A comparative study of clinical trial and real-world data in patients with diabetic kidney disease.

A growing body of research is focusing on real-world data (RWD) to supplement or replace randomized controlled trials (RCTs). However, due to the disparities in data generation mechanisms, differences are likely and necessitate scrutiny to validate the merging of these datasets. We compared the characteristics of RCT data from 5734 diabetic kidney disease patients with corresponding RWD from electronic health records (EHRs) of 23,523 patients. Demographics, diagnoses, medications, laboratory measurements, and vital signs were analyzed using visualization, statistical comparison, and cluster analysis. RCT and RWD sets exhibited significant differences in prevalence, longitudinality, completeness, and sampling density. The cluster analysis revealed distinct patient subgroups within both RCT and RWD sets, as well as clusters containing patients from both sets. We stress the importance of validation to verify the feasibility of combining RCT and RWD, for instance, in building an external control arm. Our results highlight general differences between RCT and RWD sets, which should be considered during the planning stages of an RCT-RWD study. If they are, RWD has the potential to enrich RCT data by providing first-hand baseline data, filling in missing data or by subgrouping or matching individuals, which calls for advanced methods to mitigate the differences between datasets.

Data-driven comorbidity analysis of 100 common disorders reveals patient subgroups with differing mortality risks and laboratory correlates.

The populational heterogeneity of a disease, in part due to comorbidity, poses several complexities. Individual comorbidity profiles, on the other hand, contain useful information to refine phenotyping, prognostication, and risk assessment, and they provide clues to underlying biology. Nevertheless, the spectrum and the implications of the diagnosis profiles remain largely uncharted. Here we mapped comorbidity patterns in 100 common diseases using 4-year retrospective data from 526,779 patients and developed an online tool to visualize the results. Our analysis exposed disease-specific patient subgroups with distinctive diagnosis patterns, survival functions, and laboratory correlates. Computational modeling and real-world data shed light on the structure, variation, and relevance of populational comorbidity patterns, paving the way for improved diagnostics, risk assessment, and individualization of care. Variation in outcomes and biological correlates of a disease emphasizes the importance of evaluating the generalizability of current treatment strategies, as well as considering the limitations that selective inclusion criteria pose on clinical trials.

Processing of an Audiobook in the Human Brain Is Shaped by Cultural Family Background.

Perception of the same narrative can vary between individuals depending on a listener's previous experiences. We studied whether and how cultural family background may shape the processing of an audiobook in the human brain. During functional magnetic resonance imaging (fMRI), 48 healthy volunteers from two different cultural family backgrounds listened to an audiobook depicting the intercultural social life of young adults with the respective cultural backgrounds. Shared cultural family background increased inter-subject correlation of hemodynamic activity in the left-hemispheric Heschl's gyrus, insula, superior temporal gyrus, lingual gyrus and middle temporal gyrus, in the right-hemispheric lateral occipital and posterior cingulate cortices as well as in the bilateral middle temporal gyrus, middle occipital gyrus and precuneus. Thus, cultural family background is reflected in multiple areas of speech processing in the brain and may also modulate visual imagery. After neuroimaging, the participants listened to the narrative again and, after each passage, produced a list of words that had been on their minds when they heard the audiobook during neuroimaging. Cultural family background was reflected as semantic differences in these word lists as quantified by a word2vec-generated semantic model. Our findings may depict enhanced mutual understanding between persons who share similar cultural family backgrounds.

Anaemia and enhancement of coagulation are associated with severe COVID-19 infection.

