Shape-Programming in Hyperelasticity Through Differential Growth.

This paper is concerned with the growth-driven shape-programming problem, which involves determining a growth tensor that can produce a deformation on a hyperelastic body reaching a given target shape. We consider the two cases of globally compatible growth, where the growth tensor is a deformation gradient over the undeformed domain, and the incompatible one, which discards such hypothesis. We formulate the problem within the framework of optimal control theory in hyperelasticity. The Hausdorff distance is used to quantify dissimilarities between shapes; the complexity of the actuation is incorporated in the cost functional as well. Boundary conditions and external loads are allowed in the state law, thus extending previous works where the stress-free hypothesis turns out to be essential. A rigorous mathematical analysis is then carried out to prove the well-posedness of the problem. The numerical approximation is performed using gradient-based optimisation algorithms. Our main goal in this part is to show the possibility to apply inverse techniques for the numerical approximation of this problem, which allows us to address more generic situations than those covered by analytical approaches. Several numerical experiments for beam-like and shell-type geometries illustrate the performance of the proposed numerical scheme.

Translational molecular imaging: Thrombosis imaging with positron emission tomography.

A key focus of cardiovascular medicine is the detection, treatment, and prevention of disease, with a move towards more personalized and patient-centred treatments. To achieve this goal, novel imaging approaches that allow for early and accurate detection of disease and risk stratification are needed. At present, the diagnosis, monitoring, and prognostication of thrombotic cardiovascular diseases are based on imaging techniques that measure changes in structural anatomy and biological function. Molecular imaging is emerging as a new tool for the non-invasive detection of biological processes, such as thrombosis, that can improve identification of these events above and beyond current imaging modalities. At the forefront of these evolving techniques is the use of high-sensitivity radiotracers in conjunction with positron emission tomography imaging that could revolutionise current diagnostic paradigms by improving our understanding of the role and origin of thrombosis in a range of cardiovascular diseases.

Sexually dimorphic murine brain uptake of the 18†kDa translocator protein PET radiotracer [18F]LW223.

The 18 kDa translocator protein is a well-known biomarker of neuroinflammation, but also plays a role in homeostasis. PET with 18 kDa translocator protein radiotracers [11C]PBR28 in humans and [18F]GE180 in mice has demonstrated sex-dependent uptake patterns in the healthy brain, suggesting sex-dependent 18 kDa translocator protein expression, although humans and mice had differing results. This study aimed to assess whether the 18 kDa translocator protein PET radiotracer [18F]LW223 exhibited sexually dimorphic uptake in healthy murine brain and peripheral organs. Male and female C57Bl6/J mice (13.6 ± 5.4 weeks, 26.8 ± 5.4 g, mean ± SD) underwent 2 h PET scanning post-administration of [18F]LW223 (6.7 ± 3.6 MBq). Volume of interest and parametric analyses were performed using standard uptake values (90-120 min). Statistical differences were assessed by unpaired t-test or two-way ANOVA with Sidak's test (alpha = 0.05). The uptake of [18F]LW223 was significantly higher across multiple regions of the male mouse brain, with the most pronounced difference detected in hypothalamus (P < 0.0001). Males also exhibited significantly higher [18F]LW223 uptake in the heart when compared to females (P = 0.0107). Data support previous findings on sexually dimorphic 18 kDa translocator protein radiotracer uptake patterns in mice and highlight the need to conduct sex-controlled comparisons in 18 kDa translocator protein PET imaging studies.

[18F]LW223 has low non-displaceable binding in murine brain, enabling high sensitivity TSPO PET imaging.

