Imaging the Retinal Vascular Mural Cells In Vivo: Elucidating the Timeline of Their Loss in Diabetic Retinopathy.

BACKGROUND: Vascular mural cells (VMCs) are integral components of the retinal vasculature with critical homeostatic functions such as maintaining the inner blood-retinal barrier and vascular tone, as well as supporting the endothelial cells. Histopathologic donor eye studies have shown widespread loss of pericytes and smooth muscle cells, the 2 main VMC types, suggesting these cells are critical to the pathogenesis of diabetic retinopathy (DR). There remain, however, critical gaps in our knowledge regarding the timeline of VMC demise in human DR. METHODS: In this study, we address this gap using adaptive optics scanning laser ophthalmoscopy to quantify retinal VMC density in eyes with no retinal disease (healthy), subjects with diabetes without diabetic retinopathy, and those with clinical DR and diabetic macular edema. We also used optical coherence tomography angiography to quantify capillary density of the superficial and deep capillary plexuses in these eyes. RESULTS: Our results indicate significant VMC loss in retinal arterioles before the appearance of classic clinical signs of DR (diabetes without diabetic retinopathy versus healthy, 5.0±2.0 versus 6.5±2.0 smooth muscle cells per 100 µm; P<0.05), while a significant reduction in capillary VMC density (5.1±2.3 in diabetic macular edema versus 14.9±6.0 pericytes per 100 µm in diabetes without diabetic retinopathy; P=0.01) and capillary density (superficial capillary plexus vessel density, 37.6±3.8 in diabetic macular edema versus 45.5±2.4 in diabetes without diabetic retinopathy; P<0.0001) is associated with more advanced stages of clinical DR, particularly diabetic macular edema. CONCLUSIONS: Our results offer a new framework for understanding the pathophysiologic course of VMC compromise in DR, which may facilitate the development and monitoring of therapeutic strategies aimed at VMC preservation and potentially the prevention of clinical DR and its associated morbidity. Imaging retinal VMCs provides an unparalleled opportunity to visualize these cells in vivo and may have wider implications in a range of diseases where these cells are disrupted.

How to accurately quantify brain magnetic susceptibility in the context of Parkinson's disease: Validation on phantoms and healthy volunteers at 1.5 and 3 T.

Currently, brain iron content represents a new neuromarker for understanding the physiopathological mechanisms leading to Parkinson's disease (PD). In vivo quantification of biological iron is possible by reconstructing magnetic susceptibility maps obtained using quantitative susceptibility mapping (QSM). Applying QSM is challenging, as up to now, no standardization of acquisition protocols and phase image processing has emerged from referenced studies. Our objectives were to compare the accuracy and the sensitivity of 10 QSM pipelines built from algorithms from the literature, applied on phantoms data and on brain data. Two phantoms, with known magnetic susceptibility ranges, were created from several solutions of gadolinium chelate. Twenty healthy volunteers from two age groups were included. Phantoms and brain data were acquired at 1.5 and 3 T, respectively. Susceptibility-weighted images were obtained using a 3D multigradient-recalled-echo sequence. For brain data, 3D anatomical T1- and T2-weighted images were also acquired to segment the deep gray nuclei of interest. Concerning in vitro data, the linear dependence of magnetic susceptibility versus gadolinium concentration and deviations from the theoretically expected values were calculated. For brain data, the accuracy and sensitivity of the QSM pipelines were evaluated in comparison with results from the literature and regarding the expected magnetic susceptibility increase with age, respectively. A nonparametric Mann-Whitney U-test was used to compare the magnetic susceptibility quantification in deep gray nuclei between the two age groups. Our methodology enabled quantifying magnetic susceptibility in human brain and the results were consistent with those from the literature. Statistically significant differences were obtained between the two age groups in all cerebral regions of interest. Our results show the importance of optimizing QSM pipelines according to the application and the targeted magnetic susceptibility range, to achieve accurate quantification. We were able to define the optimal QSM pipeline for future applications on patients with PD.

Assessment of cerebral drug occupancy in humans using a single PET-scan: A [11C]UCB-J PET study.

