Acylated- and unacylated ghrelin during an oral glucose tolerance test in humans at risk for type 2 diabetes mellitus.

BACKGROUND/OBJECTIVES: The orexigenic peptide hormone ghrelin has been implicated in the pathophysiology of obesity and type 2 diabetes mellitus through its effects on nutrient homeostasis. Ghrelin is subject to a unique post-translational acyl modification regulating its biochemical activity. SUBJECTS/METHODS: In this study we aimed to investigate the relation of acylated (AcG) as well as unacylated ghrelin (UnG) with body weight and insulin resistance in the fasting (n = 545) and post-oral glucose tolerance test (oGTT) state (n = 245) in a metabolically well characterized cohort covering a broad range of BMI (17.95 kg/m²-76.25 kg/m²). RESULTS: Fasting AcG (median 94.2 pg/ml) and UnG (median 175.3 pg/ml) were negatively and the AcG/UnG ratio was positively correlated with BMI (all p < 0.0001). Insulin sensitivity (ISI) correlated positively with AcG (p = 0.0014) and UnG (p = 0.0004) but not with the AcG/UnG ratio. In a multivariate analysis, including ISI and BMI, only BMI, but not ISI was independently associated with AcG and UnG concentrations. Significant changes of AcG and UnG concentrations were detectable after oGTT stimulation, with slight decreases after 30 min and increases after 90-120 min. Subject stratification into BMI-divergent groups revealed more pronounced AcG increases in the two groups with BMI < 40 kg/m². CONCLUSION: Our data demonstrate lower concentrations for both AcG and UnG with increasing BMI as well as an increased proportion of the biologically active, acylated form of ghrelin giving point to pharmacologic intervention in ghrelin acylation and/or increase in UnG for treatment of obesity despite decreased absolute AcG levels.

Impact of maternal emotional state during pregnancy on fetal heart rate variability.

Background: The fetal autonomic nervous system (ANS) is believed to be negatively affected by maternal adverse emotional states. In this study, we evaluated how depression, anxiety and stress during pregnancy are related to fetal heart rate variability (HRV) as recorded with magnetocardiography (MCG). We also considered metabolic factors such as maternal adiposity and circulating levels of cortisol during gestation. Furthermore, we followed up these fetuses after birth, recording HRV and saliva levels of cortisol in these infants to establish any effects postpartum. Methods: We calculated HRV in spontaneous MCG recordings from 32 healthy fetuses between 32 and 38 weeks of gestational age. Maternal emotional state was assessed using standardized questionnaires about anxiety, depression and stress. An overall indicator of maternal well-being was calculated by z-scoring each individual questionnaire and summation. We used a median split to divide the group into high and low z-scores (HZS and LZS), respectively. Standard HRV measures were determined in the time and frequency domain. T-test analyses were performed between LZS and HZS, with the HRV and the metabolic measures as the dependent variables. Results: We found an impaired HRV in the HZS group both during pregnancy and after birth. No differences were observed between LZS and HZS for metabolic factors. Depression and anxiety symptoms seem to affect HRV differently. No relationship was found between maternal and infant cortisol levels. Conclusions: On the basis of our results on different HRV parameters, we propose that maternal emotional state might affect the development of the fetal nervous system in utero.

Obesity and Impaired Metabolic Health Increase Risk of COVID-19-Related Mortality in Young and Middle-Aged Adults to the Level Observed in Older People: The LEOSS Registry.

Advanced age, followed by male sex, by far poses the greatest risk for severe COVID-19. An unresolved question is the extent to which modifiable comorbidities increase the risk of COVID-19-related mortality among younger patients, in whom COVID-19-related hospitalization strongly increased in 2021. A total of 3,163 patients with SARS-COV-2 diagnosis in the Lean European Open Survey on SARS-CoV-2-Infected Patients (LEOSS) cohort were studied. LEOSS is a European non-interventional multi-center cohort study established in March 2020 to investigate the epidemiology and clinical course of SARS-CoV-2 infection. Data from hospitalized patients and those who received ambulatory care, with a positive SARS-CoV-2 test, were included in the study. An additive effect of obesity, diabetes and hypertension on the risk of mortality was observed, which was particularly strong in young and middle-aged patients. Compared to young and middle-aged (18-55 years) patients without obesity, diabetes and hypertension (non-obese and metabolically healthy; n = 593), young and middle-aged adult patients with all three risk parameters (obese and metabolically unhealthy; n = 31) had a similar adjusted increased risk of mortality [OR 7.42 (95% CI 1.55-27.3)] as older (56-75 years) non-obese and metabolically healthy patients [n = 339; OR 8.21 (95% CI 4.10-18.3)]. Furthermore, increased CRP levels explained part of the elevated risk of COVID-19-related mortality with age, specifically in the absence of obesity and impaired metabolic health. In conclusion, the modifiable risk factors obesity, diabetes and hypertension increase the risk of COVID-19-related mortality in young and middle-aged patients to the level of risk observed in advanced age.

