensors into additive manufactured mouthguards., (© 2022. The Author(s).)

Purpose: The present study measured changes in arteriolar and venular capillary flow and structure in the gingival tissues during the development of plaque-induced gingival inflammation by combining dynamic optical coherence tomography (OCT), laser perfusion, and capillaroscopic video imaging., Methods: Gingival inflammation was induced in 21 healthy volunteers over a 3-week period. Gingival blood flow and capillary morphology were measured by dynamic OCT, laser perfusion imaging, and capillaroscopy, including a baseline assessment of capillary glycocalyx thickness. Venular capillary flow was estimated by analysis of the perfusion images and mean blood velocity/acceleration in the capillaroscopic images. Readings were recorded at baseline and weekly over the 3 weeks of plaque accumulation and 2 weeks after brushing was resumed., Results: Perfusion imaging demonstrated a significant reduction of gingival blood flow after 1 and 2 weeks of plaque accumulation ( P <0.05), but by 3 weeks of plaque accumulation there was a more mixed picture, with reduced flow in some participants and increased flow in others. Participants with reduced flux at 3 weeks also demonstrated venular-type flow as determined by perfusion images and evidence of the development of venular capillaries as assessed by the velocity/acceleration ratio in capillaroscopic images. After brushing resumed, these venular capillaries were broken down and replaced by arteriolar capillaries., Conclusions: After 3 weeks of plaque accumulation, there was wide variation in microvascular reactions between the participants. Reduced capillary flow was associated with the development of venular capillaries in some individuals. This is noteworthy, as an early increase in venous capillaries is a key vascular feature of cardiovascular disease, psoriasis, Sjögren syndrome, and rheumatoid arthritis-diseases with a significant association with the development of severe gingival inflammation, which leads to periodontitis. Future investigations of microvascular changes in gingival inflammation might benefit from accurate capillary flow velocity measurements to assess the development of venular capillaries., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2022. Korean Academy of Periodontology.)

Drug interactions with phospholipid bilayers underpin their behaviour in cell membranes and in liposomal delivery formulations. Liposomal drug delivery in ocular medicine can overcome the physical barriers of the eye and better enable the active molecule to reach its target. Here, Raman and 19 F solid-state NMR spectroscopy are used to characterise the interactions of two ocular corticosteroid drugs, difluprednate (DFP) and fluorometholone (FML), with multilamellar vesicles of phosphatidylcholine (PC). 31 P NMR confirms that the lipid bilayer tolerates a high drug concentration (a drug: lipid molar ratio of 1 : 10). The 19 F NMR spectra of the drugs in lipid bilayers reveal that FML and DFP have different average orientations within the lipid bilayer. Raman spectra of dried lipid films reveal that PC separates from DFP but not from FML, the less lipophilic of the two drugs. This combined approach will assist the design of, and inform the development of, improved liposomal preparations., (© 2021 The Authors. ChemPlusChem published by Wiley-VCH GmbH.)

Abstract: Extravasation is a common problem in radiopharmaceutical administration and can result in significant radiation dose to underlying tissue and skin. The resulting radiation effects are rarely studied and should be more fully evaluated to guide patient care and meet regulatory obligations. The purpose of this work was to show that a dedicated radiopharmaceutical injection monitoring system can help clinicians characterize extravasations for calculating tissue and skin doses. We employed a commercially available radiopharmaceutical injection monitoring system to identify suspected extravasation of 18F-fluorodeoxyglucose and 99mTc-methylene diphosphonate in 26 patients and to characterize their rates of biological clearance. We calculated the self-dose to infiltrated tissue using Monte Carlo simulation and standard MIRD dosimetry methods, and we used VARSKIN software to calculate the shallow dose equivalent to the epithelial basal-cell layer of overlying skin. For 26 patients, injection-site count rate data were used to characterize extravasation clearance. For each, the absorbed dose was calculated using representative tissue geometries. Resulting tissue-absorbed doses ranged from 0.6 to 11.2 Gy, and the shallow dose equivalent to a 10 cm2 area of adjacent skin in these patients ranged from about 0.1 to 5.4 Sv. Extravasated injections of radiopharmaceuticals can result in unintentional doses that exceed well-established radiation protection and regulatory limits; they should be identified and characterized. An external injection monitoring system may help to promptly identify and characterize extravasations and improve dosimetry calculations. Patient-specific characterization can help clinicians determine extravasation severity and whether the patient should be followed for adverse tissue reactions that may present later in time., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Health Physics Society.)

Purpose: To conduct a simplified lesion-detection task of a low-dose (LD) PET-CT protocol for frequent lung screening using 30% of the effective PETCT dose and to investigate the feasibility of increasing clinical value of low-statistics scans using machine learning., Methods: We acquired 33 SD PET images, of which 13 had actual LD (ALD) PET, and simulated LD (SLD) PET images at seven different count levels from the SD PET scans. We employed image quality transfer (IQT), a machine learning algorithm that performs patch-regression to map parameters from low-quality to high-quality images. At each count level, patches extracted from 23 pairs of SD/SLD PET images were used to train three IQT models - global linear, single tree, and random forest regressions with cubic patch sizes of 3 and 5 voxels. The models were then used to estimate SD images from LD images at each count level for 10 unseen subjects. Lesion-detection task was carried out on matched lesion-present and lesion-absent images., Results: LD PET-CT protocol yielded lesion detectability with sensitivity of 0.98 and specificity of 1. Random forest algorithm with cubic patch size of 5 allowed further 11.7% reduction in the effective PETCT dose without compromising lesion detectability, but underestimated SUV by 30%., Conclusion: LD PET-CT protocol was validated for lesion detection using ALD PET scans. Substantial image quality improvement or additional dose reduction while preserving clinical values can be achieved using machine learning methods though SUV quantification may be biased and adjustment of our research protocol is required for clinical use., (Copyright © 2020 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Given the COVID-19 crisis, the importance of space in the global economic system has emerged as critical in a hitherto unprecedented way. Even as large-scale, globally operating digital platform enterprises find new ways to thrive in the midst of a crisis, small and medium-sized enterprises (SMEs) nestled in local economies have proven to be fragile to shocks, causing countless local economies to unravel in the face of severe challenges to survival. Here, we discuss the role of entrepreneurship in re-building local economies that are more resilient. Specifically, we take a spatial perspective and highlight how the COVID-19 crisis has uncovered problems in the current tendency for thin contextualisation and promotion of globalisation. Based on this critique, we outline new perspectives for thinking about the relationship between entrepreneurship, resilience and local economies. Here, a particular emphasis is given to resilience building through deeply contextualised policies and research, localised flows of products and labour, and the diversification of local economies., (© The Author(s) 2020.)