PURPOSE: Here, we evaluate a PET displacement model with a Single-step and Numerical solution in healthy individuals using the synaptic vesicle glycoprotein (SV2A) PET-tracer [11C]UCB-J and the anti-seizure medication levetiracetam (LEV). We aimed to (1) validate the displacement model by comparing the brain LEV-SV2A occupancy from a single PET scan with the occupancy derived from two PET scans and the Lassen plot and (2) determine the plasma LEV concentration-SV2A occupancy curve in healthy individuals. METHODS: Eleven healthy individuals (five females, mean age 35.5 [range: 25-47] years) underwent two 120-min [11C]UCB-J PET scans where an LEV dose (5-30 mg/kg) was administered intravenously halfway through the first PET scan to partially displace radioligand binding to SV2A. Five individuals were scanned twice on the same day; the remaining six were scanned once on two separate days, receiving two identical LEV doses. Arterial blood samples were acquired to determine the arterial input function and plasma LEV concentrations. Using the displacement model, the SV2A-LEV target engagement was calculated and compared with the Lassen plot method. The resulting data were fitted with a single-site binding model. RESULTS: SV2A occupancies and VND estimates derived from the displacement model were not significantly different from the Lassen plot (p = 0.55 and 0.13, respectively). The coefficient of variation was 14.6% vs. 17.3% for the Numerical and the Single-step solution in Bland-Altman comparisons with the Lassen plot. The average half maximal inhibitory concentration (IC50), as estimated from the area under the curve of the plasma LEV concentration, was 12.5 µg/mL (95% CI: 5-25) for the Single-Step solution, 11.8 µg/mL (95% CI: 4-25) for the Numerical solution, and 6.3 µg/mL (95% CI: 0.08-21) for the Lassen plot. Constraining Emax to 100% did not significantly improve model fits. CONCLUSION: Plasma LEV concentration vs. SV2A occupancy can be determined in humans using a single PET scan displacement model. The average concentration of the three computed IC50 values ranges between 6.3 and 12.5 µg/mL. The next step is to use the displacement model to evaluate LEV occupancy and corresponding plasma concentrations in relation to treatment efficacy. CLINICAL TRIAL REGISTRATION: NCT05450822. Retrospectively registered 5 July 2022 https://clinicaltrials.gov/ct2/results? term=NCT05450822&Search=Search.

True Ileal Amino Acid Digestibility and Protein Quality of 15N-Labeled Faba Bean in Healthy Humans.

BACKGROUND: The recommended transition toward more plant-based diets, particularly containing legumes, requires a wider knowledge of plant protein bioavailability. Faba beans are cultivated at different latitudes and are used increasingly in human nutrition. OBJECTIVES: We aimed to assess the nutritional quality of faba bean protein in healthy volunteers equipped with an intestinal tube to implement the ileal 15N balance method. METHODS: Nine volunteers completed the study (7 males, 2 females, aged 33 ± 10 y, BMI: 24.7 ± 2.6 kg/m2). They were equipped with a nasoileal tube. After fasting overnight, they ingested a test meal consisting of cooked mash of dehulled faba bean seeds (20 g protein per serving of approximately 250 g) intrinsically labeled with 15N. Samples of ileal contents, plasma, and urine were collected over an 8-h postprandial period. Undigested nitrogen (N) and amino acids (AAs) were determined using isotopic MS, and subsequently, ileal digestibility and digestible indispensable amino acid score (DIAAS) were calculated. The measurement of postprandial deamination allowed calculation of the net postprandial protein utilization (NPPU). RESULTS: The ileal N digestibility was 84.1% ± 7.7%. Postprandial deamination represented 19.2% ± 3.6% of ingested N, and the NPPU was 64.7% ± 9.7%. The ileal digestibility of individual AAs varied from 85.1% ± 13.7% for histidine to 94.2% ± 3.6% for glutamine + glutamate. The mean AA digestibility was ∼6 percentage points higher than the digestibility of N, reaching 89.8% ± 5.9%, whereas indispensable AA digestibility was 88.0% ± 7.3%. Histidine and tryptophan were the first limiting AAs [DIAAS = 0.77 (calculated by legume-specific N-to-protein conversion factor 5.4); 0.67 (by default factor 6.25)]. Sulfur AAs were limiting to a lesser extent [DIAA ratio = 0.94 (N × 5.4); 0.81 (N × 6.25)]. CONCLUSIONS: Protein ileal digestibility of cooked, dehulled faba beans in humans was moderate (<85%), but that of AAs was close to 90%. Overall protein quality was restricted by the limited histidine and tryptophan content. This trial was registered at clinicaltrials.gov as NCT05047757.

Daytime Variation in Kidney Perfusion, Oxygenation, and Sodium Concentration Assessed by Multiparametric MRI in Healthy Volunteers.