Evaluation of parameters for fetal behavioural state classification.

Fetal behavioural states (fBS) describe periods of fetal wakefulness and sleep and are commonly defined by features such as body and eye movements and heart rate. Automatic state detection through algorithms relies on different parameters and thresholds derived from both the heart rate variability (HRV) and the actogram, which are highly dependent on the specific datasets and are prone to artefacts. Furthermore, the development of the fetal states is dynamic over the gestational period and the evaluation usually only separated into early and late gestation (before and after 32 weeks). In the current work, fBS detection was consistent between the classification algorithm and visual inspection in 87 fetal magnetocardiographic data segments between 27 and 39 weeks of gestational age. To identify how automated fBS detection could be improved, we first identified commonly used parameters for fBS classification in both the HRV and the actogram, and investigated their distribution across the different fBS. Then, we calculated a receiver operating characteristics (ROC) curve to determine the performance of each parameter in the fBS classification. Finally, we investigated the development of parameters over gestation through linear regression. As a result, the parameters derived from the HRV have a higher classification accuracy compared to those derived from the body movement as defined by the actogram. However, the overlapping distributions of several parameters across states limit a clear separation of states based on these parameters. The changes over gestation of the HRV parameters reflect the maturation of the fetal autonomic nervous system. Given the higher classification accuracy of the HRV in comparison to the actogram, we suggest to focus further research on the HRV. Furthermore, we propose to develop probabilistic fBS classification approaches to improve classification in less prototypical datasets.

Magnetoencephalographic signatures of conscious processing before birth.

The concept of fetal consciousness is a widely discussed topic. In this study, we applied a hierarchical rule learning paradigm to investigate the possibility of fetal conscious processing during the last trimester of pregnancy. We used fetal magnetoencephalography, to assess fetal brain activity in 56 healthy fetuses between gestational week 25 and 40, during an auditory oddball paradigm containing first- and second-order regularities. The comparison of fetal brain responses towards standard and deviant tones revealed that the investigated fetuses show signs of hierarchical rule learning, and thus the formation of a memory trace for the second-order regularity. This ability develops over the course of the last trimester of gestation, in accordance with processes in physiological brain development and was only reliably present in fetuses older than week 35 of gestation. Analysis of fetal autonomic nervous system activity replicates findings in newborns, showing importance of activity state for cognitive processes. On the whole, our results support the assumption that fetuses in the last weeks of gestation are capable of consciously processing stimuli that reach them from outside the womb.

Magnetoencephalographic signatures of hierarchical rule learning in newborns.

Estimating the extent to which newborn humans process input from their environment, especially regarding the depth of processing, is a challenging question. To approach this problem, we measured brain responses in 20 newborns with magnetoencephalography (MEG) in a "local-global" auditory oddball paradigm in which two-levels of hierarchical regularities are presented. Results suggest that infants in the first weeks of life are able to learn hierarchical rules, yet a certain level of vigilance seems to be necessary. Newborns detected violations of the first-order regularity and displayed a mismatch response between 200-400 ms. Violations of the second-order regularity only evoked a late response in newborns in an active state, which was expressed by a high heart rate variability. These findings are in line with those obtained in human adults and older infants suggesting a continuity in the functional architecture from term-birth on, despite the immaturity of the human brain at this age.

Fully Automated R-peak Detection Algorithm (FLORA) for fetal magnetoencephalographic data.

BACKGROUND AND OBJECTIVE: Fetal magnetoencephalography (fMEG) is a method for recording fetal brain signals, fetal and maternal heart activity simultaneously. The identification of the R-peaks of the heartbeats forms the basis for later heart rate (HR) and heart rate variability (HRV) analysis. The current procedure for the evaluation of fetal magnetocardiograms (fMCG) is either semi-automated evaluation using template matching (SATM) or Hilbert transformation algorithm (HTA). However, none of the methods available at present works reliable for all datasets. METHODS: Our aim was to develop a unitary, responsive and fully automated R-peak detection algorithm (FLORA) that combines and enhances both of the methods used up to now. RESULTS: The evaluation of all methods on 55 datasets verifies that FLORA outperforms both of these methods as well as a combination of the two, which applies in particular to data of fetuses at earlier gestational age. CONCLUSION: The combined analysis shows that FLORA is capable of providing good, stable and reproducible results without manual intervention.

