In silico-in vitro estimation of lipophilicity and permeability association for succinimide derivatives using chromatographic anisotropic systems and parallel artificial membrane permeability assay.

Passive permeability is one of the key features that determine absorbability and one of the most studied properties in the early phases of drug development. Newly synthesized succinimide derivatives from two different series (1-aryl-3-methylsuccinimides and 1-aryl-3-ethyl-3-methylsuccinimides) with high biological potential have been subjected to estimation of their passive permeability and their association with (a) experimentally obtained anisotropic lipophilicity, (b) in silico-calculated lipophilicity and (c) in silico-predicted permeability and absorbability. Non-cellular-based parallel artificial membrane permeability assay was applied for quantifying their passive permeation, expressed as logPapp . Passive permeation was governed by the lipophilicity of the analysed compounds, and anisotropic lipophilicity was related with statistically significant passive transcellular diffusion (r2 = 0.614, P < 0.001). Moreover, experimentally determined passive permeability, logPapp , was statistically significantly associated with both in silico-predicted absorption constant, ka (r2 = 0.7886, P < 0.001), and human intestinal absorption (HIA) in percentage (r2 = 0.484, P < 0.001), respectively. However, there was no statistically significant relationship between experimentally obtained permeability on non-cellular-based model and in silico-predicted Caco-2 permeability based on the predictions conducted on two different software. Based on the obtained results, anisotropic systems are promising surrogates for determining lipophilicity, except for compounds with acidic functional groups that are completely ionized under (pH = 7.4).

Exploiting multicompartment effects in triple-echo steady-state T2 mapping for fat fraction quantification.

PURPOSE: To investigate and exploit the effect of intravoxel off-resonance compartments in the triple-echo steady-state (TESS) sequence without fat suppression for T2 mapping and to leverage the results for fat fraction quantification. METHODS: In multicompartment tissue, where at least one compartment is excited off-resonance, the total signal exhibits periodic modulations as a function of echo time (TE). Simulated multicompartment TESS signals were synthesized at various TEs. Fat emulsion phantoms were prepared and scanned at the same TE combinations using TESS. In vivo knee data were obtained with TESS to validate the simulations. The multicompartment effect was exploited for fat fraction quantification in the stomach by acquiring TESS signals at two TE combinations. RESULTS: Simulated and measured multicompartment signal intensities were in good agreement. Multicompartment effects caused erroneous T2 offsets, even at low water-fat ratios. The choice of TE caused T2 variations of as much as 28% in cartilage. The feasibility of fat fraction quantification to monitor the decrease of fat content in the stomach during digestion is demonstrated. CONCLUSIONS: Intravoxel off-resonance compartments are a confounding factor for T2 quantification using TESS, causing errors that are dependent on the TE. At the same time, off-resonance effects may allow for efficient fat fraction mapping using steady-state imaging. Magn Reson Med 79:423-429, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

The Dynamics of Gastric Emptying and Self-Reported Feelings of Satiation Are Better Predictors Than Gastrointestinal Hormones of the Effects of Lipid Emulsion Structure on Fat Digestion in Healthy Adults-A Bayesian Inference Approach.

Background: Limited information exists on the relation between fat emulsion structure and its effect on the release of gastrointestinal hormones and feelings of satiation.Objective: We investigated the impact of fat emulsion droplet size, gravitational and acid stability, and redispersibility on gastrointestinal responses and sought to deduce the relative importance of the hormones ghrelin, cholecystokinin, glucagon-like peptide-1, and peptide YY (PYY) in controlling fat emptying and related satiation.Methods: Within a randomized, double-blind, 4-armed crossover study, an extensive data set was generated by MRI of gastric function, analysis of hormone profiles, and ratings of satiation in healthy participants [10 women and 7 men with a mean ± SD age of 25 ± 7 y and body mass index (in kg/m2) of 22 ± 1] after intake of 4 different fat emulsions. Iterative Bayesian model averaging variable selection was used to investigate the influence of hormone profiles in controlling fat emulsion emptying and satiation.Results: The emulsion structure had a distinct effect on the gastric emptying (primary outcome), gastrointestinal hormone profiles, and ratings of satiation (secondary outcomes). Gravitational and acid stability were stronger modulators of fat emptying and hormone profiles than were emulsion droplet size or redispersibility. Cholecystokinin and PYY were most strongly affected by fat emulsion instability and droplet size. Although both hormones were relevant predictors of gastric emptying, only PYY was identified as a relevant predictor of satiation.Conclusions: This work indicates that evenly dispersed, stable, small-emulsion droplets within the stomach lead to prolonged gastric distension, longer ghrelin suppression, and accelerated fat sensing (cholecystokinin and PPY), triggering prolonged feelings of satiation. It suggests that the effects of emulsion instability and droplet size on energy consumption are best studied by assessing changes in gastric emptying and ratings of satiation rather than changes in venous hormone profiles. This trial was registered at clinicaltrials.gov as NCT01253005.