BACKGROUND: MRI can provide information on kidney structure, perfusion, and oxygenation. Furthermore, it allows for the assessment of kidney sodium concentrations and handling, allowing multiparametric evaluation of kidney physiology. Multiparametric MRI is promising for establishing prognosis and monitoring treatment responses in kidney diseases, but its intraindividual variation during the day is unresolved. PURPOSE: To investigate the variation in multiparametric MRI measurements from the morning to the evening. STUDY TYPE: Prospective. POPULATION: Ten healthy volunteers, aged 29 ± 5 without history of kidney disease. FIELD STRENGTH/SEQUENCE: 3 T/T1 mapping, blood-oxygen level dependent imaging, arterial spin labeling perfusion imaging, diffusion weighted imaging, and sodium imaging. ASSESSMENT: A multiparametric MRI protocol, yielding T1, R2*, ADC, renal blood flow and renal sodium levels, was acquired in the morning, noon, and evening. The participants were fasting prior to the first examination. Urine biochemical analyses were performed to complement MRI data. The cortex and medulla were analyzed separately in a semi-automatic fashion, and gradients of total sodium concentration (TSC) and R2* gradients were calculated from outer cortex to inner medulla. STATISTICAL TEST: Analyses of variance and mixed-effects models to estimate differences from time of day. Coefficients of variation to assess variability within and between participants. A P-value <0.05 was considered statistically significant. RESULTS: The coefficients of variation varied from 5% to 18% for proton-based parametric sequences, while it was 38% for TSC over a day. DATA CONCLUSION: Multiparametric MRI is stable over the day. The coefficients of variation over a day were lower for proton multiparametric MRI, but higher for sodium MRI. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

The effects of field strength on stimulated echo and motion-compensated spin-echo diffusion tensor cardiovascular magnetic resonance sequences.

BACKGROUND: In-vivo diffusion tensor cardiovascular magnetic resonance (DT-CMR) is an emerging technique for microstructural tissue characterization in the myocardium. Most studies are performed at 3T, where higher signal-to-noise ratio (SNR) should benefit this signal-starved method. However, a few studies have suggested that DT-CMR is possible at 1.5T, where echo planar imaging artifacts may be less severe and 1.5T hardware is more widely available. METHODS: We recruited 20 healthy volunteers and performed mid-ventricular short-axis DT-CMR at 1.5T and 3T. Acquisitions were performed at peak systole and end-diastole using both stimulated echo acquisition mode (STEAM) and motion-compensated spin-echo (MCSE) sequences at matched spatial resolutions. DT-CMR parameters were averaged over the left ventricle and compared between 1.5T and 3T sequences using both datasets with and without the blow reference data included. RESULTS: Eleven (1.5T) and 12 (3T) diastolic MCSE acquisitions were rejected as the helix angle (HA) demonstrated <50% normal appearance circumferentially or the acquisition was abandoned due to poor image quality; a maximum of one acquisition was rejected for other datasets. Subjective HA map quality was significantly better at 3T than 1.5T for STEAM (p < 0.05), but not for MCSE and other DT-CMR quality measures were consistent with improvements in STEAM at 3T over 1.5T. When blow data were excluded, no significant differences in mean diffusivity were observed between field strengths, but fractional anisotropy was significantly higher at 1.5T than 3T for STEAM systole (p < 0.05). Absolute second eigenvector orientation (E2A, sheetlet angle) was significantly higher at 1.5T than 3T for MCSE systole and STEAM diastole, but significantly lower for STEAM systole (all p < 0.05). Transmural HA distribution was less steep at 1.5T than 3T for STEAM diastole data (p < 0.05). SNR was higher at 3T than 1.5T for all acquisitions (p < 0.05). CONCLUSION: While 3T provides benefits in terms of SNR, both STEAM and MCSE can be performed at 1.5T. However, MCSE is unreliable in diastole at both field strengths and STEAM benefits from the improved SNR at 3T over 1.5T. Future clinical research studies may be able to leverage the wider availability of 1.5T CMR hardware where MCSE acquisitions are desirable.

London Protocol under water-perfused HRM in a healthy population, towards novel 3D manometric parameters in an evaluation of anorectal functional disorders.