A pathological signature of Alzheimer's disease (AD) is the formation of neurofibrillary tangles comprising filamentous aggregates of the microtubule associated protein tau. Tau self-assembly is accelerated by polyanions including heparin, an analogue of heparan sulfate. Tau filaments colocalize with heparan sulfate proteoglycans (HSPGs) in vivo, and HSPGs may also assist the transcellular propagation of tau aggregates. Here, we investigate the role of the sulfate moieties of heparin in the aggregation of a recombinant tau fragment Δtau187, comprising residues 255-441 of the C-terminal microtubule-binding domain. The effects that the selective removal of the N -, 2- O -, and 6- O -sulfate groups from heparin have on the kinetics of tau aggregation, aggregate morphology, and protein structure and dynamics were examined. Aggregation kinetics monitored by thioflavin T (ThT) fluorescence revealed that aggregation is considerably slower in the presence of 2- O -desulfated heparin than with N - or 6- O -desulfated heparin. Transmission electron microscopy revealed that tau filaments induced by 2- O -desulfated heparin were more slender than filaments formed in the presence of intact heparin or 6- O -desulfated heparin. The 2- O -desulfated heparin-induced filaments had more extensive regions of flexibility than the other filaments, according to circular dichroism and solid-state NMR spectroscopy. These results indicate that the sulfation pattern of heparin regulates tau aggregation, not purely though electrostatic forces but also through conformational perturbations of heparin when the 2- O -sulfate is removed. These findings may have implications for the progression of AD, as the sulfation pattern of GAGs is known to change during the aging process, which is the main risk factor for the disease.

It has been shown extensively that glycosaminoglycan (GAG)-protein interactions can induce, accelerate, and impede the clearance of amyloid fibrils associated with systemic and localized amyloidosis. Obtaining molecular details of these interactions is fundamental to our understanding of amyloid disease. Consequently, there is a need for analytical approaches that can identify protein conformational transitions and simultaneously characterize heparin interactions. By combining Raman spectroscopy with two-dimensional (2D) perturbation correlation moving window (2DPCMW) analysis, we have successfully identified changes in protein secondary structure during pH- and heparin-induced fibril formation of apolipoprotein A-I (apoA-I) associated with atherosclerosis. Furthermore, from the 2DPCMW, we have identified peak shifts and intensity variations in Raman peaks arising from different heparan sulfate moieties, indicating that protein-heparin interactions vary at different heparin concentrations. Raman spectroscopy thus reveals new mechanistic insights into the role of GAGs during amyloid fibril formation.

Potential drug treatments for Alzheimer's disease (AD) may be found by identifying compounds that block the assembly of the microtubule-associated protein tau into neurofibrillar tangles associated with neuron destabilization and cell death. Here, a small library of structurally diverse compounds was screened in vitro for the ability to inhibit tau aggregation, using high-throughput synchrotron radiation circular dichroism as a novel tool to monitor the structural changes in the protein as it assembles into filaments. The catecholamine epinephrine was found to be the most effective tau aggregation inhibitor of all 88 screened compounds. Subsequently, we tested chemically similar phenolamine drugs from the β-adrenergic receptor agonist class, using conventional circular dichroism spectroscopy, thioflavin T fluorescence, and transmission electron microscopy. Two compounds, salbutamol and dobutamine, used widely in the treatment of respiratory and cardiovascular disease, impede the aggregation of tau in vitro . Dobutamine reduces both the rate and yield of tau filament formation over 24 h; however, it has little effect on the structural transition of tau into β-sheet structures over 24 h. Salbutamol also reduces the yield and rate of filament formation and additionally inhibits tau's structural change into β-sheet-rich aggregates. Salbutamol has a good safety profile and a half-life that facilitates permeation through the blood-brain barrier and could represent an expediated approach to developing AD therapeutics. These results provide the motivation for the in vivo evaluation of pre-existing β-adrenergic receptor agonists as a potential therapy for AD through the reduction of tau deposition.

PET/CT radiotracer infiltration is not uncommon and is often outside the imaging field of view. Infiltration can negatively affect image quality, image quantification, and patient management. Until recently, there has not been a simple way to routinely practice PET radiopharmaceutical administration quality control and quality assurance. Our objectives were to quantify infiltration rates, determine associative factors for infiltration, and assess whether rates could be reduced at multiple centers and then sustained. Methods: A "design, measure, analyze, improve, and control" quality improvement methodology requiring novel technology was used to try to improve PET/CT injection quality. Teams were educated on the importance of quality injections. Baseline infiltration rates were measured, center-specific associative factors were analyzed, team meetings were held, improvement plans were established and executed, and rates remeasured. To ensure that injection-quality gains were retained, real-time feedback and ongoing monitoring were used. Sustainability was assessed. Results: Seven centers and 56 technologists provided data on 5,541 injections. The centers' aggregated baseline infiltration rate was 6.2% (range, 2%-16%). On the basis of their specific associative factors, 4 centers developed improvement plans and reduced their aggregated infiltration rate from 8.9% to 4.6% ( P < 0.0001). Ongoing injection monitoring showed sustainability. Significant variation was found in center- and technologist-level infiltration rates ( P < 0.0001 and P = 0.0020, respectively). Conclusion: A quality improvement approach with new technology can help centers measure infiltration rates, determine associative factors, implement interventions, and improve and sustain injection quality. Because PET/CT images help guide patient management, the monitoring and improvement of radiotracer injection quality are important., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Objective: This study aimed to compare the associations of positron emission tomography (PET), magnetic resonance (MR), and infrared thermography (IRT) imaging modalities with energy expenditure (EE) after brown adipose tissue (BAT) activation using capsinoid ingestion and cold exposure., Methods: Twenty participants underwent PET-MR, IRT imaging, and whole-body calorimetry after capsinoid ingestion and cold exposure. Standardized uptake values (SUV) and the fat fraction (FF) of the supraclavicular brown adipose tissue regions were estimated. The anterior supraclavicular temperature (Tscv) from IRT at baseline and postintervention was measured. Two-hour post-capsinoid ingestion EE and post-cold exposure EE served as a reference to correlate fluorodeoxyglucose uptake, FF, and Tscv for BAT assessment. IRT images were geometrically transformed to overlay on PET-MR for visualization of the hottest regions., Results: The supraclavicular hot spot identified on IRT closely corresponded to the area of maximal fluorodeoxyglucose uptake on PET images. Controlling for body weight, post-cold exposure Tscv was a significant variable associated with EE (P = 0.025). The SUV was significantly inversely correlated with FF (P = 0.012) and significantly correlated with peak of Tscv during cold exposure in BAT-positive participants (P = 0.022)., Conclusions: Tscv correlated positively with EE and was also significantly correlated with SUV after cold exposure. Both IRT and MR FF are promising methods to study BAT activity noninvasively., (© 2019 The Authors. Obesity published by Wiley Periodicals, Inc. on behalf of The Obesity Society (TOS).)