Neuroinflammation is associated with a number of brain diseases, making it a common feature of cerebral pathology. Among the best-known biomarkers for neuroinflammation in Positron Emission Tomography (PET) research is the 18 kDa translocator protein (TSPO). This study aims to investigate the binding kinetics of a novel TSPO PET radiotracer, [18F]LW223, in mice and specifically assess its volume of non-displaceable binding (VND) in brain as well as investigate the use of simplified analysis approaches for quantification of [18F]LW223 PET data. Adult male mice were injected with [18F]LW223 and varying concentrations of LW223 (0.003-0.55 mg/kg) to estimate VND of [18F]LW223. Dynamic PET imaging with arterial input function studies and radiometabolite studies were conducted. Simplified quantification methods, standard uptake values (SUV) and apparent volume of distribution (VTapp), were investigated. [18F]LW223 had low VND in the brain (<10% of total binding) and low radiometabolism (∼15-20%). The 2-tissue compartment model provided the best fit for [18F]LW223 PET data, although its correlation with SUV90-120min or VTapp allowed for [18F]LW223 brain PET data quantification in healthy animals while using simpler experimental and analytical approaches. [18F]LW223 has the required properties to become a successful TSPO PET radiotracer.

Critical illness-associated cerebral microbleeds: What we learned after the COVID-19 pandemic. A systematic review.

BACKGROUND: Cerebral microbleeds in critically ill patients have been a reported complication of COVID-19. However, they have also been described in patients with other respiratory infections and conditions requiring intensive care unit (ICU) admission. Here, we aim to describe the clinical characteristics of critical illness-associated cerebral microbleeds and compare COVID-19 cases with those related to other conditions. METHODS: We performed a systematic literature review in PubMed and Embase for Critical Illness-Associated Cerebral Microbleeds to describe the clinical characteristics of this entity, in both COVID-19 and non-COVID-19 patients. RESULTS: Of 157 manuscripts screened, 23 were included, totalling 143 cases (median age 61, interquartile range [IQR] 54-66), 104 (73 %) men. SARS-CoV2-associated pneumonia was found in 105 (73 %) cases. The median ICU stay was 34 (IQR 26-42) days and the median mechanical ventilation time was 24 (IQR 14-35) days. Cerebral microbleeds were more frequently juxtacortical (79 %) or located in the corpus callosum (75 %) and deep white matter (71 %) for both COVID-19 and non-COVID-19 individuals, whilst brainstem location was more frequent in non-COVID-19 patients (37 % vs 13 %; p = 0.02). Non-COVID-19 patients were younger (median age 42, IQR 30-54 years) than COVID-19 patients (median age 62, IQR 57-67 years; p < 0.001), and the median platelet count was significantly higher (200,000; IQR 116,000-284,000 ng/dL) in COVID-19 patients than non-COVID-19 patients (50,000; IQR 39,000-61,000 ng/mL; (p < 0.001). CONCLUSIONS: In this systematic review, most patients presented respiratory failure with prolonged mechanical ventilation and ICU stay. Juxtacortical white matter and corpus callosum are characteristic locations of critical illness-associated microbleeds.

In vivo18F-DOPA PET imaging identifies a dopaminergic deficit in a rat model with a G51D α-synuclein mutation.

Parkinson's disease (PD) is a neurodegenerative condition with several major hallmarks, including loss of substantia nigra neurons, reduction in striatal dopaminergic function, and formation of α-synuclein-rich Lewy bodies. Mutations in SNCA, encoding for α-synuclein, are a known cause of familial PD, and the G51D mutation causes a particularly aggressive form of the condition. CRISPR/Cas9 technology was used to introduce the G51D mutation into the endogenous rat SNCA gene. SNCAG51D/+ and SNCAG51D/G51D rats were born in Mendelian ratios and did not exhibit any severe behavourial defects. L-3,4-dihydroxy-6-18F-fluorophenylalanine (18F-DOPA) positron emission tomography (PET) imaging was used to investigate this novel rat model. Wild-type (WT), SNCAG51D/+ and SNCAG51D/G51D rats were characterized over the course of ageing (5, 11, and 16 months old) using 18F-DOPA PET imaging and kinetic modelling. We measured the influx rate constant (Ki) and effective distribution volume ratio (EDVR) of 18F-DOPA in the striatum relative to the cerebellum in WT, SNCAG51D/+ and SNCAG51D/G51D rats. A significant reduction in EDVR was observed in SNCAG51D/G51D rats at 16 months of age indicative of increased dopamine turnover. Furthermore, we observed a significant asymmetry in EDVR between the left and right striatum in aged SNCAG51D/G51D rats. The increased and asymmetric dopamine turnover observed in the striatum of aged SNCAG51D/G51D rats reflects one aspect of prodromal PD, and suggests the presence of compensatory mechanisms. SNCAG51D rats represent a novel genetic model of PD, and kinetic modelling of 18F-DOPA PET data has identified a highly relevant early disease phenotype.