Gastric and Postgastric Processing of 13C Markers Renders the 13C Breath Test an Inappropriate Measurement Method for the Gastric Emptying of Lipid Emulsions in Healthy Adults.

Background: Breath tests (BTs) present an alternative gastric-emptying (GE) measure. However, their efficacy in the measurement of the GE rate of lipid emulsions (LEs) is unknown.Objective: The objective of this work was to investigate the validity of 13C BTs as a measure of fat GE rate in LEs.Methods: The lipophilic 13C octanoate (OCC) BT marker was investigated for fat GE with the hydrophilic 13C sodium acetate (ACC) and the triglyceride 13C trioctanoin (TCC) markers as comparators. Data from 2 randomized studies were combined [50 healthy participants; 25 men, mean ± SD age: 23 ± 2.8 y; mean ± SD body mass index (in kg/m2): 22.4 ± 1.7]. Each participant was given either an acid-stable LE (LE1) or an acid-unstable LE (LE4) at each visit. Twenty-three participants underwent simultaneous MRI. The effect of LEs on 13CO2 excretion profiles was determined. The BT half-emptying times (BT T50) were validated with the MRI half-emptying time of the ingested fat volume (MRI T50).Results: The effect of LEs on 13CO2 excretion depended on the properties of the 13C marker. T50 for OCC was shorter by 98 min for LE1 than for LE4 (P < 0.001). Other markers showed either no LE dependency or a longer T50 for LE1 than for LE4. No difference in T50 between OCC and ACC was detected in LE1. In LE4, the T50 was longer by 154 min (P < 0.0001). There was some concordance between MRI T50 and OCC BT T50 for LE1 (rc = 0.7). No other marker showed any concordance with fat GE. 13C-Nuclear magnetic resonance in vitro findings were compatible with changes in the kinetics of phase transfer of OCC dependent on its protonation state.Conclusions: The structure of fat present in the stomach affects 13CO2 excretion. The chemical properties of the 13C marker and their gastric and postgastric interaction with fat renders 13CO2 excretion an inappropriate measure of LE emptying in healthy adults. This trial was registered at clinicaltrials.gov as NCT02226029 and NCT02602158.

Emulsion Stability Modulates Gastric Secretion and Its Mixing with Emulsified Fat in Healthy Adults in a Randomized Magnetic Resonance Imaging Study.

BACKGROUND: Oil-in-water emulsions have recently become of interest to nutritional sciences because of their ability to influence gastrointestinal digestive processes and ultimately benefit human health. MRI offers the potential to noninvasively characterize the interaction between emulsified lipids and gastric secretion within the stomach. OBJECTIVES: We determined noninvasively how emulsion stability modulates volumes of fat and secretion, layering of fat, and the mixing of emulsified fat with secretion within the stomach. This required the development of MRI technology for quantifying fat and secretion concentrations inside the stomach. METHODS: Twenty-one healthy adults [13 men, mean ± SD age: 22.5 ± 2.5 y, mean ± SD body mass index (in kg/m2): 22.7 ± 1.8] were analyzed in a single-blind, randomized, parallel design. MRI was used to acquire the distributions of fat and secretion in the stomach after ingestion of 2 emulsions: a stable emulsion (E1) or an unstable emulsion (E4) with 20% fat fraction and ∼0.3 mm droplet sizes. Layer, volume, and mixing variables were fitted to the data and compared between the 2 emulsions. RESULTS: The intragastric mixing between fat and secretion was better with the E4 than the E1 [increase in content heterogeneity of 17.1% (95% CI: 12.3%, 21.9%)]. The E4 demonstrated a linear relation [slope 1.57 (95% CI: 0.86, 2.29)] between the degree of layering and mixing. In contrast, no such relation was detected for the E1. Accumulated secretion volume in the stomach was lower with the E4 [decrease in volume variable ks of 2.3 (95% CI: -3.9, -0.7)] and correlated with the degree of layering (r = 0.62, P < 0.001). CONCLUSIONS: In healthy adults, intragastric fat layering was influenced mainly by the degree of intragastric mixing, rather than the overall dominance of secretion. The E1 triggered a higher accumulation of gastric secretion, which in turn facilitated homogenization of intragastric content in comparison with its unstable counterpart. This trial was registered at clinicaltrials.gov as NCT02602158.