The toxic diatom genus Pseudo-nitzschia is a growing presence in the Gulf of Maine (GOM), where regionally unprecedented levels of domoic acid (DA) in 2016 led to the first Amnesic Shellfish Poisoning closures in the region. However, factors driving GOM Pseudo-nitzschia dynamics, DA concentrations, and the 2016 event are unclear. Water samples were collected at the surface and at depth in offshore transects in summer 2012, 2014, and 2015, and fall 2016, and a weekly time series of surface water samples was collected in 2013. Temperature and salinity data were obtained from NERACOOS buoys and measurements during sample collection. Samples were processed for particulate DA (pDA), dissolved nutrients (nitrate, ammonium, silicic acid, and phosphate), and cellular abundance. Species composition was estimated via Automated Ribosomal Intergenic Spacer Analysis (ARISA), a semi-quantitative DNA finger-printing tool. Pseudo-nitzschia biogeography was consistent in the years 2012, 2014, and 2015, with greater Pseudo-nitzschia cell abundance and P. plurisecta dominance in low-salinity inshore samples, and lower Pseudo-nitzschia cell abundance and P. delicatissima and P. seriata dominance in high-salinity offshore samples. During the 2016 event, pDA concentrations were an order of magnitude higher than in previous years, and inshore-offshore contrasts in biogeography were weak, with P. australis present in every sample. Patterns in temporal and spatial variability confirm that pDA increases with the abundance and the cellular DA of Pseudo-nitzschia species, but was not correlated with any one environmental factor. The greater pDA in 2016 was caused by P. australis - the observation of which is unprecedented in the region - and may have been exacerbated by low residual silicic acid. The novel presence of P. australis may be due to local growth conditions, the introduction of a population with an anomalous water mass, or both factors. A definitive cause of the 2016 bloom remains unknown, and continued DA monitoring in the GOM is warranted., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: The fundamental nature of positron emission tomography (PET), as an event detection system, provides some flexibility for data handling, including retrospective data manipulation. The reorganization of acquisition data allows the emulation of new scans arising from identical radiotracer spatial distributions, but with different statistical compositions, and is especially useful for evaluating the stability and reproducibility of reconstruction algorithms or when investigating extremely low count conditions. This approach is ubiquitous in the research literature but has only been validated, from the point of view of the noise properties, with numerical simulations and phantom data. We present here the first experiment comparing PET images of the same human subjects generated with two separate injections of radiotracer, using actual low dose (LD) data to validate a randomly decimated emulation from a standard dose scan. A key point of the work is focused on the randoms fractions, which scale differently than the trues at varying activity levels., Methods: Eleven patients with non-small cell lung cancer were enrolled in the study. Each imaging session consisted of two independent FDG-PET/CT scans: a LD scan followed by a standard dose (SD) scan. Images were first reconstructed, using filtered back-projection (FBP) and OSEM incorporating time-of-flight information and point-spread function modeling (PSFTOF), from the LD and SD datasets comprising all counts from each scanned bed position. The number of true counts was recorded for all LD scans, and independent, count-matched emulations (ELD) were reconstructed from the SD data. Noise distribution within the liver and standardized uptake value reproducibility within a population of contoured, tracer-avid lesion volumes were evaluated across scans and statistics., Results: The randoms fraction estimates were 17.4 ± 1.6% (14.9-19.4) in the LD data and 42 ± 2.3% (37.1-45.5) in the SD data. Eleven lesions were identified and volumes of interest were generated with a 50% threshold isocontour for each lesion, in every image. The distributions of metabolic volumes, means and maxima defined by the contoured volumes-of-interest (VOIs) were similar between the LD and SD sets. A two-tailed, matched t-test was performed on the populations of region statistics for both LD and ELD reconstructions, and the t-statistics were 1.1 (P = 0.267) and -0.22 (P = 0.828) for the background liver VOIs and -0.54 (P = 0.603) and 0.23 (P = 0.821) for the lesion VOIs, for FBP and PSFTOF respectively. In every test, the null hypothesis that the two populations had the same mean could not be rejected at the 5% significance level., Conclusions: Our results demonstrate that clinical LD PET scans can indeed be accurately emulated by the statistical decimation of standard dose scans, and this was achieved through validation by images generated with unbiased random coincidence estimations., (© 2019 American Association of Physicists in Medicine.)

Background: The understanding of early events following TB exposure is limited by traditional tests that rely on detection of an immune response to infection, which is delayed, or on imaging tests with low sensitivity for early disease. We investigated for evidence of lung abnormalities in heavily exposed TB contacts using PET/MRI., Methods: 30 household contacts of 20 index patients underwent clinical assessment, IGRA testing, chest x-ray and PET/MRI scan using 18-F-FDG. MRI images were examined by a radiology/nuclear medicine dual-qualified physician using a standardised report form, while PET/MRI images were examined independently by another radiology/nuclear medicine dual-qualified physician using a similar form. Standardised uptake value (SUV) was quantified for each abnormal lesion., Results: IGRA was positive in 40%. PET/MRI scan was abnormal in 30%, predominantly FDG uptake in hilar or mediastinal lymph nodes and lung apices. We did not identify any relationship between PET/MRI findings and degree of exposure or IGRA status., Conclusion: PET-based imaging may provide important insights into the natural history following exposure to TB that may not be available from traditional tests of TB immune response or imaging. The clinical significance of the abnormalities is uncertain and merits further investigation in longitudinal studies.

Little is known about the influence of personal health history and depression self-care practices on screening for depression by health care providers among African Americans with chronic conditions. African Americans (N = 203) aged 18 years or older and living with at least one chronic health condition in a metropolitan city completed a 45-item community perceptions survey. The number of depression symptoms experienced per month was positively associated with screening for depression by a health care provider; perceived ability to identify depression symptoms was inversely associated with screening by a health care provider. Understanding patients' health history and self-care practices can initiate provision of information or support services to improve patient-provider communication about depression.