BACKGROUND/AIM: London Protocol (LP) and Classification allied to high-resolution manometry (HRM) technological evolution has updated and enhanced the diagnostic armamentarium in anorectal disorders. This study aims to evaluate LP reproducibility under water-perfused HRM, provide normal data and new parameters based on 3D and healthy comparison studies under perfusional HRM. METHODS: Fifty healthy (25 F) underwent water-perfused 36 channel HRM based on LP at resting, squeeze, cough, push, and rectal sensory. Additional 3D manometric parameters were: pressure-volume (PV) 104mmHg2.cm (resting, short and long squeeze, cough); highest and lowest pressure asymmetry (resting, short squeeze, and cough). Complementary parameters (CP) were: resting (mean pressure, functional anal canal length); short squeeze (mean and maximum absolute squeeze pressure), endurance (fatigue rate, fatigue rate index, capacity to sustain); cough (anorectal gradient pressure); push (rectum-anal gradient pressure, anal canal relaxation percent); recto-anal inhibitory reflex (anal canal relaxation percent). RESULTS: No difference to genders: resting (LP, CP, and 3D); short squeeze (highest pressure asymmetry); endurance (CP); cough (CP, highest and lowest pressure asymmetry); push (gradient pressure); rectal sensory. Higher pressure in men: short squeeze (maximum incremental, absolute, and mean pressure, PV, lowest pressure asymmetry); long squeeze (PV); cough (anal canal and rectum maximum pressure, anal canal PV); push (anal canal and rectum maximum pressure). Anal canal relaxation was higher in women (push). CONCLUSIONS: LP reproducibility is feasible under water-perfused HRM, and comparative studies could bring similarity to dataset expansion. Novel 3D parameters need further studies with healthy and larger data to be validated and for disease comparisons. KEY POINTS: • London Protocol and Classification allied with the technological evolution of HRM (software and probes) has refined the diagnostic armamentarium in anorectal disorders. • Novel 3D and deepening the analysis of manometric parameters before the London Classification as a contributory diagnostic tool. • Comparison of healthy volunteers according to the London Protocol under a perfusional high-resolution system could establish equivalence points.

Mapping the pre-reflective experience of "self" to the brain - An ERP study.

The neural underpinnings of selfhood encompass pre-reflective and reflective self-experience. The former refers to a basic, immediate experience of being a self, while the latter involves cognition and introspection. Although neural correlates of reflective self-experience have been studied, the pre-reflective remains underinvestigated. This research aims to bridge this gap by comparatively investigating ERP correlates of reading first- vs. third-person pronouns - approximating pre-reflective self-experience - and self- vs. other-related adjectives - approximating reflective self-experience - in 30 healthy participants. We found differential neural engagement between pre-reflective and reflective self-experience at 254-310 ms post-stimulus onset. Source estimation suggested that our sensor-level results could be plausibly explained by the involvement of cortical midline structures and default mode network in the general sense of self but selective recruitment of anterior cingulate and top-down dorsal attention network in the pre-reflective self. These findings offer a deeper understanding of the experiential self, especially pre-reflective, providing a foundation for investigating self-disorders.

Investigation of the acute impact of rosemary consumption on brain activity in healthy volunteers.

OBJECTIVES: Rosmarinus officinalis L. (rosemary) is a fragrant plant of the mint family, broadly known as a nourishment flavoring agent; it is additionally utilized in conventional people cures for its anti-inflammatory, diuretic, and antibacterial properties. Intense cognitive impacts from devouring plant-based flavonoids can be measured with electroencephalography (EEG), which records unconstrained brain movement. Brain activity can be evaluated amid independent states or whereas performing attentional assignments. This study aimed to determine the impact of rosemary consumption on cognitive consequences. METHODS: Twenty volunteers took part in the study. EEG was taken for each volunteer twice, before drinking rosemary extract and around one hour after drinking it. EEG information was recorded with a Micromed recording framework inspecting rate of 512 Hz. EEG signals were prepared to be utilized in EEGLAB, an open-source toolbox within the MATLAB environment. The information obtained after the EEG recording was compared with the preliminary EEG information. RESULTS: The signal's power spectral density in theta, delta, and beta frequency bands modestly increased in males and females. Even though there was a significant increase in power at the alpha frequency band in both sexes, this increment was not specific channel-wise. DISCUSSION: The obtained data are consistent with the expected results and similar studies conducted, suggesting that the consumption of rosemary is beneficial for cognitive function in the short term. It is anticipated that forthcoming long-term studies will support the existing data.

A non-invasive continuous and real-time volumetric monitoring in spontaneous breathing subjects based on bioimpedance-ExSpiron®Xi: a validation study in healthy volunteers.