The visualisation and quantification of human gastrointestinal fat distribution with MRI: a randomised study in healthy subjects.

We aimed to study the fate of fat during digestion. For this purpose, we validated and investigated the non-invasive quantification of gastric and duodenal fat emptying and emulsion processing (creaming and phase separation) using the MRI method iterative decomposition with echo asymmetry and least squares estimation (IDEAL). In total, twelve healthy subjects were studied on two separate visits in a single-blind, randomised, cross-over design study. IDEAL was utilised to repeatedly acquire quantitative fat fraction maps of the gastrointestinal tract after infusion of one of two fat emulsions: E1 (acid stable, droplet size 0·33 mm) and E4 (acid unstable, 0·38 mm). In vitro and in vivo validation was carried out using diluted emulsion and gastric content samples, respectively, and resulted in Lin's concordance correlation coefficients of 1·00 (95% CI 0·98, 1·00) and 0·91 (95% CI 0·87, 0·94), respectively. Fat fraction maps and intragastric emulsion profiles enabled the identification of features of intraluminal phase separation and creaming that were not visible in conventional MRI. Gastric fat emptying was faster for E4 compared with E1 with a difference of 2·5 (95% CI 1·9, 3·1) ml/h. Duodenal content volumes were larger for E1 than for E4 with a difference of 4·9 (95% CI 3·9, 8·5) ml. This study demonstrated that with IDEAL it was possible (1) to visualise the intragastric and duodenal fat distribution and (2) to quantify the differences in emptying, phase separation and creaming of an acid-stable and an acid-unstable emulsion. This method has potential to bridge the gap between current in vitro digestive models and in vivo behaviour and to be applied in the development of effective functional foods.

Validation of a golden angle radial sequence (GOLD) for abdominal T1 mapping during free breathing: demonstrating clinical feasibility for quantifying gastric secretion and emptying.

PURPOSE: To validate a magnetic resonance imaging sequence suitable for quantitative assessment of acid suppression by a proton pump inhibitor (PPI) on gastric secretion and emptying in clinical practice. METHODS: A golden angle radial sequence (GOLD) was validated in a series of in vitro and in vivo experiments and clinical feasibility was shown in two studies. The impact of free breathing and image plane orientation on T1 values was evaluated in a controlled in vivo experiment. The free-breathing GOLD sequence was compared against a standard breath-hold gradient echo sequence for gastric half emptying time in 23 subjects during a gastric emptying study. Pilot data from five subjects assessed the sensitivity of the GOLD sequence to detect changes in acid secretion volume produced by PPI treatment. RESULTS: The coronal free-breathing GOLD sequence and the axial breath-hold standard gradient echo sequence showed good agreement of the gastric half emptying time (6 ± 3 min, P = 0.053). The GOLD sequence demonstrated sensitivity to reduction of gastric secretion volumes induced by PPI treatment (55 ± 5 mL, P < 0.001). CONCLUSION: The GOLD sequence allowed for free breathing, multislice, combined imaging and T1 mapping of the stomach content. GOLD presents a promising multipurpose, noninvasive imaging tool for monitoring gastric function in clinical studies.

Volume, distribution and acidity of gastric secretion on and off proton pump inhibitor treatment: a randomized double-blind controlled study in patients with gastro-esophageal reflux disease (GERD) and healthy subjects.

BACKGROUND: Postprandial accumulation of gastric secretions in the proximal stomach above the meal adjacent to the esophagogastric junction (EGJ), referred to as the 'acid pocket', has been proposed as a pathophysiological factor in gastro-esophageal reflux disease (GERD) and as a target for GERD treatment. This study assessed the effect of proton pump inhibitor (PPI) therapy on the volume, distribution and acidity of gastric secretions in GERD and healthy subjects (HS). METHODS: A randomized, double blind, cross-over study in 12 HS and 12 GERD patients pre-treated with 40 mg pantoprazole (PPI) or placebo b.i.d. was performed. Postprandial secretion volume (SV), formation of a secretion layer and contact between the layer and the EGJ were quantified by Magnetic Resonance Imaging (MRI). Multi-channel pH-monitoring assessed intragastric pH. RESULTS: A distinct layer of undiluted acid secretion was present on top of gastric contents in almost all participants on and off high-dose acid suppression. PPI reduced SV (193 ml to 100 ml, in HS, 227 ml to 94 ml in GERD; p < 0.01) and thickness of the acid layer (26 mm to 7 mm, 36 mm to 9 mm respectively, p < 0.01). No differences in secretion volume or layer thickness were observed between groups; however, off treatment, contact time between the secretion layer and EGJ was 2.6 times longer in GERD compared to HS (p = 0.012). This was not the case on PPI. CONCLUSIONS: MRI can visualize and quantify the volume and distribution dynamics of gastric secretions that form a layer in the proximal stomach after ingestion of a liquid meal. The secretion volume and the secretion layer on top of gastric contents is similar in GERD patients and HS; however contact between the layer of undiluted secretion and the EGJ is prolonged in patients. High dose PPI reduced secretion volume by about 50% and reduced contact time between secretion and EGJ towards normal levels. TRIAL REGISTRATION: NCT01212614.