Background: Following an acute coronary syndrome, combined CT and PET with 18 F-NaF can identify coronary atherosclerotic plaques that have ruptured or eroded. However, the processes behind 18 F-NaF uptake in vulnerable plaques remain unclear., Methods and Results: Ten patients with STEMI were scanned after 18 F-NaF injection, for 75 minutes in a Siemens PET/MR scanner using delayed enhancement (LGE). They were then scanned in a Siemens PET/CT scanner for 10 minutes. Tissue-to-background ratio (TBR) was compared between the culprit lesion in the IRA and remote non-culprit lesions in an effort to independently validate prior studies. Additionally, we performed a proof-of-principle study comparing TBR in scar tissue and remote myocardium using LGE images and PET/MR or PET/CT data. From the 33 coronary lesions detected on PET/CT, TBRs for culprit lesions were higher than for non-culprit lesions (TBR = 2.11 ± 0.45 vs 1.46 ± 0.48; P < 0.001). Interestingly, the TBR measured on the PET/CT was higher for infarcted myocardium than for remote myocardium (TBR = 0.81 ± 0.10 vs 0.71 ± 0.05; P = 0.003). These results were confirmed using the PET/MR data (TBR = 0.81 ± 0.10 for scar, TBR = 0.71 ± 0.06 for healthy myocardium, P = 0.03)., Conclusions: We confirmed the potential of 18 F-NaF PET/CT imaging to detect vulnerable coronary lesions. Moreover, we demonstrated proof-of-principle that 18 F-NaF concurrently detects myocardial scar tissue.

With amyloid diseases poised to become a major health burden in countries with aging populations, diagnostic molecules that aid the detection of amyloid in vitro and in vivo are of considerable clinical value. Understanding how such ligands recognize their amyloid targets would help to design diagnostics that target specific amyloid types associated with a particular disease, but methods to provide comprehensive information are underdeveloped. Here, solid-state NMR is used to determine the molecular orientation of the amyloid diagnostic 1-fluoro-2,5-bis[( E)-3-carboxy-4-hydroxystyryl]-benzene (FSB) when bound to fibrils of the Alzheimer's amyloid-β polypeptide aligned on a planar substrate. The 19 F NMR spectrum of the aligned complex reveals that FSB is oriented approximately parallel with the fibril long axis and bridges four hydrogen-bonded β-sheets. In addition to providing atomic details to aid the design of amyloid-specific diagnostics, this approach will also illuminate the molecular mechanisms of accessory molecules in amyloid disease.

Head motion occurring during brain PET studies leads to image blurring and to bias in measured local quantities. The objective of this work was to implement a correction method for PET data acquired with the mMR synchronous PET/MR scanner. Methods: A list-mode-based motion-correction approach has been designed. The developed rebinner chronologically reads the recorded events from the Siemens list-mode file, applies the estimated geometric transformations, and frames the detected counts into sinograms. The rigid-body motion parameters were estimated from an initial dynamic reconstruction of the PET data. We then optimized the correction for 11 C-Pittsburgh compound B ( 11 C-PIB) scans using simulated and actual data with well-controlled motion. Results: An efficient list-mode-based motion correction approach has been implemented, fully optimized, and validated using simulated and actual PET data. The average spatial resolution loss induced by inaccuracies in motion parameter estimates and by the rebinning process was estimated to correspond to a 1-mm increase in full width at half maximum with motion parameters estimated directly from the PET data with a temporal frequency of 20 s. The results show that the rebinner can be safely applied to the 11 C-PIB scans, allowing almost complete removal of motion-induced artifacts. The application of the correction method to a large cohort of 11 C-PIB scans led to the following observations: first, that more than 21% of the scans were affected by motion greater than 10 mm (39% for subjects with Mini-Mental State Examination scores below 20), and second, that the correction led to quantitative changes in Alzheimer-specific cortical regions of up to 30%. Conclusion: The rebinner allows accurate motion correction at a cost of minimal resolution reduction. Application of the correction to a large cohort of 11 C-PIB scans confirmed the necessity of systematically correcting for motion to obtain quantitative results., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Infiltrations of 18F-fluorodeoxyglucose (FDG) injections affect positron emission tomography/computed tomography (PET/CT) image quality and quantification. A device using scintillation sensors (Lucerno Dynamics, Cary, NC) provides dynamic measurements acquired during FDG uptake to identify and characterize radioactivity near the injection site prior to patient imaging. Our aim was to compare sensor measurements against dynamic PET image acquisition, our proposed reference in assessing injection quality during the uptake period. Methods: Subjects undergoing routine FDG PET/CT imaging were eligible for this Institutional Review Board approved prospective study. After providing informed consent, subjects had sensors topically placed on their arms. FDG was injected into subjects' veins directly on the PET imaging table. Dynamic images of the injection site were acquired during 45 min of the uptake period. These dynamic image acquisitions and subjects' routine standard static images were evaluated by nuclear medicine physicians for abnormal FDG accumulation near the injection site. Sensor measurements were interpreted independently by Lucerno staff. Dynamic image acquisition interpretation results were compared to the sensor measurement interpretations and to static image interpretations. Results: Twenty-four subjects were consented and enrolled. Data from 21 subjects were gathered. During dynamic image acquisition review, physicians interpreted 4 subjects with no FDG accumulation at the injection site, whereas 17 showed evidence of accumulation. In 10 of the 17 cases that showed FDG accumulation, the FDG presence at the injection site resolved completely during uptake corresponding to venous stasis, the temporary sequestration of blood from circulation. Static image interpretation agreed with dynamic images interpretation in 11/21 (52%) subjects. Sensor measurement interpretations agreed with the dynamic images interpretations in 18/21 (86%) subjects. Conclusions: Sensor measurements can be an effective way to identify and characterize infiltrations and venous stasis. Comparable to an infiltration, venous stasis may produce spurious and clinically meaningful measurement bias and possibly even scan misinterpretation. Since the quality and quantification of PET/CT studies are of clinical importance, sensor measurements acquired during the FDG uptake may prove to be a useful quality control measure to reduce infiltration rates and potentially improve patient care. Registration: Clinicaltrials.gov, Identifier: NCT03041090.