Coagulation disturbances are common in severe COVID-19 infection. We examined laboratory markers in COVID-19 patients during the first wave of the pandemic in Finland. We analysed a wide panel of coagulation tests (IL ACL TOP 750/500®) from anonymously collected samples of 78 hospitalized COVID-19 patients in intensive care units (ICUs; n = 34) or medical wards (n = 44) at Helsinki University Hospital in April-May 2020. These coagulation data were supplemented with the laboratory information system results, including complete blood count and C reactive protein (CRP). Coagulation and inflammatory markers were elevated in most: FVIII in 52%, fibrinogen 77%, D-dimer 74%, CRP 94%, platelet count 37%. Anaemia was common, especially in men (73% vs. 44% in women), and overall weakly correlated with FVIII (women R2 = 0.48, men R2 = 0.24). ICU patients had higher fibrinogen and D-dimer levels (p < .01). Men admitted to the ICU also had higher platelet count, leukocytes and FVIII and lower haemoglobin than the non-ICU patients. None of the patients met the disseminated intravascular coagulation (DIC) criteria, but 31% had a D-dimer level of at least 1.5 mg/L. Presence of both anaemia and high D-dimer together with FVIII is independently associated with ICU admission. Antithrombin was reduced in 47% of the patients but did not distinguish severity. Overall, CRP was associated with coagulation activation. Elevated FVIII, fibrinogen and D-dimer reflected a strong inflammatory response and were characteristic of hospitalized COVID-19 patients. The patients were often anaemic, as is typical in severe inflammation, while anaemia was also associated with coagulation activity.

Hydroxychloroquine reduces interleukin-6 levels after myocardial infarction: The randomized, double-blind, placebo-controlled OXI pilot trial.

OBJECTIVES: To determine the anti-inflammatory effect and safety of hydroxychloroquine after acute myocardial infarction. METHOD: In this multicenter, double-blind, placebo-controlled OXI trial, 125 myocardial infarction patients were randomized at a median of 43 h after hospitalization to receive hydroxychloroquine 300 mg (n = 64) or placebo (n = 61) once daily for 6 months and, followed for an average of 32 months. Laboratory values were measured at baseline, 1, 6, and 12 months. RESULTS: The levels of interleukin-6 (IL-6) were comparable at baseline between study groups (p = 0.18). At six months, the IL-6 levels were lower in the hydroxychloroquine group (p = 0.042, between groups), and in the on-treatment analysis, the difference at this time point was even more pronounced (p = 0.019, respectively). The high-sensitivity C-reactive protein levels did not differ significantly between study groups at any time points. Eleven patients in the hydroxychloroquine group and four in the placebo group had adverse events leading to interruption or withdrawal of study medication, none of which was serious (p = 0.10, between groups). CONCLUSIONS: In patients with myocardial infarction, hydroxychloroquine reduced IL-6 levels significantly more than did placebo without causing any clinically significant adverse events. A larger randomized clinical trial is warranted to prove the potential ability of hydroxychloroquine to reduce cardiovascular endpoints after myocardial infarction.

Brain activity reflects the predictability of word sequences in listened continuous speech.

Natural speech builds on contextual relations that can prompt predictions of upcoming utterances. To study the neural underpinnings of such predictive processing we asked 10 healthy adults to listen to a 1-h-long audiobook while their magnetoencephalographic (MEG) brain activity was recorded. We correlated the MEG signals with acoustic speech envelope, as well as with estimates of Bayesian word probability with and without the contextual word sequence (N-gram and Unigram, respectively), with a focus on time-lags. The MEG signals of auditory and sensorimotor cortices were strongly coupled to the speech envelope at the rates of syllables (4-8 â€‹Hz) and of prosody and intonation (0.5-2 â€‹Hz). The probability structure of word sequences, independently of the acoustical features, affected the ≤ 2-Hz signals extensively in auditory and rolandic regions, in precuneus, occipital cortices, and lateral and medial frontal regions. Fine-grained temporal progression patterns occurred across brain regions 100-1000 â€‹ms after word onsets. Although the acoustic effects were observed in both hemispheres, the contextual influences were statistically significantly lateralized to the left hemisphere. These results serve as a brain signature of the predictability of word sequences in listened continuous speech, confirming and extending previous results to demonstrate that deeply-learned knowledge and recent contextual information are employed dynamically and in a left-hemisphere-dominant manner in predicting the forthcoming words in natural speech.

Consistency and similarity of MEG- and fMRI-signal time courses during movie viewing.