Abnormal structure and function of the esophagogastric junction and proximal stomach in gastroesophageal reflux disease.

OBJECTIVES: This study applies concurrent magnetic resonance imaging (MRI) and high-resolution manometry (HRM) to test the hypothesis that structural factors involved in reflux protection, in particular, the acute insertion angle of the esophagus into the stomach, are impaired in gastroesophageal reflux disease (GERD) patients. METHODS: A total of 24 healthy volunteers and 24 patients with mild-moderate GERD ingested a test meal. Three-dimensional models of the esophagogastric junction (EGJ) were reconstructed from MRI images. Measurements of the esophagogastric insertion angle, gastric orientation, and volume change were obtained. Esophageal function was assessed by HRM. Number of reflux events and EGJ opening during reflux events were assessed by HRM and cine-MRI. Statistical analysis applied mixed-effects modeling. RESULTS: The esophagogastric insertion angle was wider in GERD patients than in healthy subjects (+7° ± 3°; P=0.03). EGJ opening during reflux events was greater in GERD patients than in healthy subjects (19.3 mm vs. 16.8 mm; P=0.04). The position of insertion and gastric orientation within the abdomen were also altered (both P<0.05). Median number of reflux events was 3 (95% CI: 2.5-4.6) in GERD and 2 (95% CI: 1.8-3.3) in healthy subjects (P=0.09). Lower esophageal sphincter (LES) pressure was lower (-11 ± 2 mm Hg; P<0.0001) and intra-abdominal LES length was shorter (-1.0 ± 0.3 cm, P<0.0006) in GERD patients. CONCLUSIONS: GERD patients have a wider esophagogastric insertion angle and have altered gastric morphology; structural changes that could compromise reflux protection by the "flap valve" mechanism. In addition, the EGJ opens wider during reflux in GERD patients than in healthy volunteers: an effect that facilitates volume reflux of gastric contents.

Feasibility and usability of remote monitoring in Alzheimer's disease.

Introduction: Remote monitoring technologies (RMTs) can measure cognitive and functional decline objectively at-home, and offer opportunities to measure passively and continuously, possibly improving sensitivity and reducing participant burden in clinical trials. However, there is skepticism that age and cognitive or functional impairment may render participants unable or unwilling to comply with complex RMT protocols. We therefore assessed the feasibility and usability of a complex RMT protocol in all syndromic stages of Alzheimer's disease and in healthy control participants. Methods: For 8 weeks, participants (N = 229) used two activity trackers, two interactive apps with either daily or weekly cognitive tasks, and optionally a wearable camera. A subset of participants participated in a 4-week sub-study (N = 45) using fixed at-home sensors, a wearable EEG sleep headband and a driving performance device. Feasibility was assessed by evaluating compliance and drop-out rates. Usability was assessed by problem rates (e.g., understanding instructions, discomfort, forgetting to use the RMT or technical problems) as discussed during bi-weekly semi-structured interviews. Results: Most problems were found for the active apps and EEG sleep headband. Problem rates increased and compliance rates decreased with disease severity, but the study remained feasible. Conclusions: This study shows that a highly complex RMT protocol is feasible, even in a mild-to-moderate AD population, encouraging other researchers to use RMTs in their study designs. We recommend evaluating the design of individual devices carefully before finalizing study protocols, considering RMTs which allow for real-time compliance monitoring, and engaging the partners of study participants in the research.

Digital endpoints in clinical trials of Alzheimer's disease and other neurodegenerative diseases: challenges and opportunities.