Amyloid deposits of WT apolipoprotein A-I (apoA-I), the main protein component of high-density lipoprotein, accumulate in atherosclerotic plaques where they may contribute to coronary artery disease by increasing plaque burden and instability. Using CD analysis, solid-state NMR spectroscopy, and transmission EM, we report here a surprising cooperative effect of heparin and the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG), a known inhibitor and modulator of amyloid formation, on apoA-I fibrils. We found that heparin, a proxy for glycosaminoglycan (GAG) polysaccharides that co-localize ubiquitously with amyloid in vivo , accelerates the rate of apoA-I formation from monomeric protein and associates with insoluble fibrils. Mature, insoluble apoA-I fibrils bound EGCG ( K D = 30 ± 3 μm; B max = 40 ± 3 μm), but EGCG did not alter the kinetics of apoA-I amyloid assembly from monomer in the presence or absence of heparin. EGCG selectively increased the mobility of specific backbone and side-chain sites of apoA-I fibrils formed in the absence of heparin, but the fibrils largely retained their original morphology and remained insoluble. By contrast, fibrils formed in the presence of heparin were mobilized extensively by the addition of equimolar EGCG, and the fibrils were remodeled into soluble 20-nm-diameter oligomers with a largely α-helical structure that were nontoxic to human umbilical artery endothelial cells. These results argue for a protective effect of EGCG on apoA-I amyloid associated with atherosclerosis and suggest that EGCG-induced remodeling of amyloid may be tightly regulated by GAGs and other amyloid co-factors in vivo , depending on EGCG bioavailability., (© 2018 Townsend et al.)

Background: Major changes to the teaching of anatomy associated with the integration of basic and clinical sciences in modern medical curricula have coincided with students reporting concern over achievement of learning outcomes in anatomy. Little guidance exists for medical educators designing anatomy courses that account for factors that positively influence medical student confidence in their own anatomy knowledge. We sought to determine what factors are associated with medical students' self-reported confidence in their anatomy knowledge in preparation for clinical practice., Methods: Cross-sectional national survey of Australian medical students distributed using social media. We performed univariate and multivariable ordinal regression to determine the factors in anatomy learning and teaching that influence medical student self-reported confidence to have sufficient anatomy knowledge by the time of graduation, for practice as a junior doctor., Results: Of 1309 surveyed, 1101 (84%) responded, representing 6.5% of the Australian medical student population. Mean age was 23.9 years (SD 4.8 years), a majority were female (644, 58.5%), and students in all years of both undergraduate (52%, 575) and graduate entry courses (48%, 529) were represented. Items associated with increased self-reported confidence in anatomy knowledge included adequate assessment of anatomy (Odds Ratio 2.17 [95% CI 1.69-2.81]), integration of anatomy with other basic sciences (OR 1.97 [1.52-2.56]) and clinical teaching (OR 1.90 [1.46-2.48]), male gender (OR 1.89 [1.48-2.42]), anatomy education prior to medical school (OR 1.46 [1.14-1.87]) and exposure to dissection (OR 1.39 [1.08-1.78]). Medical students in their clinical years reported lower confidence in their anatomy knowledge (OR 0.6 [0.47-0.77], p < 0.0001). Age and career intention were not significant predictors of confidence., Conclusions: Medical educators can enhance student confidence in their own anatomy knowledge by developing curricula that vertically integrating anatomy learning and teaching, integrate anatomy teaching with other basic sciences, and providing consistent assessment through both the pre-clinical and clinical stages of medical training. Anatomy education should also incorporate dissection as a teaching method, and students could benefit from completion of anatomy education prior to medical school. Consideration should also be given to further investigate the confidence of female students in their anatomy knowledge.

Objectives: To estimate the frequency of patient-perceived potentially harmful problems occurring in primary care. To describe the type of problem, patient predictors of perceiving a problem, the primary care service involved, how the problem was discussed and patient suggestions as to how the problem might have been prevented. To describe clinician/public opinions regarding the likelihood that the patient-described scenario is potentially harmful., Design: Population-level survey., Setting: Great Britain., Participants: A nationally representative sample of 3975 members of the public aged ≥15 years interviewed during April 2016., Main Outcome Measures: Counts of patient-perceived potentially harmful problems in the last 12 months, descriptions of patient-described scenarios and review by clinicians/members of the public., Results: 3975 of 3996 participants in a nationally representative survey completed the relevant questions (99.5%). 300 (7.6%; 95% CI 6.7% to 8.4%) of respondents reported experiencing a potentially harmful preventable problem in primary care during the past 12 months and 145 (48%) discussed their concerns within primary care. This did not vary with age, gender or type of service used. A substantial minority (30%) of the patient-perceived problems occurred outside general practice, particularly the dental surgery, walk in clinic, out of hours care and pharmacy. Patients perceiving a potentially harmful preventable problem were eight times more likely to have 'no confidence and trust in primary care' compared with 'yes, definitely' (OR 7.9; 95% CI 5.9 to 10.7) but those who discussed their perceived-problem appeared to maintain higher trust and confidence. Generally, clinicians ranked the patient-described scenarios as unlikely to be potentially harmful., Conclusions: This study highlights the importance of actively soliciting patient's views about preventable harm in primary care as patients frequently perceive potentially harmful preventable problems and make useful suggestions for their prevention. Such engagement may also help to improve confidence and trust in primary care., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Yttrium-90 ( 90 Y) radioembolization involves the intra-arterial delivery of radioactive microspheres to treat hepatic malignancies. Though this therapy involves careful pre-treatment planning and imaging, little is known about the precise location of the microspheres once they are administered. Recently, there has been growing interest post-radioembolization imaging using positron-emission tomography (PET) for quantitative dosimetry and identifying lesions that may benefit from additional salvage therapy. In this study, we aim to measure the inter-center variability of 90 Y PET measurements as measured on PET/MRI in preparation for a multi-institutional prospective phase I/II clinical trial. Eight institutions participated in this study and followed a standardized phantom filling and imaging protocol. The NEMA NU2-2012 body phantom was filled with 3 GBq of 90 Y chloride solution. The phantom was imaged for 30 min in listmode on a Siemens Biograph mMR non-TOF PET/MRI scanner at five time points across 10 days (0.3-3.0 GBq). Raw PET data were sent to a central site for image reconstruction and data analysis. Images were reconstructed with optimal parameters determined from a previous study. Volumes of interest (VOIs) matching the known sphere diameters were drawn on the vendor-provided attenuation map and propagated to the PET images. Recovery coefficients (RCs) and coefficient of variation of the RCs (COV) were calculated from these VOIs for each sphere size and activity level., Results: Mean RCs ranged from 14.5 to 75.4%, with the lowest mean RC coming from the smallest sphere (10 mm) on the last day of imaging (0.16 MBq/ml) and the highest mean RC coming from the largest sphere (37 mm) on the first day of imaging (2.16 MBq/ml). The smaller spheres tended to exhibit higher COVs. In contrast, the larger spheres tended to exhibit lower COVs. COVs from the 37 mm sphere were < 25.3% in all scans. For scans with ≥ 0.60 MBq/ml, COVs were ≤ 25% in spheres ≥ 22 mm. However, for all other spheres sizes and activity levels, COVs were usually > 25%., Conclusions: Post-radioembolization dosimetry of lesions or other VOIs ≥ 22 mm in diameter can be consistently obtained (< 25% variability) at a multi-institutional level using PET/MRI for any clinically significant activity for 90 Y radioembolization.