The effects of caloric restriction on adipose tissue and metabolic health are sex- and age-dependent.

Caloric restriction (CR) reduces the risk of age-related diseases in numerous species, including humans. CR's metabolic effects, including decreased adiposity and improved insulin sensitivity, are important for its broader health benefits; however, the extent and basis of sex differences in CR's health benefits are unknown. We found that 30% CR in young (3-month-old) male mice decreased fat mass and improved glucose tolerance and insulin sensitivity, whereas these effects were blunted or absent in young females. Females' resistance to fat loss was associated with decreased lipolysis, energy expenditure and fatty acid oxidation, and increased postprandial lipogenesis, compared to males. The sex differences in glucose homeostasis were not associated with differential glucose uptake but with altered hepatic ceramide content and substrate metabolism: compared to CR males, CR females had lower TCA cycle activity and higher blood ketone concentrations, a marker of hepatic acetyl-CoA content. This suggests that males use hepatic acetyl-CoA for the TCA cycle whereas in females it accumulates, stimulating gluconeogenesis and limiting hypoglycaemia during CR. In aged mice (18-months old), when females are anoestrus, CR decreased fat mass and improved glucose homeostasis similarly in both sexes. Finally, in a cohort of overweight and obese humans, CR-induced fat loss was also sex- and age-dependent: younger females (<45 years) resisted fat loss compared to younger males while in older subjects (>45 years) this sex difference was absent. Collectively, these studies identify age-dependent sex differences in the metabolic effects of CR and highlight adipose tissue, the liver and oestrogen as key determinants of CR's metabolic benefits. These findings have important implications for understanding the interplay between diet and health, and for maximising the benefits of CR in humans.

Desarrollo de una solución integrada para pacientes con dolor crónico portadores de neuroestimulador en tiempos del COVID-19: una aplicación para móvil con centro de soporte / Development of an integrated solution for patients with neurostimulator for chronic pain in times of COVID-19: A mobile application with a support center

Introducción El dolor crónico es una de las afecciones más prevalentes en el mundo. El tratamiento con neuroestimuladores se realiza en los casos más extremos tras una cuidadosa selección, y demanda una gran inversión de recursos en su seguimiento. En estos momentos de pandemia por la COVID-19, presentamos una solución integrada para el seguimiento de estos de pacientes, que incluye el desarrollo de una aplicación para dispositivos móviles y un centro de soporte para seguimiento remoto (CSSR). Material y metodología El proyecto se ha desarrollado basándose en evidencia científica en las siguientes fases: 1) Aprobación de la idea en sesión clínica multidisciplinar de implantes para dolor crónico, 2) Formación de un grupo de expertos, 3) Adaptación del protocolo para el seguimiento de los pacientes con dolor crónico a las características del entorno de un smartphone, 4) Adaptación de la plataforma tecnológica al protocolo clínico (entorno tecnológico y flujo de trabajo entre el hospital y el CSSR) y 5) Evaluación de la calidad mediante encuesta (cuantitativa y cualitativa) con una pequeña muestra de pacientes. Resultados La aplicación de paciente se evaluó solicitando opiniones de los usuarios sobre el diseño y la utilidad de la misma entre los primeros pacientes implantados que la usaron. Se realizaron algunos ajustes menores en relación con el material para descargar, y sobre el texto y el color de la pantalla. Conclusiones El proceso de creación de una solución integrada debe estar basado en principios científicos y acorde con los protocolos establecidos. Un centro de soporte permite asegurar una mayor adherencia al seguimiento y una mejor atención a los pacientes (AU)