Fully Automated Subtraction of Heart Activity for Fetal Magnetoencephalography Data.

Fetal magnetoencephalography (fMEG) is a method to record human fetal brain signals in pregnant mothers. Nevertheless the amplitude of the fetal brain signal is very small and the fetal brain signal is overlaid by interfering signals mainly caused by maternal and fetal heart activity. Several methods are used to attenuate the interfering signals for the extraction of the fetal brain signal. However currently used methods are often affected by a reduction of the fetal brain signal or redistribution of the fetal brain signal. To overcome this limitation we developed a new fully automated procedure for removal of heart activity (FAUNA) based on Principal Component Analysis (PCA) and Ridge Regression. We compared the results with an orthogonal projection (OP) algorithm which is widely used in fetal research. The analysis was performed on simulated data sets containing spontaneous and averaged brain activity. The new analysis was able to extract fetal brain signals with an increased signal to noise ratio and without redistribution of activity across sensors compared to OP. The attenuation of interfering heart signals in fMEG data was significantly improved by FAUNA and supports fully automated evaluation of fetal brain signal.

Automated Detection of Fetal Brain Signals with Principal Component Analysis.

Detection of fetal brain signals in fetal magnetoencephalographic recordings is - due to the low signal to noise ratio - challenging for researchers in this field. Up to now, state of the art is a manual evaluation of the signal. To make the evaluation more reproducible and less time consuming, an approach using Principal Component Analysis is introduced. Locations of the channels of most importance for the first three principal components are taken into account and their possibility of resembling brain activity evaluated. Data with auditory stimulation are taken for this analysis and trigger averaged signals from the channels selected as brain activity (manually & automatically) compared. Comparisons are done with regard to their average baseline activity, activity during a window of interest and timing and amplitude of their highest auditory event-related peak. The number of evaluable data sets showed to be lower for the automated compared to manual approach but auditory event-related peaks did not differ significantly in amplitude or timing and in both cases there was a significant activity change following the tone event. The given results and the advantage of reproducibility make this method a valid alternative.

Agreement of driving simulator and on-road driving performance in patients with binocular visual field loss.

PURPOSE: On-road testing is considered the standard for assessment of driving performance; however, it lacks standardization. In contrast, driving simulators provide controlled experimental settings in a virtual reality environment. This study compares both testing conditions in patients with binocular visual field defects due to bilateral glaucomatous optic neuropathy or due to retro-chiasmal visual pathway lesions. METHODS: Ten glaucoma patients (PG), ten patients with homonymous visual field defects (PH), and 20 age- and gender-matched ophthalmologically normal control subjects (CG and CH, respectively) participated in a 40-min on-road driving task using a dual brake vehicle. A subset of this sample (8 PG, 8 PH, 8 CG, and 7 CH) underwent a subsequent driving simulator test of similar duration. For both settings, pass/fail rates were assessed by a masked driving instructor. RESULTS: For on-road driving, hemianopia patients (PH) and glaucoma patients (PG) showed worse performance than their controls (CH and CG groups): PH 40%, CH 30%, PG 60%, CG 0%, failure rate. Similar results were obtained for the driving simulator test: PH 50%, CH 29%, PG 38%, CG 0%, failure rate. Twenty-four out of 31 participants (77%) showed concordant results with regard to pass/fail under both test conditions (p > 0.05; McNemar test). CONCLUSIONS: Driving simulator testing leads to results comparable to on-road driving, in terms of pass/fail rates in subjects with binocular (glaucomatous or retro-chiasmal lesion-induced) visual field defects. Driving simulator testing seems to be a well-standardized method, appropriate for assessment of driving performance in individuals with binocular visual field loss.

Homonymous Visual Field Loss and Its Impact on Visual Exploration: A Supermarket Study.