Tidal volume (TV) monitoring breath-by-breath is not available at bedside in non-intubated patients. However, TV monitoring may be useful to evaluate the work of breathing. A non-invasive device based on bioimpedance provides continuous and real-time volumetric tidal estimation during spontaneous breathing. We performed a prospective study in healthy volunteers aimed at evaluating the accuracy, the precision and the trending ability of measurements of ExSpiron®Xi as compared with the gold standard (i.e. spirometry). Further, we explored whether the differences between the 2 devices would be improved by the calibration of ExSpiron®Xi with a pre-determined tidal volume. Analysis accounted for the repeated nature of measurements within each subject. We enrolled 13 healthy volunteers, including 5 men and 8 women. Tidal volume, TV/ideal body weight (IBW) and respiratory rate (RR) measured with spirometer (TVSpirometer) and with ExSpiron®Xi (TVExSpiron) showed a robust correlation, while minute ventilation (MV) showed a weak correlation, in both non/calibrated and calibrated steps. The analysis of the agreement showed that non-calibrated TVExSpiron underestimated TVspirometer, while in the calibrated steps, TVExSpiron overestimated TVspirometer. The calibration procedure did not reduce the average absolute difference (error) between TVSpirometer and TVExSpiron. This happened similarly for TV/IBW and MV, while RR showed high accuracy and precision. The trending ability was excellent for TV, TV/IBW and RR. The concordance rate (CR) was >95% in both calibrated and non-calibrated measurements. The trending ability of minute ventilation was limited. Absolute error for both calibrated and not calibrated values of TV, TV/IBW and MV accounting for repeated measurements was variably associated with BMI, height and smoking status. Conclusions: Non-invasive TV, TV/IBW and RR estimation by ExSpiron®Xi was strongly correlated with tidal ventilation according to the gold standard spirometer technique. This data was not confirmed for MV. The calibration of the device did not improve its performance. Although the accuracy of ExSpiron®Xi was mild and the precision was limited for TV, TV/IBW and MV, the trending ability of the device was strong specifically for TV, TV/IBW and RR. This makes ExSpiron®Xi a non-invasive monitoring system that may detect real-time tidal volume ventilation changes and then suggest the need to better optimize the patient ventilatory support.

Associations Between Cognition and Serotonin 1B Receptor Availability in Healthy Volunteers: A [11C]AZ10419369 Positron Emission Tomography Study.

BACKGROUND: The serotonin system has been implicated in several psychiatric disorders. All major psychiatric disorders are associated with cognitive impairment, but treatment improving cognitive deficits is lacking, partly due to limited understanding of the neurobiology of cognitive functioning. Several markers for the serotonin system have been associated with cognitive functions. Our research group previously has reported a positive correlation between serotonin (5-HT1B) receptor availability in the dorsal brainstem and visuospatial memory in a pilot study of healthy individuals. Here, we aim to replicate our previous finding in a larger group of healthy volunteers as well as to investigate putative associations between 5-HT1B receptor availability and other cognitive domains. METHODS: Forty-three healthy individuals were examined with positron emission tomography using the 5-HT1B receptor radioligand [11C]AZ10419369 and a visuospatial memory test to replicate our previous finding as well as tests of verbal fluency, cognitive flexibility, reaction time, and planning ability to explore other domains potentially associated with the serotonin system. RESULTS: Replication analysis revealed no statistically significant association between 5-HT1B receptor availability in the dorsal brainstem and visuospatial memory performance. Exploratory analyses showed age-adjusted correlations between 5-HT1B receptor availability in whole brain gray matter and specific brain regions, and number of commission errors, reaction time, and planning ability. CONCLUSIONS: Higher 5-HT1B receptor availability was associated with more false-positive responses and faster reaction time but lower performance in planning and problem-solving. These results corroborate previous research supporting an important role of the serotonin system in impulsive behavior and planning ability.

A multimodal, comprehensive characterization of a cutaneous wound model in healthy volunteers.

Development of pharmacological interventions for wound treatment is challenging due to both poorly understood wound healing mechanisms and heterogeneous patient populations. A standardized and well-characterized wound healing model in healthy volunteers is needed to aid in-depth pharmacodynamic and efficacy assessments of novel compounds. The current study aims to objectively and comprehensively characterize skin punch biopsy-induced wounds in healthy volunteers with an integrated, multimodal test battery. Eighteen (18) healthy male and female volunteers received three biopsies on the lower back, which were left to heal without intervention. The wound healing process was characterized using a battery of multimodal, non-invasive methods as well as histology and qPCR analysis in re-excised skin punch biopsies. Biophysical and clinical imaging read-outs returned to baseline values in 28 days. Optical coherence tomography detected cutaneous differences throughout the wound healing progression. qPCR analysis showed involvement of proteins, quantified as mRNA fold increase, in one or more healing phases. All modalities used in the study were able to detect differences over time. Using multidimensional data visualization, we were able to create a distinction between wound healing phases. Clinical and histopathological scoring were concordant with non-invasive imaging read-outs. This well-characterized wound healing model in healthy volunteers will be a valuable tool for the standardized testing of novel wound healing treatments.

Brain Hypoxia Is Associated With Neuroglial Injury in Humans Post-Cardiac Arrest.

[Figure: see text].

Effects of the combination of vitamins C and E supplementation on oxidative stress, inflammation, muscle soreness, and muscle strength following acute physical exercise: meta-analyses of randomized controlled trials.