Introduction Chronic pain is one of the most prevalent pathologies in the world. Treatment with neurostimulators is carried out in the most extreme cases and requires a large investment of resources. In these times of COVID-19 pandemic, we present a comprehensive solution for monitoring this kind of patient, this solution includes the development of a mobile application and a support center for remote monitoring (SCRM). MMaterial and methodology The project was developed according to the scientific evidence in the following phases: (1) approval in a multidisciplinary clinical committee of implants for chronic pain, (2) setting up a group of experts, (3) protocol adaptation for the follow-up of patients with chronic pain to the Smartphone environment, (4) technology platform adaptation to the clinical protocol (technological environment and workflow between the hospital and the SCRM), and (5) quality evaluation by survey (quantitative and qualitative) of a small series of patients. Results The application was evaluated by asking for user opinions about design and usefulness with the first implanted patients. Some minor adjustments were made concerning downloadable material and screen color and text. Conclusions Developing a comprehensive solution should be based on scientific principles and in accordance with established protocols. A support center ensures greater adherence for follow-up and better patient care (AU)

[Development of an integrated solution for patients with neurostimulator for chronic pain in times of COVID-19: A mobile application with a support center]. / Desarrollo de una solución integrada para pacientes con dolor crónico portadores de neuroestimulador en tiempos del COVID-19: una aplicación para móvil con centro de soporte.

Introduction: Chronic pain is one of the most prevalent pathologies in the world. Treatment with neurostimulators is carried out in the most extreme cases and requires a large investment of resources. In these times of COVID-19 pandemic, we present a comprehensive solution for monitoring this kind of patient, this solution includes the development of a mobile application and a support center for remote monitoring (SCRM). MMaterial and methodology: The project was developed according to the scientific evidence in the following phases: (1) approval in a multidisciplinary clinical committee of implants for chronic pain, (2) setting up a group of experts, (3) protocol adaptation for the follow-up of patients with chronic pain to the Smartphone environment, (4) technology platform adaptation to the clinical protocol (technological environment and workflow between the hospital and the SCRM), and (5) quality evaluation by survey (quantitative and qualitative) of a small series of patients. Results: The application was evaluated by asking for user opinions about design and usefulness with the first implanted patients. Some minor adjustments were made concerning downloadable material and screen color and text. Conclusions: Developing a comprehensive solution should be based on scientific principles and in accordance with established protocols. A support center ensures greater adherence for follow-up and better patient care.

18F-NaF PET/MRI for Detection of Carotid Atheroma in Acute Neurovascular Syndrome.