Two experiments examined the relation between event structure, situational likelihood and eye fixation time while reading predicate modifiers in isolated sentences. Experiment 1 used activity predicates and preparatory process predicates ( climbed a mountain ), which make salient the process that leads to a culmination. Preparatory process predicates increased first pass time on durative modifiers ( for several years ) and decreased total time on frequency modifiers (e.g., every year ). Situational likelihood was associated with fixation times on frame modifiers ( last year ) but not with fixation times on durative or frequency modifiers. Experiment 2 used activity predicates and result state predicates ( halted a class ), which make salient the result that follows from a culmination. Result state predicates had no effect on fixation times on durative modifiers and decreased total time on frequency modifiers. Situational likelihood was associated only with total time on durative modifiers. These results demonstrate that readers use the meanings of predicates and modifiers to form an initial model of a sentence and that the likelihood of the reported situation is related to reading time relatively late. The results are discussed in terms of type coercion theory and situation models in sentences and narratives.

Objectives: To design and pilot a survey to be used at the population level to estimate the frequency of patient-perceived potentially harmful preventable problems occurring in UK primary care. To explore the nature of the problems, patient-suggested strategies for prevention and opinions of clinicians and the public regarding the potential for harm., Design: A survey was codesigned by three members of the public and one researcher and piloted through public and patient involvement and engagement networks., Setting: Self-selected sample of the UK population., Participants: 977 members of the public accessed the online survey during October and November 2015., Primary Outcome Measures: Respondent feedback about the ease of completion of the survey, quality of responses in terms of review by clinicians and members of the public, preliminary estimates of the frequency and nature of patient-perceived potentially harmful problems occurring in the last 12 months., Results: 638 (65%) members of the public completed the survey and few respondents reported any difficulty in understanding or completing the survey. 132 (21%) respondents reported experiencing a potentially harmful preventable problem during the past 12 months and 108 (82%) of these respondents provided a description that was adequate for at least one clinician to form an opinion about the potentially harmful problem. Respondents were older than the UK generally, more likely to work or volunteer in the healthcare sector and tended to use primary care more frequently but their confidence and trust in their own general practitioner (GP) was similar to that of the UK population as measured by the annual English GP patient survey., Conclusions: The survey was acceptable to patients and mostly provided data of sufficient quality for review by clinicians and members of the public. It is now ready to use at a population level to estimate the frequency and nature of potentially harmful preventable problems in primary care from a patient's perspective., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at (available on request from the corresponding author)., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Capsinoids are reported to increase energy expenditure (EE) via brown adipose tissue (BAT) stimulation. However, imaging of BAT activation by capsinoids remains limited. Because BAT activation is a potential therapeutic strategy for obesity and related metabolic disorders, we sought to prove that capsinoid-induced BAT activation can be visualized by 18-fluorine fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)., Objective: We compared capsinoids and cold exposure on BAT activation and whole-body EE., Design: Twenty healthy participants (8 men, 12 women) with a mean age of 26 y (range: 21-35 y) and a body mass index (kg/m2) of 21.7 (range: 18.5-26.0) underwent 18F-FDG PET and whole-body calorimetry after ingestion of 12 mg capsinoids or ≤2 h of cold exposure (∼14.5°C) in a crossover design. Mean standardized uptake values (SUVs) of the region of interest and BAT volumes were calculated. Blood metabolites were measured before and 2 h after each treatment., Results: All of the participants showed negligible 18F-FDG uptake post-capsinoid ingestion. Upon cold exposure, 12 participants showed avid 18F-FDG uptake into supraclavicular and lateral neck adipose tissues (BAT-positive group), whereas the remaining 8 participants (BAT-negative group) showed undetectable uptake. Capsinoids and cold exposure increased EE, although cold induced a 2-fold increase in whole-body EE and higher fat oxidation, insulin sensitivity, and HDL cholesterol compared with capsinoids., Conclusions: Capsinoids only increased EE in BAT-positive participants, which suggests that BAT mediates EE evoked by capsinoids. This implies that capsinoids stimulate BAT to a lesser degree than cold exposure as evidenced by 18F-FDG uptake below the presently accepted SUV thresholds defining BAT activation. This trial was registered at www.clinicaltrials.gov as NCT02964442., (© 2018 American Society for Nutrition. All rights reserved.)

Background: The use of radiolabeled choline as a positron emission tomography (PET) agent for imaging primary tumors in the prostate has been evaluated extensively over the past two decades. There are, however, conflicting reports of its sensitivity and the relationship between choline PET imaging and disease staging is not fully understood. Moreover, relatively few studies have investigated the correlation between tracer uptake and histological tumor grade. This work quantified 18 F-fluorocholine in tumor and healthy prostate tissue using pharmacokinetic modeling and stratified uptake parameters by histology grade. Additionally, the effect of scan time on the estimation of the kinetic exchange rate constants was evaluated, and the tracer influx parameters from full compartmental analysis were compared to uptake values quantified by Patlak and standardized uptake value (SUV) analyses. 18 F-fluorocholine was administered as a 222 MBq bolus injection to ten patients with biopsy-confirmed prostate tumors, and dynamic PET data were acquired for 60 min. Image-derived arterial input functions were scaled by discrete blood samples, and a 2-tissue, 4-parameter model accounting for blood volume (2T4k+Vb) was used to perform fully quantitative compartmental modeling on tumor, healthy prostate, and muscle tissue. Subsequently, all patients underwent radical prostatectomy, and histological analyses were performed on the prostate specimens; kinetic parameters for tumors were stratified by Gleason score. Correlations were investigated between compartmental K 1 and K i parameters and SUV and Patlak slope; the effect of scan time on parameter bias was also evaluated., Results: Choline activity curves in seven tumors, eight healthy prostate regions, and nine muscle regions were analyzed. Net tracer influx was generally higher in tumor relative to healthy prostate, with the values in the highest grade tumors markedly higher than those in lower grade tumors. Influx terms from Patlak and full compartmental modeling showed good correlation within individual tissue groups. Kinetic parameters calculated from the entire 60-min scan data were accurately reproduced from the first 30 min of acquired data (R 2  ≈ 0.9)., Conclusions: Strong correlations were observed between K i and Patlak slope in tumor tissue, and K 1 and SUV were also correlated but to a lesser degree. Reliable estimates of all kinetic parameters can be achieved from the first 30 min of dynamic 18 F-choline data. Although SUV, K 1 , K i , and Patlak slope were found to be poor differentiators of low-grade tumor compared to healthy prostate tissue, they are strong indicators of aggressive disease.