Movie viewing allows human perception and cognition to be studied in complex, real-life-like situations in a brain-imaging laboratory. Previous studies with functional magnetic resonance imaging (fMRI) and with magneto- and electroencephalography (MEG and EEG) have demonstrated consistent temporal dynamics of brain activity across movie viewers. However, little is known about the similarities and differences of fMRI and MEG or EEG dynamics during such naturalistic situations. We thus compared MEG and fMRI responses to the same 15-min black-and-white movie in the same eight subjects who watched the movie twice during both MEG and fMRI recordings. We analyzed intra- and intersubject voxel-wise correlations within each imaging modality as well as the correlation of the MEG envelopes and fMRI signals. The fMRI signals showed voxel-wise within- and between-subjects correlations up to r = 0.66 and r = 0.37, respectively, whereas these correlations were clearly weaker for the envelopes of band-pass filtered (7 frequency bands below 100 Hz) MEG signals (within-subjects correlation r < 0.14 and between-subjects r < 0.05). Direct MEG-fMRI voxel-wise correlations were unreliable. Notably, applying a spatial-filtering approach to the MEG data uncovered consistent canonical variates that showed considerably stronger (up to r = 0.25) between-subjects correlations than the univariate voxel-wise analysis. Furthermore, the envelopes of the time courses of these variates up to about 10 Hz showed association with fMRI signals in a general linear model. Similarities between envelopes of MEG canonical variates and fMRI voxel time-courses were seen mostly in occipital, but also in temporal and frontal brain regions, whereas intra- and intersubject correlations for MEG and fMRI separately were strongest only in the occipital areas. In contrast to the conventional univariate analysis, the spatial-filtering approach was able to uncover associations between the MEG envelopes and fMRI time courses, shedding light on the similarities of hemodynamic and electromagnetic brain activities during movie viewing.

Abnormal Brain Responses to Action Observation in Complex Regional Pain Syndrome.

Patients with complex regional pain syndrome (CRPS) display various abnormalities in central motor function, and their pain is intensified when they perform or just observe motor actions. In this study, we examined the abnormalities of brain responses to action observation in CRPS. We analyzed 3-T functional magnetic resonance images from 13 upper limb CRPS patients (all female, ages 31-58 years) and 13 healthy, age- and sex-matched control subjects. The functional magnetic resonance imaging data were acquired while the subjects viewed brief videos of hand actions shown in the first-person perspective. A pattern-classification analysis was applied to characterize brain areas where the activation pattern differed between CRPS patients and healthy subjects. Brain areas with statistically significant group differences (q < .05, false discovery rate-corrected) included the hand representation area in the sensorimotor cortex, inferior frontal gyrus, secondary somatosensory cortex, inferior parietal lobule, orbitofrontal cortex, and thalamus. Our findings indicate that CRPS impairs action observation by affecting brain areas related to pain processing and motor control. PERSPECTIVE: This article shows that in CRPS, the observation of others' motor actions induces abnormal neural activity in brain areas essential for sensorimotor functions and pain. These results build the cerebral basis for action-observation impairments in CRPS.

Haptic contents of a movie dynamically engage the spectator's sensorimotor cortex.

Observation of another person's actions and feelings activates brain areas that support similar functions in the observer, thereby facilitating inferences about the other's mental and bodily states. In real life, events eliciting this kind of vicarious brain activations are intermingled with other complex, ever-changing stimuli in the environment. One practical approach to study the neural underpinnings of real-life vicarious perception is to image brain activity during movie viewing. Here the goal was to find out how observed haptic events in a silent movie would affect the spectator's sensorimotor cortex. The functional state of the sensorimotor cortex was monitored by analyzing, in 16 healthy subjects, magnetoencephalographic (MEG) responses to tactile finger stimuli that were presented once per second throughout the session. Using canonical correlation analysis and spatial filtering, consistent single-trial responses across subjects were uncovered, and their waveform changes throughout the movie were quantified. The long-latency (85-175 ms) parts of the responses were modulated in concordance with the participants' average moment-by-moment ratings of own engagement in the haptic content of the movie (correlation r = 0.49; ratings collected after the MEG session). The results, obtained by using novel signal-analysis approaches, demonstrate that the functional state of the human sensorimotor cortex fluctuates in a fine-grained manner even during passive observation of temporally varying haptic events. Hum Brain Mapp 37:4061-4068, 2016. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Identifying fragments of natural speech from the listener's MEG signals.