Background MRI and fluorine 18-labeled sodium fluoride (18F-NaF) PET can be used to identify features of plaque instability, rupture, and disease activity, but large studies have not been performed. Purpose To evaluate the association between 18F-NaF activity and culprit carotid plaque in acute neurovascular syndrome. Materials and Methods In this prospective observational cohort study (October 2017 to January 2020), participants underwent 18F-NaF PET/MRI. An experienced clinician determined the culprit carotid artery based on symptoms and record review. 18F-NaF uptake was quantified using standardized uptake values and tissue-to-background ratios. Statistical significance was assessed with the Welch, χ2, Wilcoxon, or Fisher test. Multivariable models were used to evaluate the relationship between the imaging markers and the culprit versus nonculprit vessel. Results A total of 110 participants were evaluated (mean age, 68 years ± 10 [SD]; 70 men and 40 women). Of the 110, 34 (32%) had prior cerebrovascular disease, and 26 (24%) presented with amaurosis fugax, 54 (49%) with transient ischemic attack, and 30 (27%) with stroke. Compared with nonculprit carotids, culprit carotids had greater stenoses (≥50% stenosis: 30% vs 15% [P = .02]; ≥70% stenosis: 25% vs 4.5% [P < .001]) and had increased prevalence of MRI-derived adverse plaque features, including intraplaque hemorrhage (42% vs 23%; P = .004), necrotic core (36% vs 18%; P = .004), thrombus (7.3% vs 0%; P = .01), ulceration (18% vs 3.6%; P = .001), and higher 18F-NaF uptake (maximum tissue-to-background ratio, 1.38 [IQR, 1.12-1.82] vs 1.26 [IQR, 0.99-1.66], respectively; P = .04). Higher 18F-NaF uptake was positively associated with necrosis, intraplaque hemorrhage, ulceration, and calcification and inversely associated with fibrosis (P = .04 to P < .001). In multivariable analysis, carotid stenosis at or over 70% (odds ratio, 5.72 [95% CI: 2.2, 18]) and MRI-derived adverse plaque characteristics (odds ratio, 2.16 [95% CI: 1.2, 3.9]) were both associated with the culprit versus nonculprit carotid vessel. Conclusion Fluorine 18-labeled sodium fluoride PET/MRI characteristics were associated with the culprit carotid vessel in study participants with acute neurovascular syndrome. Clinical trial registration no. NCT03215550 and NCT03215563 © RSNA, 2022 Online supplemental material is available for this article.

Bimetallic gold-platinum nanoparticles as a drug delivery system coated with a new drug to target glioblastoma.

A drug delivery nanosystem of noble bimetallic nanoparticles (NPs) which consists of Au NPs capped with Pt NPs (Au@Pt NPs) is constructed and functionalised with a quinazoline based small molecule (Au@Pt@Q NPs), acting as a theranostic agent against glioblastoma. Two different hydrothermal synthetic procedures for bimetallic Au@Pt NPs are presented and the resulting nanostructures are fully characterised by means of spectroscopic and microscopic methods. The imaging and targeting capacity of the new drug delivery system is assessed through fluorescent optical microscopy and cytotoxicity evaluations. The constructed Au@Pt NPs consist a monodispersed colloidal solution of 25 nm with photoluminescent, fluorescent and X-Ray absorption properties that confirm their diagnostic potential. Haemolysis testing demonstrated that Au@Pt NPs are biocompatible and fluorescent microscopy confirmed their entering the cells. Cytological evaluation of the NPs through MTT assay showed that they do not inhibit the proliferation of control cell line HEK293, whereas they are toxic in U87MG, U251 and D54 glioblastoma cell lines; rendering them selective targeting agents for treating glioblastoma.

18F-GP1 Positron Emission Tomography and Bioprosthetic Aortic Valve Thrombus.

BACKGROUND: Bioprosthetic valve thrombosis may have implications for valve function and durability. OBJECTIVES: Using a novel glycoprotein IIb/IIIa receptor radiotracer 18F-GP1, we investigated whether positron emission tomography (PET)-computed tomography (CT) could detect thrombus formation on bioprosthetic aortic valves. METHODS: Ex vivo experiments were performed on human platelets and explanted bioprosthetic aortic valves. In a prospective cross-sectional study, patients with either bioprosthetic or normal native aortic valves underwent echocardiography, CT angiography, and 18F-GP1 PET-CT. RESULTS: Flow cytometric analysis, histology, immunohistochemistry, and autoradiography demonstrated selective binding of 18F-GP1 to activated platelet glycoprotein IIb/IIIa receptors and thrombus adherent to prosthetic valves. In total, 75 participants were recruited: 53 with bioprosthetic valves (median time from implantation 37 months [IQR: 12-80 months]) and 22 with normal native aortic valves. Three participants had obstructive valve thrombosis, and a further 3 participants had asymptomatic hypoattenuated leaflet thickening on CT angiography. All bioprosthetic valves, but none of the native aortic valves, demonstrated focal 18F-GP1 uptake on the valve leaflets: median maximum target-to-background ratio 2.81 (IQR: 2.29-3.48) vs 1.43 (IQR: 1.28-1.53) (P < 0.001). Higher 18F-GP1 uptake was independently associated with duration of valve implantation and hypoattenuated leaflet thickening. All 3 participants with obstructive valve thrombosis were anticoagulated for 3 months, leading to resolution of their symptoms, improvement in mean valve gradients, and a reduction in 18F-GP1 uptake. CONCLUSIONS: Adherence of activated platelets is a common and sustained finding on bioprosthetic aortic valves. 18F-GP1 uptake is higher in the presence of thrombus, regresses with anticoagulation, and has potential use as an adjunctive clinical tool. (18F-GP1 PET-CT to Detect Bioprosthetic Aortic Valve Thrombosis; NCT04073875).