PURPOSE: Homonymous visual field defects (HVFDs) may critically interfere with quality of life. The aim of this study was to assess the impact of HVFDs on a supermarket search task and to investigate the influence of visual search on task performance. METHODS: Ten patients with HVFDs (four with a right-sided [HR] and six with a left-sided defect [HL]), and 10 healthy-sighted, sex-, and age-matched control subjects were asked to collect 20 products placed on two supermarket shelves as quickly as possible. Task performance was rated as "passed" or "failed" with regard to the time per correctly collected item (TC -failed = 4.84 seconds based on the performance of healthy subjects). Eye movements were analyzed regarding the horizontal gaze activity, glance frequency, and glance proportion for different VF areas. RESULTS: Seven of 10 HVFD patients (three HR, four HL) passed the supermarket search task. Patients who passed needed significantly less time per correctly collected item and looked more frequently toward the VFD area than patients who failed. HL patients who passed the test showed a higher percentage of glances beyond the 60° VF (P < 0.05). CONCLUSION: A considerable number of HVFD patients performed successfully and could compensate for the HVFD by shifting the gaze toward the peripheral VF and the VFD area. TRANSLATIONAL RELEVANCE: These findings provide new insights on gaze adaptations in patients with HVFDs during activities of daily living and will enhance the design and development of realistic examination tools for use in the clinical setting to improve daily functioning. (http://www.clinicaltrials.gov, NCT01372319, NCT01372332).

Binocular glaucomatous visual field loss and its impact on visual exploration--a supermarket study.

Advanced glaucomatous visual field loss may critically interfere with quality of life. The purpose of this study was to (i) assess the impact of binocular glaucomatous visual field loss on a supermarket search task as an example of everyday living activities, (ii) to identify factors influencing the performance, and (iii) to investigate the related compensatory mechanisms. Ten patients with binocular glaucoma (GP), and ten healthy-sighted control subjects (GC) were asked to collect twenty different products chosen randomly in two supermarket racks as quickly as possible. The task performance was rated as "passed" or "failed" with regard to the time per correctly collected item. Based on the performance of control subjects, the threshold value for failing the task was defined as µ+3σ (in seconds per correctly collected item). Eye movements were recorded by means of a mobile eye tracker. Eight out of ten patients with glaucoma and all control subjects passed the task. Patients who failed the task needed significantly longer time (111.47 s ±12.12 s) to complete the task than patients who passed (64.45 s ±13.36 s, t-test, p < 0.001). Furthermore, patients who passed the task showed a significantly higher number of glances towards the visual field defect (VFD) area than patients who failed (t-test, p < 0.05). According to these results, glaucoma patients with defects in the binocular visual field display on average longer search times in a naturalistic supermarket task. However, a considerable number of patients, who compensate by frequent glancing towards the VFD, showed successful task performance. Therefore, systematic exploration of the VFD area seems to be a "time-effective" compensatory mechanism during the present supermarket task.

Driving with binocular visual field loss? A study on a supervised on-road parcours with simultaneous eye and head tracking.

Post-chiasmal visual pathway lesions and glaucomatous optic neuropathy cause binocular visual field defects (VFDs) that may critically interfere with quality of life and driving licensure. The aims of this study were (i) to assess the on-road driving performance of patients suffering from binocular visual field loss using a dual-brake vehicle, and (ii) to investigate the related compensatory mechanisms. A driving instructor, blinded to the participants' diagnosis, rated the driving performance (passed/failed) of ten patients with homonymous visual field defects (HP), including four patients with right (HR) and six patients with left homonymous visual field defects (HL), ten glaucoma patients (GP), and twenty age and gender-related ophthalmologically healthy control subjects (C) during a 40-minute driving task on a pre-specified public on-road parcours. In order to investigate the subjects' visual exploration ability, eye movements were recorded by means of a mobile eye tracker. Two additional cameras were used to monitor the driving scene and record head and shoulder movements. Thus this study is novel as a quantitative assessment of eye movements and an additional evaluation of head and shoulder was performed. Six out of ten HP and four out of ten GP were rated as fit to drive by the driving instructor, despite their binocular visual field loss. Three out of 20 control subjects failed the on-road assessment. The extent of the visual field defect was of minor importance with regard to the driving performance. The site of the homonymous visual field defect (HVFD) critically interfered with the driving ability: all failed HP subjects suffered from left homonymous visual field loss (HL) due to right hemispheric lesions. Patients who failed the driving assessment had mainly difficulties with lane keeping and gap judgment ability. Patients who passed the test displayed different exploration patterns than those who failed. Patients who passed focused longer on the central area of the visual field than patients who failed the test. In addition, patients who passed the test performed more glances towards the area of their visual field defect. In conclusion, our findings support the hypothesis that the extent of visual field per se cannot predict driving fitness, because some patients with HVFDs and advanced glaucoma can compensate for their deficit by effective visual scanning. Head movements appeared to be superior to eye and shoulder movements in predicting the outcome of the driving test under the present study scenario.