It is a challenge for current signal analysis approaches to identify the electrophysiological brain signatures of continuous natural speech that the subject is listening to. To relate magnetoencephalographic (MEG) brain responses to the physical properties of such speech stimuli, we applied canonical correlation analysis (CCA) and a Bayesian mixture of CCA analyzers to extract MEG features related to the speech envelope. Seven healthy adults listened to news for an hour while their brain signals were recorded with whole-scalp MEG. We found shared signal time series (canonical variates) between the MEG signals and speech envelopes at 0.5-12 Hz. By splitting the test signals into equal-length fragments from 2 to 65 s (corresponding to 703 down to 21 pieces per the total speech stimulus) we obtained better than chance-level identification for speech fragments longer than 2-3 s, not used in the model training. The applied analysis approach thus allowed identification of segments of natural speech by means of partial reconstruction of the continuous speech envelope (i.e., the intensity variations of the speech sounds) from MEG responses, provided means to empirically assess the time scales obtainable in speech decoding with the canonical variates, and it demonstrated accurate identification of the heard speech fragments from the MEG data.

Functional magnetic resonance imaging blood oxygenation level-dependent signal and magnetoencephalography evoked responses yield different neural functionality in reading.

It is often implicitly assumed that the neural activation patterns revealed by hemodynamic methods, such as functional magnetic resonance imaging (fMRI), and electrophysiological methods, such as magnetoencephalography (MEG) and electroencephalography (EEG), are comparable. In early sensory processing that seems to be the case, but the assumption may not be correct in high-level cognitive tasks. For example, MEG and fMRI literature of single-word reading suggests differences in cortical activation, but direct comparisons are lacking. Here, while the same human participants performed the same reading task, analysis of MEG evoked responses and fMRI blood oxygenation level-dependent (BOLD) signals revealed marked functional and spatial differences in several cortical areas outside the visual cortex. Divergent patterns of activation were observed in the frontal and temporal cortex, in accordance with previous separate MEG and fMRI studies of reading. Furthermore, opposite stimulus effects in the MEG and fMRI measures were detected in the left occipitotemporal cortex: MEG evoked responses were stronger to letter than symbol strings, whereas the fMRI BOLD signal was stronger to symbol than letter strings. The EEG recorded simultaneously during MEG and fMRI did not indicate neurophysiological differences that could explain the observed functional discrepancies between the MEG and fMRI results. Acknowledgment of the complementary nature of hemodynamic and electrophysiological measures, as reported here in a cognitive task using evoked response analysis in MEG and BOLD signal analysis in fMRI, represents an essential step toward an informed use of multimodal imaging that reaches beyond mere combination of location and timing of neural activation.

Aberrant temporal and spatial brain activity during rest in patients with chronic pain.

In the absence of external stimuli, human hemodynamic brain activity displays slow intrinsic variations. To find out whether such fluctuations would be altered by persistent pain, we asked 10 patients with unrelenting chronic pain of different etiologies and 10 sex- and age-matched control subjects to rest with eyes open during 3-T functional MRI. Independent component analysis was used to identify functionally coupled brain networks. Time courses of an independent component comprising the insular cortices of both hemispheres showed stronger spectral power at 0.12 to 0.25 Hz in patients than in control subjects, with the largest difference at 0.16 Hz. A similar but weaker effect was seen in the anterior cingulate cortex, whereas activity of the precuneus and early visual cortex, used as a control site, did not differ between the groups. In the patient group, seed point-based correlation analysis revealed altered spatial connectivity between insulae and anterior cingulate cortex. The results imply both temporally and spatially aberrant activity of the affective pain-processing areas in patients suffering from chronic pain. The accentuated 0.12- to 0.25-Hz fluctuations in the patient group might be related to altered activity of the autonomic nervous system.

Effect of remifentanil on the nonlinear electroencephalographic entropy parameters in propofol anesthesia.