Development of an integrated solution for patients with neurostimulator for chronic pain in times of COVID-19: A mobile application with a support center.

INTRODUCTION: Chronic pain is one of the most prevalent pathologies in the world. Treatment with neurostimulators is carried out in the most extreme cases and requires a large investment of resources. In these times of the COVID19 pandemic, we present a comprehensive solution for monitoring this kind of patient, this solution includes the development of a mobile application and a support center for remote monitoring (SCRM). MATERIAL AND METHODOLOGY: The project was developed according to the scientific evidence in the following phases: (1) Approval in a multidisciplinary clinical committee of implants for chronic pain, (2) Setting up a group of experts, (3) Protocol adaptation for the follow-up of patients with chronic pain to the Smartphone environment, (4) Technology platform adaptation to the clinical protocol (technological environment and workflow between the hospital and the SCRM), and (5) Quality evaluation by survey (quantitative and qualitative) of a small series of patients. RESULTS: The application was evaluated by asking for user opinions about design and usefulness with the first implanted patients. Some minor adjustments were made concerning downloadable material and screen color and text. CONCLUSIONS: Developing a comprehensive solution should be based on scientific principles and in accordance with established protocols. A support center ensures greater adherence for follow-up and better patient care.

A Systems-Level Analysis of Total-Body PET Data Reveals Complex Skeletal Metabolism Networks in vivo.

Bone is now regarded to be a key regulator of a number of metabolic processes, in addition to the regulation of mineral metabolism. However, our understanding of complex bone metabolic interactions at a systems level remains rudimentary. in vitro molecular biology and bioinformatics approaches have frequently been used to understand the mechanistic changes underlying disease at the cell level, however, these approaches lack the capability to interrogate dynamic multi-bone metabolic interactions in vivo. Here we present a novel and integrative approach to understand complex bone metabolic interactions in vivo using total-body positron emission tomography (PET) network analysis of murine 18F-FDG scans, as a biomarker of glucose metabolism in bones. In this report we show that different bones within the skeleton have a unique glucose metabolism and form a complex metabolic network, which could not be identified using single tissue simplistic PET standard uptake values analysis. The application of our approach could reveal new physiological and pathological tissue interactions beyond skeletal metabolism, due to PET radiotracers diversity and the advent of clinical total-body PET systems.

Modelling [18F]LW223 PET data using simplified imaging protocols for quantification of TSPO expression in the rat heart and brain.