Alzheimer's disease (AD) and other neurodegenerative diseases such as Parkinson's disease (PD) and Huntington's disease (HD) are associated with progressive cognitive, motor, affective and consequently functional decline considerably affecting Activities of Daily Living (ADL) and quality of life. Standard assessments, such as questionnaires and interviews, cognitive testing, and mobility assessments, lack sensitivity, especially in early stages of neurodegenerative diseases and in the disease progression, and have therefore a limited utility as outcome measurements in clinical trials. Major advances in the last decade in digital technologies have opened a window of opportunity to introduce digital endpoints into clinical trials that can reform the assessment and tracking of neurodegenerative symptoms. The Innovative Health Initiative (IMI)-funded projects RADAR-AD (Remote assessment of disease and relapse-Alzheimer's disease), IDEA-FAST (Identifying digital endpoints to assess fatigue, sleep and ADL in neurodegenerative disorders and immune-mediated inflammatory diseases) and Mobilise-D (Connecting digital mobility assessment to clinical outcomes for regulatory and clinical endorsement) aim to identify digital endpoints relevant for neurodegenerative diseases that provide reliable, objective, and sensitive evaluation of disability and health-related quality of life. In this article, we will draw from the findings and experiences of the different IMI projects in discussing (1) the value of remote technologies to assess neurodegenerative diseases; (2) feasibility, acceptability and usability of digital assessments; (3) challenges related to the use of digital tools; (4) public involvement and the implementation of patient advisory boards; (5) regulatory learnings; and (6) the significance of inter-project exchange and data- and algorithm-sharing.

Description of the Method for Evaluating Digital Endpoints in Alzheimer Disease Study: Protocol for an Exploratory, Cross-sectional Study.

BACKGROUND: More sensitive and less burdensome efficacy end points are urgently needed to improve the effectiveness of clinical drug development for Alzheimer disease (AD). Although conventional end points lack sensitivity, digital technologies hold promise for amplifying the detection of treatment signals and capturing cognitive anomalies at earlier disease stages. Using digital technologies and combining several test modalities allow for the collection of richer information about cognitive and functional status, which is not ascertainable via conventional paper-and-pencil tests. OBJECTIVE: This study aimed to assess the psychometric properties, operational feasibility, and patient acceptance of 10 promising technologies that are to be used as efficacy end points to measure cognition in future clinical drug trials. METHODS: The Method for Evaluating Digital Endpoints in Alzheimer Disease study is an exploratory, cross-sectional, noninterventional study that will evaluate 10 digital technologies' ability to accurately classify participants into 4 cohorts according to the severity of cognitive impairment and dementia. Moreover, this study will assess the psychometric properties of each of the tested digital technologies, including the acceptable range to assess ceiling and floor effects, concurrent validity to correlate digital outcome measures to traditional paper-and-pencil tests in AD, reliability to compare test and retest, and responsiveness to evaluate the sensitivity to change in a mild cognitive challenge model. This study included 50 eligible male and female participants (aged between 60 and 80 years), of whom 13 (26%) were amyloid-negative, cognitively healthy participants (controls); 12 (24%) were amyloid-positive, cognitively healthy participants (presymptomatic); 13 (26%) had mild cognitive impairment (predementia); and 12 (24%) had mild AD (mild dementia). This study involved 4 in-clinic visits. During the initial visit, all participants completed all conventional paper-and-pencil assessments. During the following 3 visits, the participants underwent a series of novel digital assessments. RESULTS: Participant recruitment and data collection began in June 2020 and continued until June 2021. Hence, the data collection occurred during the COVID-19 pandemic (SARS-CoV-2 virus pandemic). Data were successfully collected from all digital technologies to evaluate statistical and operational performance and patient acceptance. This paper reports the baseline demographics and characteristics of the population studied as well as the study's progress during the pandemic. CONCLUSIONS: This study was designed to generate feasibility insights and validation data to help advance novel digital technologies in clinical drug development. The learnings from this study will help guide future methods for assessing novel digital technologies and inform clinical drug trials in early AD, aiming to enhance clinical end point strategies with digital technologies. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/35442.

GREB1L, CRELD2 and ITGA10 expression in the human developmental and postnatal kidneys: an immunohistochemical study.