Purpose: PET/computed tomography (CT) has been shown to detect lesions in patients with pulmonary tuberculosis (PTB) and may be useful for assessing PTB disease in clinical research studies. However, radiation dose is of concern for clinical research in individuals with an underlying curable disease. This study aimed to determine whether PET/MR is equivalent to PET/CT in PTB., Materials and Methods: Ten patients with microbiologically confirmed PTB were recruited. Patients received 129.0±4.1 MBq of fluorine-18-fluorodeoxyglucose. Five of the 10 patients underwent a PET/MR scan, followed by PET/CT. The remaining five were first imaged on the PET/CT, followed by the PET/MRI. PET acquisition began at 66.7±14.4 min (mean±SD) after injection when performing PET/MR first (PET/CT: 117.2±5.6 min) and 92.4±7.6 min when patients were imaged on PET/MR second (PET/CT: 61.1±3.9 min). PET data were reconstructed iteratively with Ordinary-Poisson Ordered-Subset Expectation-Maximization and reconstruction parameters were matched across the two scanners. A visual lesion detection task and a standardized uptake value (SUV) analysis were carried out. The CT Hounsfield unit values of PTB lesions were also compared with MR-based attenuation correction mu-map tissue classes., Results: A total of 108 PTB lesions were detected on PET/MR and 112 on PET/CT. SUV analysis was carried out on 50 of these lesions that were observed with both modalities. Mean standardized uptake value (SUVmean) and maximum standardized uptake value (SUVmax) were significantly lower on PET/MR (SUVmean: 2.6±1.4; SUVmax: 4.3±2.5) than PET/CT (SUVmean: 3.5±1.5; SUVmax: 5.3±2.4)., Conclusion: PET/MR visual performance was shown to be comparable to PET/CT in terms of the number of PTB lesions detected. SUVs were significantly lower on PET/MR. Dixon-based attenuation correction underestimates the linear attenuation coefficient of PTB lesions, resulting in lower SUVs compared with PET/CT. However, the use of PET/MR to measure the response of lung lesions to assess response to treatment in research studies is unlikely to be affected by these differences in quantification.

LSO and LYSO are today the most common scintillators used in positron emission tomography. Lutetium contains traces of 176 Lu, a radioactive isotope that decays β - with a cascade of γ photons in coincidence. Therefore, Lutetium-based scintillators are characterized by a small natural radiation background. In this paper, we investigate and characterize the 176 Lu radiation background via experiments performed on LSO-based PET scanners. LSO background was measured at different energy windows and different time coincidence windows, and by using shields to alter the original spectrum. The effect of radiation background in particularly count-starved applications, such as 90 Y imaging, is analysed and discussed. Depending on the size of the PET scanner, between 500 and 1000 total random counts per second and between 3 and 5 total true coincidences per second were measured in standard coincidence mode. The LSO background counts in a Siemens mCT in the standard PET energy and time windows are in general negligible in terms of trues, and are comparable to that measured in a BGO scanner of similar size.

Peptides derived from apolipoprotein A-I (apoA-I), the main component of high-density lipoprotein (HDL), constitute the main component of amyloid deposits that colocalize with atherosclerotic plaques. Here we investigate the molecular details of full-length, lipid-deprived apoA-I after assembly into insoluble aggregates under physiologically relevant conditions known to induce aggregation in vitro. Unmodified apoA-I is shown to remain soluble at pH 7 for at least 3 days, retaining its native α-helical-rich structure. Upon acidification to pH 4, apoA-I rapidly assembles into insoluble nonfibrillar aggregates lacking the characteristic cross-β features of amyloid. In the presence of heparin, the rate and thioflavin T responsiveness of the aggregates formed at pH 4 increase and short amyloid-like fibrils are observed, which give rise to amyloid-characteristic X-ray reflections at 4.7 and 10 Å. Solid-state nuclear magnetic resonance (SSNMR) and synchrotron radiation circular dichroism spectroscopy of fibrils formed in the presence of heparin show they retain some α-helical characteristics together with new β-sheet structures. Interestingly, SSNMR indicates a similar molecular structure of aggregates formed in the absence of heparin at pH 6 after oxidation of the three methionine residues, although their morphology is rather different from that of the heparin-derived fibrils. We propose a model for apoA-I aggregation in which perturbations of a four-helix bundle-like structure, induced by interactions of heparin or methionine oxidation, cause the partially helical N-terminal residues to disengage from the remaining, intact helices, thereby allowing self-assembly via β-strand associations.

We have previously established that mucosal uptake of recombinant fowlpox virus (rFPV) vaccines is far superior to other vector-based vaccines. Specifically, intranasal priming with rFPV vaccines can recruit unique antigen-presenting cells, which induce excellent mucosal and systemic HIV-specific CD8+ T-cell immunity. In this study, we have for the first time investigated the in vivo dissemination, safety and expression kinetics of rFPV post intranasal delivery using recombinant viruses expressing green fluorescent protein or mCherry. Both confocal microscopy of tissue sections using green fluorescent protein and in vivo Imaging System (IVIS) spectrum live animal and whole organ imaging studies using mCherry revealed that (i) the peak antigen expression occurs 12 to 24 h post vaccination and no active viral gene expression is detected 96 h post vaccination. (ii) The virus only infects the initial vaccination site (lung and nasal cavity) and does not disseminate to distal sites such as the spleen or gut. (iii) More importantly, rFPV does not cross the olfactory receptor neuron pathway. Collectively, our findings indicate that rFPV vector-based vaccines have all the hallmarks of a safe and effective mucosal delivery vector, suitable for clinical evaluation.