Background:The combined supplementation of vitamins C and E potentially can mitigate oxidative stress (OS) and accelerate recovery following exercise. However, there is little evidence and a lack of consensus on the effects of these vitamins for this purpose. The objective of this systematic review was to summarize the evidence on the effects of the combined supplementation of vitamins C and E in OS, inflammatory markers, muscle damage, muscle soreness, and musculoskeletal functionality following acute exercise. Methods: The search was carried out from inception until March 2021, on MEDLINE, EMBASE, Cochrane CENTRAL, Web of Science, and SPORT Discus. We included placebo-controlled randomized clinical trials (RCTs) that evaluated the effects of combined supplementation of vitamins C and E in OS, inflammatory markers, muscle damage, muscle soreness, and muscle strength following a single bout of exercise. Random-effect meta-analyses were used to compare pre to post-exercise mean changes in subjects who received supplementation with vitamins C and E or placebo versus controls. Data are presented as standard mean difference (SMD) and 95% confidence interval (95% CI). Results: Eighteen RCTs, accounting for data from 322 individuals, were included. The use of vitamins attenuated lipid peroxidation (SMD= -0.703; 95% CI= -1.035 to -0.372; p < 0.001), IL-6 (SMD= -0.576; 95%CI= -1.036 to -0.117; p = 0.014), and cortisol levels (SMD= -0.918; 95%CI= -1.475 to -0.361; p = 0.001) immediately, and creatine kinase levels 48 h following exercise (SMD= -0.991; 95%CI= -1.611 to -0.372; p = 0.002). Supplementing the combination of vitamins had no effects on protein carbonyls, reduced/oxidized glutathione ratio, catalase, interleukin-1Ra, C-reactive protein, lactate dehydrogenase, muscle soreness, and muscle strength. Conclusion: Prior supplementation of the combination of vitamins C and E attenuates OS (lipid peroxidation), the inflammatory response (interleukin-6), cortisol levels, and muscle damage (creatine kinase) following a session of exercise.

Prediction of effective humoral response to SARS-CoV-2 vaccines in healthy subjects by cortical thickness of post-vaccination reactive lymphadenopathy.

PURPOSE: To study the association between ultrasound cortical thickness in reactive post-vaccination lymph nodes and the elicited humoral response and to evaluate the performance of cortical thickness as a predictor of vaccine effectiveness in patients with and without a previous history of COVID-19 infection. METHODS: A total of 156 healthy volunteers were recruited and followed prospectively after receiving two COVID-19 vaccination doses using different protocols. Within a week after receiving the second dose, an axillary ultrasound of the ipsilateral vaccinated arm was performed, and serial post-vaccination serologic tests (PVST) were collected. Maximum cortical thickness was chosen as a nodal feature to analyze association with humoral immunity. Total antibodies quantified during consecutive PVST in previously-infected patients and in coronavirus-naïve volunteers were compared (Mann-Whitney U test). The association between hyperplastic-reactive lymph nodes and effective humoral response was studied (odds ratio). The performance of cortical thickness in detecting vaccination effectiveness was evaluated (area under the ROC curve). RESULTS: Significantly higher values for total antibodies were observed in volunteers with a previous history of COVID-19 infection (p < 0.001). The odds ratio associating immunized coronavirus-naïve volunteers after 90 and 180 days of the second dose with a cortical thickness ≥ 3 mm was statistically significant (95% CI 1.52-6.97 and 95% CI 1.47-7.29, respectively). The best AUC result was obtained comparing antibody secretion of coronavirus-naïve volunteers at 180 days (0.738). CONCLUSIONS: Ultrasound cortical thickness of reactive lymph nodes in coronavirus-naïve patients may reflect antibody production and a long-term effective humoral response elicited by vaccination. CLINICAL RELEVANCE STATEMENT: In coronavirus-naïve patients, ultrasound cortical thickness of post-vaccination reactive lymphadenopathy shows a positive association with protective antibody titers against SARS-CoV-2, especially in the long term, providing new insights into previous publications. KEY POINTS: • Hyperplastic lymphadenopathy was frequently observed after COVID-19 vaccination. • Ultrasound cortical thickness of reactive post-vaccine lymph nodes may reflect a long-term effective humoral response in coronavirus-naïve patients.

Functional MRI but not white matter fibre dissection identifies language dominance.