PURPOSE: To provide a comprehensive assessment of the novel 18 kDa translocator protein (TSPO) radiotracer, [18F]LW223, kinetics in the heart and brain when using a simplified imaging approach. METHODS: Naive adult rats and rats with surgically induced permanent coronary artery ligation received a bolus intravenous injection of [18F]LW223 followed by 120 min PET scanning with arterial blood sampling throughout. Kinetic modelling of PET data was applied to estimated rate constants, total volume of distribution (VT) and binding potential transfer corrected (BPTC) using arterial or image-derived input function (IDIF). Quantitative bias of simplified protocols using IDIF versus arterial input function (AIF) and stability of kinetic parameters for PET imaging data of different length (40-120 min) were estimated. RESULTS: PET outcome measures estimated using IDIF significantly correlated with those derived with invasive AIF, albeit with an inherent systematic bias. Truncation of the dynamic PET scan duration to less than 100 min reduced the stability of the kinetic modelling outputs. Quantification of [18F]LW223 uptake kinetics in the brain and heart required the use of different outcome measures, with BPTC more stable in the heart and VT more stable in the brain. CONCLUSION: Modelling of [18F]LW223 PET showed the use of simplified IDIF is acceptable in the rat and the minimum scan duration for quantification of TSPO expression in rats using kinetic modelling with this radiotracer is 100 min. Carefully assessing kinetic outcome measures when conducting a systems level as oppose to single-organ centric analyses is crucial. This should be taken into account when assessing the emerging role of the TSPO heart-brain axis in the field of PET imaging.

High-frequency spinal cord stimulation as rescue therapy for chronic pain patients with failure of conventional spinal cord stimulation.

BACKGROUND: This study aims to evaluate the efficacy of 10-kHz high-frequency (HF10) devices as a rescue treatment in patients with failure of conventional spinal cord stimulation (SCS) therapy for chronic pain without the need to change the spinal hardware. METHODS: In this real-world prospective study, patients with neuropathic pain treated with conventional tonic SCS in whom the therapy had failed, either during the trial phase or after a period of optimal functioning, were recruited throughout 2 years for HF10-SCS therapy. Data on analgesia, functionality, analgesics use and treatment safety were collected 12 months after treatment. RESULTS: Eleven of the 18 (61%) patients included in the study were successfully rescued with HF10-SCS. Of them, 5 out of 12 (45%) were in the trial phase and six out of six (100%) had previously functioning implants. A significant improvement in low-back and limb pain was obtained (p = 0.003 and p = 0.0001, respectively). Treatment success was significantly associated with gender (p = 0.037), weight (p = 0.014), body mass index (BMI) (p = 0.007) and time of rescue (p = 0.015). A linear regression test confirmed a significant association between treatment failure and BMI and gender (p = 0.004). CONCLUSIONS: Our results suggest that analgesic rescue with HF10-SCS is an effective therapeutic option for non-responders to conventional SCS, although obesity might be a limiting factor for treatment success. Nevertheless, more comprehensive studies are needed to corroborate our findings. SIGNIFICANCE: This study shows that high-frequency stimulation may be useful in patients with failure of conventional tonic stimulation for chronic pain, both in the trial phase and in previously implanted subjects. The novelty of this study lies in the use of the implanted epidural electrodes, which avoids the need for further surgery. The results in terms of pain control and recovery of functionality are satisfactory. In addition, variables such as male gender and high body mass index could be predictors of therapy failure.

Effects of administration route on uptake kinetics of 18F-sodium fluoride positron emission tomography in mice.

18F-sodium fluoride (18F-NaF) is a positron emission tomography (PET) radiotracer widely used in skeletal imaging and has also been proposed as a biomarker of active calcification in atherosclerosis. Like most PET radiotracers, 18F-NaF is typically administered intravenously. However in small animal research intravenous administrations can be challenging, because partial paravenous injection is common due to the small calibre of the superficial tail veins and repeat administrations via tail veins can lead to tissue injury therefore limiting the total number of longitudinal scanning points. In this paper, the feasibility of using intra-peritoneal route of injection of 8F-NaF to study calcification in mice was studied by looking at the kinetic and uptake profiles of normal soft tissues and bones versus intra-vascular injections. Dynamic PET was performed for 60 min on nineteen isoflurane-anesthetized male Swiss mice after femoral artery (n = 7), femoral vein (n = 6) or intraperitoneal (n = 6) injection of 8F-NaF. PET data were reconstructed and the standardised uptake value (SUV) and standardised uptake value ratio (SUVr) were estimated from the last three frames between 45- and 60-min and 8F-NaF uptake constant (Ki) was derived by Patlak graphical analysis. In soft tissue, the 18F-NaF perfusion phase changes depending on the type on injection route, whereas the uptake phase is similar regardless of the administration route. In bone tissue SUV, SUVr and Ki measures were not significantly different between the three administration routes. Comparison between PET and CT measures showed that bones that had the highest CT density displayed the lowest PET activity and conversely, bones where CT units were low had high 8F-NaF uptake. Intraperitoneal injection is a valid and practical alternative to the intra-vascular injections in small-animal 18F-NaF PET imaging providing equivalent pharmacokinetic data. CT outcome measures report on sites of stablished calcification whereas PET measures sites of higher complexity and active calcification.