BACKGROUND: Aim of our study is to provide an insight into the genetic expression landscape of GREB1L, ITGA10 and CRELD2 which are important in human genitourinary tract development which might help elucidate the critical stages for the onset of kidney anomalies. METHODS: Morphological parameters were analyzed using immunohistochemistry on human foetal (13-38 w) and postnatal (1.5 and 7.5y) human kidney samples. RESULTS: GREB1L marker had a strong intensity and the highest rate in proximal tubules (PTC) of 1.5 years' kidney (90.25%). In the distal tubules (DCT) there were statistically significant differences in 13 w, 15 w, 16 w, 21 w, 38 w and 7.5y regarding 1.5y (Kruskal-Wallis test, p < 0.001). There was significantly more GREB1L in the glomeruli at 21 w and 38 w in regard to all other stages (Kruskal-Wallis test, p < 0.01). ITGA10 staining intensity was strongest in PCT with the highest rate in 13 w (92.75%), while the lowest rate was found in glomeruli and DCT (Kruskal-Wallis test, p < 0.001). CRELD2 had the strongest staining intensity in PCT with the highest rate in 13 w and 1.5y (92.25%) and lowest in the glomeruli of 7.5 years (24.3 %). In DCT there were statistically significant differences in CRELD2 positive cells in 13 w, 15 w, 16 w, 21 w, 38 w and 7.5y regarding 1.5y (Kruskal-Wallis test, p < 0.01). ITGA10 and CRELD2 co-localised in the postnatal period in DCT. CONCLUSION: High kidney expressions of GREB1L, ITGA10 and CRELD2 even in the postnatal period implicate their importance not only for the onset of CAKUT in the case of their mutation but also for maintenance of kidney homeostasis.

A Study of Novel Exploratory Tools, Digital Technologies, and Central Nervous System Biomarkers to Characterize Unipolar Depression.

Background: Digital technologies have the potential to provide objective and precise tools to detect depression-related symptoms. Deployment of digital technologies in clinical research can enable collection of large volumes of clinically relevant data that may not be captured using conventional psychometric questionnaires and patient-reported outcomes. Rigorous methodology studies to develop novel digital endpoints in depression are warranted. Objective: We conducted an exploratory, cross-sectional study to evaluate several digital technologies in subjects with major depressive disorder (MDD) and persistent depressive disorder (PDD), and healthy controls. The study aimed at assessing utility and accuracy of the digital technologies as potential diagnostic tools for unipolar depression, as well as correlating digital biomarkers to clinically validated psychometric questionnaires in depression. Methods: A cross-sectional, non-interventional study of 20 participants with unipolar depression (MDD and PDD/dysthymia) and 20 healthy controls was conducted at the Centre for Human Drug Research (CHDR), the Netherlands. Eligible participants attended three in-clinic visits (days 1, 7, and 14), at which they underwent a series of assessments, including conventional clinical psychometric questionnaires and digital technologies. Between the visits, there was at-home collection of data through mobile applications. In all, seven digital technologies were evaluated in this study. Three technologies were administered via mobile applications: an interactive tool for the self-assessment of mood, and a cognitive test; a passive behavioral monitor to assess social interactions and global mobility; and a platform to perform voice recordings and obtain vocal biomarkers. Four technologies were evaluated in the clinic: a neuropsychological test battery; an eye motor tracking system; a standard high-density electroencephalogram (EEG)-based technology to analyze the brain network activity during cognitive testing; and a task quantifying bias in emotion perception. Results: Our data analysis was organized by technology - to better understand individual features of various technologies. In many cases, we obtained simple, parsimonious models that have reasonably high diagnostic accuracy and potential to predict standard clinical outcome in depression. Conclusion: This study generated many useful insights for future methodology studies of digital technologies and proof-of-concept clinical trials in depression and possibly other indications.

Gastroesophageal junction: structure and function as assessed by using MR imaging.

PURPOSE: To develop and validate magnetic resonance (MR) imaging protocols for quantitative assessment of the structural and functional properties of the gastroesophageal junction (GEJ) and to compare MR imaging detection of reflux events against concurrent manometry as a reference method. MATERIALS AND METHODS: The local ethics committee approved this study, and written informed consent was obtained. Twelve healthy volunteers were examined. Three-dimensional models of the GEJ and proximal portion of the stomach were reconstructed from high-spatial-resolution anatomic MR images to assess the insertion angle of the esophagus into the stomach and proximal stomach distention before and after ingestion of a large test meal. A linear mixed-effects model was used to detect differences in the insertion angle and proximal stomach distention with respect to the respiratory cycle and gastric filling. Additionally, dynamic MR imaging at high temporal resolution was used to detect reflux events. RESULTS: The esophageal insertion angle, given in units of plane angle (radians), was more acute in expiration than in inspiration (0.57 vs 0.73 radian, P = .004) but was not affected by feeding. Progressive distention of the proximal stomach was observed from baseline compared with the postprandial period (0.95 vs 0.65 radian(-1), P < .05). Eighteen reflux events detected by using MR imaging were also detected by using manometry. CONCLUSION: MR imaging methods were developed and validated for the assessment of GEJ structure and function (a) to describe the effects of respiration and feeding on the reflux barrier and (b) to detect reflux events in real time. Anatomic and dynamic MR imaging may be useful techniques in the assessment of GEJ physiology and reflux.