OBJECTIVES: Lateralisation of some language pathways has been reported in the literature using diffusion tractography, which is more feasible than functional magnetic resonance imaging (fMRI) in challenging patients. Our retrospective study investigates whether a correlation exists between threshold-independent fMRI language lateralisation and structural lateralisation using tractography in healthy controls and brain tumour patients. METHODS: Fifteen healthy subjects and 61 patients underwent language fMRI and diffusion-weighted MRI. A regional fMRI laterality index (LI) was calculated. Tracts dissected were the arcuate fasciculus (long direct and short indirect tracts), uncinate fasciculus, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus and frontal aslant tract. An asymmetry index (AI) for each tract was calculated using tract volume analysed with single tensor (ST) and spherical deconvolution (SD) models, as well as hindrance modulated orientational anisotropy (HMOA) for SD tracts. Linear regression assessed the correlation between LI and AI. RESULTS: In all subjects, there was no significant correlation between LI and AI for any of the dissected tracts. Significant correlations were only found when handedness for controls and tumour volume for patients were included as covariates. In handedness subgroups, the average AI of some tracts showed the same laterality as LI, and some the opposite. Discordant results were observed for ST- and SD-based AIs. CONCLUSIONS: Our results do not support using tractography in the assessment of language lateralisation. The discordant results between ST and SD indicate that either the structural lateralisation of dissected tracts is less robust than functional lateralisation, or tractography is not sensitive methodology. Other diffusion analysis approaches should be developed. CLINICAL RELEVANCE STATEMENT: Although diffusion tractography may be more feasible than fMRI in challenging tumour patients and where sedation or anaesthesia is required, our results do not currently recommend replacing fMRI with tractography using volume or HMOA in the assessment of language lateralisation. KEY POINTS: • No correlation found between fMRI and tractography in language lateralisation. • Discordance between asymmetry indices of different tractography models and metrics. • Tractography not currently recommended in language lateralisation assessment.

Feasibility of accelerated non-contrast-enhanced whole-heart bSSFP coronary MR angiography by deep learning-constrained compressed sensing.

OBJECTIVES: To examine a compressed sensing artificial intelligence (CSAI) framework to accelerate image acquisition in non-contrast-enhanced whole-heart bSSFP coronary magnetic resonance (MR) angiography. METHODS: Thirty healthy volunteers and 20 patients with suspected coronary artery disease (CAD) scheduled for coronary computed tomography angiography (CCTA) were enrolled. Non-contrast-enhanced coronary MR angiography was performed with CSAI, compressed sensing (CS), and sensitivity encoding (SENSE) methods in healthy participants and with CSAI in patients. Acquisition time, subjective image quality score, and objective image quality measurement (blood pool homogeneity, signal-to-noise ratio [SNR], and contrast-to-noise ratio [CNR]) were compared among the three protocols. The diagnostic performance of CASI coronary MR angiography for predicting significant stenosis (≥ 50% diameter stenosis) on CCTA was evaluated. The Friedman test was performed to compare the three protocols. RESULTS: Acquisition time was significantly shorter in the CSAI and CS groups than in the SENSE group (10.2 ± 3.2 min vs. 10.9 ± 2.9 min vs. 13.0 ± 4.1 min, p < 0.001). However, the CSAI approach had the highest image quality scores, blood pool homogeneity, mean SNR value, and mean CNR value (all p < 0.001) compared with the CS and SENSE approaches. The sensitivity, specificity, and accuracy of CSAI coronary MR angiography per patient were 87.5% (7/8), 91.7% (11/12), and 90.0% (18/20); those per vessel were 81.8% (9/11), 93.9% (46/49), and 91.7% (55/60); and those per segment were 84.6% (11/13), 98.0% (244/249), and 97.3% (255/262), respectively. CONCLUSIONS: CSAI yielded superior image quality within a clinically feasible acquisition time in healthy participants and patients with suspected CAD. CLINICAL RELEVANCE STATEMENT: The non-invasive and radiation-free CSAI framework could be a promising tool for rapid screening and comprehensive examination of the coronary vasculature in patients with suspected CAD. KEY POINTS: • This prospective study showed that CSAI enables a reduction in acquisition time by 22% with superior diagnostic image quality compared with the SENSE protocol. • CSAI replaces the wavelet transform with a CNN as a sparsifying transform in the CS algorithm, achieving high coronary MR image quality with reduced noise. • CSAI achieved per-patient sensitivity of 87.5% (7/8) and specificity of 91.7% (11/12) respectively for detecting significant coronary stenosis.

Time course of CYP3A activity during and after metamizole (dipyrone) in healthy volunteers.

AIMS: In patients of all ages, metamizole is a frequently used analgesic. Recently, metamizole has been identified as an inducer of, among others, cytochrome P450 (CYP) 3A activity, but the time course of this interaction has not been evaluated. METHODS: Using repeated oral microdoses (30 µg) of the CYP3A index substrate midazolam, we assessed changes in midazolam pharmacokinetics (area under the concentration-time curve from 2-4 h: AUC2-4 and estimated partial metabolic clearance: eClmet ) before, at steady-state, and after discontinuation of 3 × 1000 mg metamizole/day orally for 8 days. RESULTS: Significant changes in pharmacokinetic parameters were detected already 3 days after start of metamizole treatment. At the steady-state of enzyme induction, the geometric mean ratio of midazolam AUC2-4 was substantially reduced to 0.18 (90% confidence interval: 0.14-0.24) with a corresponding 5.43-fold (4.15-7.10) increase of eClmet . After discontinuation of metamizole, the changes slowly recovered, but were still significant at the end of the observation period on the fifth day after discontinuation of metamizole therapy (AUC2-4 reduced to 0.50 [0.41-0.63] and eClmet 1.99-fold increased [1.60-2.47, P < 0.05]). CONCLUSION: Metamizole acts as a strong inducer of CYP3A already few days after start of metamizole administration and, thus, should be avoided in patients using drugs with narrow therapeutic index and major clearance via CYP3A. If their administration is essential, close monitoring and dose adjustment of comedication should be performed as early as the first week after the initiation and after discontinuation of metamizole therapy.