Quantification of Macrophage-Driven Inflammation During Myocardial Infarction with 18F-LW223, a Novel TSPO Radiotracer with Binding Independent of the rs6971 Human Polymorphism.

Myocardial infarction (MI) is one of the leading causes of death worldwide, and inflammation is central to tissue response and patient outcomes. The 18-kDa translocator protein (TSPO) has been used in PET as an inflammatory biomarker. The aims of this study were to screen novel, fluorinated, TSPO radiotracers for susceptibility to the rs6971 genetic polymorphism using in vitro competition binding assays in human brain and heart; assess whether the in vivo characteristics of our lead radiotracer, 18F-LW223, are suitable for clinical translation; and validate whether 18F-LW223 can detect macrophage-driven inflammation in a rat MI model. Methods: Fifty-one human brain and 29 human heart tissue samples were screened for the rs6971 polymorphism. Competition binding assays were conducted with 3H-PK11195 and the following ligands: PK11195, PBR28, and our novel compounds (AB5186 and LW223). Naïve rats and mice were used for in vivo PET kinetic studies, radiometabolite studies, and dosimetry experiments. Rats underwent permanent coronary artery ligation and were scanned using PET/CT with an invasive input function at 7 d after MI. For quantification of PET signal in the hypoperfused myocardium, K1 (rate constant for transfer from arterial plasma to tissues) was used as a surrogate marker of perfusion to correct the binding potential for impaired radiotracer transfer from plasma to tissue (BPTC). Results: LW223 binding to TSPO was not susceptible to the rs6971 genetic polymorphism in human brain and heart samples. In rodents, 18F-LW223 displayed a specific uptake consistent with TSPO expression, a slow metabolism in blood (69% of parent at 120 min), a high plasma free fraction of 38.5%, and a suitable dosimetry profile (effective dose of 20.5-24.5 µSv/MBq). 18F-LW223 BPTC was significantly higher in the MI cohort within the infarct territory of the anterior wall relative to the anterior wall of naïve animals (32.7 ± 5.0 vs. 10.0 ± 2.4 cm3/mL/min, P ≤ 0.001). Ex vivo immunofluorescent staining for TSPO and CD68 (macrophage marker) resulted in the same pattern seen with in vivo BPTC analysis. Conclusion:18F-LW223 is not susceptible to the rs6971 genetic polymorphism in in vitro assays, has favorable in vivo characteristics, and is able to accurately map macrophage-driven inflammation after MI.

Ex vivo 18F-fluoride uptake and hydroxyapatite deposition in human coronary atherosclerosis.

Early microcalcification is a feature of coronary plaques with an increased propensity to rupture and to cause acute coronary syndromes. In this ex vivo imaging study of coronary artery specimens, the non-invasive imaging radiotracer, 18F-fluoride, was highly selective for hydroxyapatite deposition in atherosclerotic coronary plaque. Specifically, coronary 18F-fluoride uptake had a high signal to noise ratio compared with surrounding myocardium that makes it feasible to identify coronary mineralisation activity. Areas of 18F-fluoride uptake are associated with osteopontin, an inflammation-associated glycophosphoprotein that mediates tissue mineralisation, and Runt-related transcription factor 2, a nuclear protein involved in osteoblastic differentiation. These results suggest that 18F-fluoride is a non-invasive imaging biomarker of active coronary atherosclerotic mineralisation.