Effects of Laparoscopic Sleeve Gastrectomy on Gastric Structure and Function Documented by Magnetic Resonance Imaging Are Strongly Associated with Post-operative Weight Loss and Quality of Life: a Prospective Study.

BACKGROUND: This prospective study applied magnetic resonance imaging (MRI) to assess the effect of laparoscopic sleeve gastrectomy (LSG) on gastric structure and function. The impact of these changes on patient outcomes was analyzed. METHOD: Obese patients without gastrointestinal symptoms referred for bariatric surgery were recruited prospectively. Pre-operative assessment included (i) high-resolution manometry and pH-impedance monitoring and (ii) magnetic resonance imaging (MRI) measurement of gastric capacity, accommodation, and emptying with the 400 ml liquid Nottingham test meal (NTM). Studies were repeated 6-7 months after LSG. Weight loss and changes in the Gastrointestinal Quality of Life Index (GIQLI) assessed patient outcomes. RESULTS: From 35 patients screened, 23 (66%) completed the study (17 females, age 36 ± 10 years, BMI 42 ± 5 kg/m2). Mean excess weight loss was 59 ± 18% at follow-up. Total gastric volume (capacity) after the meal was 467 mL (455-585 ml) before and 139 mL (121-185 ml) after LSG (normal reference 534 (419-675) mL), representing a mean 70% reduction (p < 0.0001). Similar findings were present for gastric content volume indicating rapid early-phase gastric emptying (GE) post-LSG. Conversely, late-phase GE was slower post-LSG (2.5 ± 1.0 vs. 1.4 ± 0.6 mL/min; p < 0.0001; (reference 1.5(1.4-4.9) mL/min)). Patients with ≥ 80% reduction in gastric capacity had greater weight loss (p = 0.008), but worse gastrointestinal outcomes (p = 0.023). CONCLUSIONS: MRI studies quantified the marked reduction in gastric capacity after LSG. The reduction in capacity was associated with rapid early- but slow late-phase GE after surgery. These changes were associated with weight loss; however, reductions in gastric capacity ≥ 80% were linked to increased acid reflux and impacted on gastrointestinal quality of life.

The Causes of Gastroesophageal Reflux after Laparoscopic Sleeve Gastrectomy: Quantitative Assessment of the Structure and Function of the Esophagogastric Junction by Magnetic Resonance Imaging and High-Resolution Manometry.

BACKGROUND: The incidence of de novo gastroesophageal reflux disease (GERD) after LSG is substantial. However, an objective correlation with the structural gastric and EGJ changes has not been demonstrated yet. We aimed to prospectively evaluate the effects of laparoscopic sleeve gastrectomy (LSG) on the structure and function of the esophagogastric junction (EGJ) and stomach. METHODS: Investigations were performed before and after > 50% reduction in excess body weight (6-12 months after LSG). Subjects with GERD at baseline were excluded. Magnetic Resonance Imaging (MRI), high-resolution manometry (HRM), and ambulatory pH-impedance measurements were used to assess the structure and function of the EGJ and stomach before and after LSG. RESULTS: From 35 patients screened, 23 (66%) completed the study (age 36 ± 10 years, BMI 42 ± 5 kg/m2). Mean excess weight loss was 59 ± 18% after 7.1 ± 1.7-month follow-up. Esophageal acid exposure (2.4 (1.5-3.2) to 5.1 (2.8-7.3); p = 0.040 (normal < 4.0%)) and reflux events increased after surgery (57 ± 24 to 84 ± 38; p = 0.006 (normal < 80/day)). Esophageal motility was not altered by surgery; however, intrabdominal EGJ length and pressure were reduced (both p < 0.001); whereas the esophagogastric insertion angle (35° ± 11° to 51° ± 16°; p = 0.0004 (normal < 60°)) and esophageal opening diameter (16.9 ± 2.8 mm to 18.0 ± 3.7 mm; p = 0.029) were increased. The increase in reflux events correlated with changes in EGJ insertion angle (p = 0.010). Patients with > 80% reduction in gastric capacity (TGV) had the highest prevalence of symptomatic GERD. CONCLUSION: LSG has multiple effects on the EGJ and stomach that facilitate reflux. In particular, EGJ disruption as indicated by increased (more obtuse) esophagogastric insertion angle and small gastric capacity were associated with the risk of GERD after LSG. clinicaltrials.gov: NCT01980420.