CYP11B2 inhibitor dexfadrostat phosphate suppresses the aldosterone-to-renin ratio, an indicator of sodium retention, in healthy volunteers.

AIMS: High aldosterone is a key driver of hypertension and long-term negative sequelae. We evaluated the safety and efficacy of dexfadrostat phosphate (DP13), a novel aldosterone synthase (CYP11B2) inhibitor, in healthy participants. METHODS: This randomized, double-blind, placebo-controlled study was conducted in two parts. In part A, a single-ascending dose escalation, 16 participants received oral DP13 1-16 mg. Part B was a multiple-ascending dose, sequential group study in which 32 participants received oral DP13 4, 8 or 16 mg once daily for 8 days. Safety and tolerability were monitored throughout. An adrenocorticotropic hormone (ACTH) stimulation test at maximal blood drug concentrations defined the dose range for multiple dosing. RESULTS: DP13 was well tolerated at all doses, with no serious adverse events. In part B, all DP13 doses (4, 8 and 16 mg) over 8 days effectively suppressed aldosterone production, increased the urinary sodium/potassium ratio, decreased plasma sodium and increased plasma potassium and renin levels compared with placebo, resulting in potent suppression of the aldosterone-to-renin ratio (ARR). Endocrine counter-regulation resulted in the 4 mg dose no longer sustaining 24-h aldosterone suppression after 8 days of treatment, unlike the 8- and 16 mg doses. There was no evidence of drug-induced adrenal insufficiency (ACTH stress challenge). CONCLUSIONS: In patients with excess aldosterone and ensuing sodium retention driving hypertension, managing sodium balance is critical. A CYP11B2 inhibitor like DP13, whose effectiveness can be monitored by a reduction in ARR, may prove valuable in managing aldosterone-dependent hypertension and primary aldosteronism.

Effect of Clarithromycin, a Strong CYP3A and P-glycoprotein Inhibitor, on the Pharmacokinetics of Edoxaban in Healthy Volunteers and the Evaluation of the Drug Interaction with Other Oral Factor Xa Inhibitors by a Microdose Cocktail Approach.

PURPOSE: We assessed the differential effect of clarithromycin, a strong inhibitor of cytochrome P450 (CYP) 3A4 and P-glycoprotein, on the pharmacokinetics of a regular dose of edoxaban and on a microdose cocktail of factor Xa inhibitors (FXaI). Concurrently, CYP3A activity was determined with a midazolam microdose. METHODS: In an open-label fixed-sequence trial in 12 healthy volunteers, the pharmacokinetics of a microdosed FXaI cocktail (µ-FXaI; 25 µg apixaban, 50 µg edoxaban, and 25 µg rivaroxaban) and of 60 mg edoxaban before and during clarithromycin (2 x 500 mg/d) dosed to steady-state was evaluated. Plasma concentrations of study drugs were quantified using validated ultra-performance liquid chromatography-tandem mass spectrometry methods. RESULTS: Therapeutic clarithromycin doses increased the exposure of a therapeutic 60 mg dose of edoxaban with a geometric mean ratio (GMR) of the area under the plasma concentration-time curve (AUC) of 1.53 (90 % CI: 1.37-1.70; p < 0.0001). Clarithromycin also increased the GMR (90% CI) of the exposure of microdosed FXaI apixaban to 1.38 (1.26-1.51), edoxaban to 2.03 (1.84-2.24), and rivaroxaban to 1.44 (1.27-1.63). AUC changes observed for the therapeutic edoxaban dose were significantly smaller than those observed with the microdose (p < 0.001). CONCLUSION: Clarithromycin increases FXaI exposure. However, the magnitude of this drug interaction is not expected to be clinically relevant. The edoxaban microdose overestimates the extent of the drug interaction with the therapeutic dose, whereas AUC ratios for apixaban and rivaroxaban were comparable to the interaction with therapeutic doses as reported in the literature. TRIAL REGISTRATION: EudraCT Number: 2018-002490-22.