Lung cancer remains responsible for more deaths worldwide than any other cancer, but recently there has been a significant shift in the clinical paradigm regarding the initial management of subjects at high risk for this disease. Low-dose CT has demonstrated significant improvements over planar x-ray screening for patient prognoses and is now performed in the United States. Specificity of this modality, however, is poor, and the additional information from PET has the potential to improve its accuracy. Routine screening requires consideration of the effective dose delivered to the patient, and this work investigates image quality of PET for low-dose conditions, in the context of lung lesion detectability. Reduced radiotracer doses were simulated by randomly discarding counts from clinical lung cancer scans acquired in list-mode. Bias and reproducibility of lesion activity values were relatively stable even at low total counts of around 5 million trues. Additionally, numeric observer models were developed and trained with the results of 2 physicians and 3 postdoctoral researchers with PET experience in a detection task; detection sensitivity of the observers was well correlated with lesion signal-to-noise ratio. The models were used prospectively to survey detectability of lung cancer lesions, and the findings suggested a lower limit around 10 million true counts for maximizing performance. Under the acquisition parameters used in this study, this translates to an effective patient dose of less than 0.4 mSv, potentially allowing a complete low-dose PET/CT lung screening scan to be obtained under 1 mSv., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Instrumentation for positron emission tomography (PET) imaging has experienced tremendous improvements in performance over the past 60 years since it was first conceived as a medical imaging modality. Spatial resolution has improved by a factor of 10 and sensitivity by a factor of 40 from the early designs in the 1970s to the high-performance scanners of today. Multimodality configurations have emerged that combine PET with computed tomography (CT) and, more recently, with MR. Whole-body scans for clinical purposes can now be acquired in under 10 min on a state-of-the-art PET/CT. This paper will review the history of these technical developments over 40 years and summarize the important clinical research and healthcare applications that have been made possible by these technical advances. Some perspectives for the future of this technology will also be presented that promise to bring about new applications of this imaging modality in clinical research and healthcare.

Purpose: To dynamically detect and characterize 18 F-fluorodeoxyglucose (FDG) dose infiltrations and evaluate their effects on positron emission tomography (PET) standardized uptake values (SUV) at the injection site and in control tissue., Methods: Investigational gamma scintillation sensors were topically applied to patients with locally advanced breast cancer scheduled to undergo limited whole-body FDG-PET as part of an ongoing clinical study. Relative to the affected breast, sensors were placed on the contralateral injection arm and ipsilateral control arm during the resting uptake phase prior to each patient's PET scan. Time-activity curves (TACs) from the sensors were integrated at varying intervals (0-10, 0-20, 0-30, 0-40, and 30-40 min) post-FDG and the resulting areas under the curve (AUCs) were compared to SUVs obtained from PET., Results: In cases of infiltration, observed in three sensor recordings (30 %), the injection arm TAC shape varied depending on the extent and severity of infiltration. In two of these cases, TAC characteristics suggested the infiltration was partially resolving prior to image acquisition, although it was still apparent on subsequent PET. Areas under the TAC 0-10 and 0-20 min post-FDG were significantly different in infiltrated versus non-infiltrated cases (Mann-Whitney, p < 0.05). When normalized to control, all TAC integration intervals from the injection arm were significantly correlated with SUV peak and SUV max measured over the infiltration site (Spearman ρ ≥ 0.77, p < 0.05). Receiver operating characteristic (ROC) analyses, testing the ability of the first 10 min of post-FDG sensor data to predict infiltration visibility on the ensuing PET, yielded an area under the ROC curve of 0.92., Conclusions: Topical sensors applied near the injection site provide dynamic information from the time of FDG administration through the uptake period and may be useful in detecting infiltrations regardless of PET image field of view. This dynamic information may also complement the static PET image to better characterize the true extent of infiltrations., Competing Interests: of potential conflicts of interest: WJG, JGK, RKL, SRP, and CWS are employees of Lucerno Dynamics, LLC, which provided the investigational device to Vanderbilt without charge. DWT is a Scientific Advisor for Lucerno.

Background: Lowering injected dose will have an effect on PET image quality. In this article, we aim to investigate this effect in terms of signal-to-noise ratio (SNR) in the liver, contrast-to-noise ratio (CNR) in the lesion, bias and ensemble image noise., Methods: We present here our method and preliminary results using tuberculosis (TB) cases. Sixteen patients who underwent (18)F-FDG PET/MR scans covering the whole lung and portion of the liver were selected for the study. Reduced doses were simulated by randomly discarding events in the PET list mode data stream, and ten realizations at each simulated dose were generated and reconstructed. The volumes of interest (VOI) were delineated on the image reconstructed from the original full statistics data for each patient. Four thresholds (20, 40, 60 and 80 % of SUVmax) were used to quantify the effect of the threshold on CNR at the different count level. Image metrics were calculated for each VOI. This experiment allowed us to quantify the loss of SNR and CNR as a function of the counts in the scan, in turn related to dose injected. Reproducibility of mean and maximum standardized uptake value (SUVmean and SUVmax) measurement in the lesions was studied as standard deviation across 10 realizations., Results: At 5 × 10(6) counts in the scan, the average SNR in the liver in the observed samples is about 3, and the CNR is reduced to 60 % of the full statistics value. The CNR in the lesion and SNR in the liver decreased with reducing count data. The variation of CNR across the four thresholds does not significantly change until the count level of 5 × 10(6). After correcting the factor related to subject's weight, the square of the SNR in the liver was found to have a very good linear relationship with detected counts. Some quantitative bias appears with count reduction. At the count level of 5 × 10(6), bias and noise in terms of SUVmean and SUVmax are up to 10 and 20 %, respectively. To keep both bias and noise less than 10 %, 5 × 10(6) counts and 20 × 10(6) counts were required for SUVmean and SUVmax, respectively., Conclusions: Initial results with the given data of 16 patients diagnosed as TB demonstrated that 5 × 10(6) counts in the scan could be sufficient to yield good images in terms of SNR, CNR, bias and noise. In the future, more work needs to be done to validate the proposed method with a larger population and lung cancer patient data.

Background: The aim of this study is to investigate vascular fragility and endothelial glycocalyx (ECG) in images of the healthy gingival crevice (GC). The ECG is a surface layer lining the luminal walls of blood vessels composed of proteoglycans and glycoproteins with other components. Degradation of the layer has been shown to drastically affect microvascular flow, permeability, and immune function., Methods: Videomicroscopic images from tissues lining the healthy GC in 20 healthy volunteers were analyzed to determine the presence of microhemorrhage related to branched dilated microvessels. Imaging of capillary ECG in human labial mucosa was achieved by the use of a 1-mm-diameter 0.5 numerical aperture gradient index objective lens and one-sided oblique illumination using light at 450 nm. This allows resolution of red blood cells within the capillary and the endothelial cell wall of the lumen. The cell-free plasma gap between the red cell and endothelial wall represents the ECG., Results: In the healthy GC there was no evidence of microhemorrhage in participants that had only simple capillary loops (seven of 20). Microhemorrhage was present in the majority of participants with branched dilated microvessels (11 of 13) (McNemar Test for equal distribution, P = 0.05). A cell-free plasma gap representing the ECG could be imaged in the superficial tissues lining the labial sulcus. No such cell-free plasma gap could be detected in the branched dilated microvessels in tissues lining the GC., Conclusions: There is an association between the presence of vascular microhemorrhage and branched dilated microvessels in the tissues lining the clinically healthy GC. Loss of ECG might be part of the inflammatory process in these tissues.