Chromatographic and computational screening of anisotropic lipophilicity and pharmacokinetics of newly synthesized 1-aryl-3-ethyl-3-methylsuccinimides.

The present study is focused on a series of newly synthesized 1-aryl-3-ethyl-3-methylsuccinimide derivatives, as potential anticonvulsants. The retention behavior of eleven succinimide derivatives was determined by using reversed phase high performance liquid chromatography (RP-HPLC) and reversed phase high performance thin layer chromatography (RP-HPTLC). The estimated retention behavior was correlated with partition (logP) and distribution coefficients (logD). These high correlations pointed out that the determined retention parameters (logk0 and RM0) can be considered chromatographic (anisotropic) lipophilicity of the studied succinimide derivatives. The structural properties, which dominantly affect the chromatographic lipophilicity, were determined as well. The significant correlations between the chromatographic lipophilicity and plasma protein binding (PPB), Madin-Darby Canine Kidney (MDCK) cells permeability, volume of distribution (Vd) and absorption constant (Ka) indicate the strong influence of lipophilicity on pharmacokinetics of 1-aryl-3-ethyl-3-methylsuccinimide derivatives. These derivatives have also been tested applying Comprehensive Medicinal Chemistry (CMC) drug-like rules which confirmed their drug-like properties. Besides, their blood-brain penetration (BBB) ability has been estimated applying the set of Clark's rules and by using Pre-ADMET software. Regarding toxicity, it was predicted that only one compound from the set might have toxic effects by blocking the hERG potassium channel. The present study reveals which molecular features in the structure of novel succinimide derivatives could be crucial for their lipophilicity, and consequently for their pharmacokinetic properties. The results indicate that the newly synthesized series of succinimide derivatives should be further considered in design of novel anticonvulsants.

Comparative chemometric and quantitative structure-retention relationship analysis of anisotropic lipophilicity of 1-arylsuccinimide derivatives determined in high-performance thin-layer chromatography system with aprotic solvents.

Numerous structurally different amides and imides including succinimide derivatives exhibit diverse bioactive potential. The development of new compounds requires rationalization in the design in order to provide structural changes that guarantee favorable physico-chemical properties, pharmacological activity and safety. In the present research, a comprehensive study with comparison of the chromatographic lipophilicity and other physico-chemical properties of five groups of 1-arylsuccinimide derivatives was conducted. The chemometric analysis of their physico-chemical properties was carried out by using unsupervised (hierarchical cluster analysis and principal component analysis) and supervised pattern recognition methods (linear discriminant analysis), while the correlations between the in silico molecular features and chromatographic lipophilicity were examined applying linear and non-linear Quantitative Structure-Retention Relationship (QSRR) approaches. The main aim of the conducted research was to determine similarities and dissimilarities among the studied 1-arylsuccinimides, to point out the molecular features which have significant influence on their lipophilicity, as well as to establish high-quality QSRR models which can be used in prediction of chromatographic lipophilicity of structurally similar 1-arylsuccinimides. This study is a continuation of analysis and determination of the physico-chemical properties of 1-arylsuccinimides which could be important guidelines in further in vitro and eventually in vivo studies of their biological potential.

Prospective self-gating for simultaneous compensation of cardiac and respiratory motion.

Segmented cardiac acquisitions generally require the use of an electrocardiogram (ECG) in combination with a breathhold or a respiratory navigator placed on the diaphragm. These techniques necessitate patient cooperation and increase the complexity of cardiac imaging. The ECG signal may be distorted inside the magnet by interferences from radiofrequency and gradient action. Breathhold acquisition limits the total scan time, while navigators on the diaphragm might not fully reflect respiratory-induced motion of the heart. To overcome some of these problems, several self-gating (SG) or "wireless" techniques have recently been presented. All of these approaches, however, are based on either cardiac triggering or respiratory gating, or the data are processed retrospectively, reducing the efficiency of data acquisition. In this work a prospective SG approach for free-breathing imaging is presented that requires neither ECG gating nor respiratory navigation. The motion data used for cardiac triggering and respiratory gating are extracted from the repeatedly acquired k-space center. Based on computer simulations and in vivo data of the heart, it is shown that cardiac as well as respiratory motion can be accurately extracted in real time. Using the method proposed, the scan efficiency could be significantly increased while preserving image quality relative to retrospective SG approaches.