Nonlinear electroencephalographic entropy parameters have been proposed for the assessment of depth of anesthesia. The influence of remifentanil, a commonly used intraoperative opioid, on these parameters, namely approximate entropy (ApEn), sample entropy (SampEn), and permutation entropy (PeEn), during induction of propofol anesthesia was studied. Remifentanil was shown to reduce the propofol-induced changes in ApEn and SampEn throughout the transition from awake to burst suppression state. Coadministration of opioids therefore challenges the reliability of these parameters as indicators of depth of anesthesia. No consistent influence on PeEn was observed. However, this may have been due to strong interindividual variation in PeEn values.

Effects of remifentanil on the spectrum and quantitative parameters of electroencephalogram in propofol anesthesia.

BACKGROUND: A high dose of opioids associated with a low dose of propofol has become a popular anesthetic technique. However, the influence of opioids on the electroencephalographic phenomenon related to induction of anesthesia and, thereby, on the quantitative parameters used in the depth-of-anesthesia estimation is not well known. METHODS: Twenty-seven patients were divided into three groups to receive saline, low-dose remifentanil (7.5 microg x kg x h) or high-dose remifentanil (30 microg x kg x h) during induction of anesthesia with propofol (30 mg . kg . h). Electroencephalogram was recorded from Fz electrode, and its time-frequency properties in the patient groups were analyzed from the induction of anesthesia to the occurrence of burst suppression pattern. The group differences in 14 quantitative spectral parameters used in the depth-of-anesthesia estimation were examined as well. RESULTS: The time-frequency properties of electroencephalogram were different between groups. The high-frequency (greater than 14 Hz) activity during light anesthesia was decreased in remifentanil groups; whereas, increased activity in extended alpha band (7-14 Hz) and decreased activity in delta band (0.5-4 Hz) was observed during deep anesthesia. This resulted in statistically significant changes in all 14 quantitative parameters. CONCLUSIONS: The effect of remifentanil on the spectrum and quantitative parameters of electroencephalogram is significant and strongly dependent on the level of anesthesia. Coadministration of opioids therefore challenges the reliability of the spectral properties of electroencephalogram in the depth-of-anesthesia estimation by using a frontal montage. Furthermore, the finding has implications for design of opioid coadministration studies.

Removal of imaging artifacts in EEG during simultaneous EEG/fMRI recording: reconstruction of a high-precision artifact template.

Functional magnetic resonance imaging (fMRI) induces coarse electromagnetic artifacts into the simultaneously recorded electroencephalogram (EEG). The problem in the signal processing framework is to model the underlying artifact, which is time-continuous, as a discretely sampled waveform. To build up an artifact template, the EEG sampling in relation to the phase of the imaging artifacts should be known. If the MR scanner and EEG sampling are not synchronized, this relation is not constant and a time adjustment of the template with the individual slice artifacts becomes essential. However, lack of synchrony opens up the possibility for approximating a high-precision and continuous artifact template by using the samples acquired from slightly different phases of the induced artifact. In this work, methodology for reconstructing such a template was developed using EEG data recorded simultaneously with fMRI at 3 T. A time-continuous cubic spline approximation was used as the slice artifact model. To overcome the problem of non-synchronized clocks, two methods were proposed to find the starting times of the slice artifacts at sub-sample precision. This approach yielded efficient imaging artifact reduction: the amplitude at the dominant frequency was attenuated by 55-70 dB (the median values over EEG channels) and the residual signal, at its best, was practically free from sharp transients even with 5000 Hz sampling frequency and without further residual artifact reduction algorithms. The presented methods may reduce the need for post-processing of the residual signal after the template subtraction and may help to preserve the EEG bandwidth.

Time-frequency properties of electroencephalogram during induction of anesthesia.

A method for detailed description of the time-frequency characteristics of electroencephalogram during induction of anesthesia is proposed. The method, based on averaging of time-normalized smoothed pseudo-Wigner-Ville distributions, is applied to data recorded from nine patients undergoing propofol anesthesia. An extensive representation of the frequency progression pattern related to the induction of anesthesia is given and the time-frequency characteristics that are consistent/not consistent between patients are determined. It is also illustrated how four different clinical end-points, generally used in the assessment of the depth of anesthesia, can be related to different phases of the frequency progression pattern. The method presented has importance in providing information about the neurophysiological phenomenon during induction of anesthesia and can therefore be used in the development of new monitoring algorithms.

Remifentanil modifies the relation of electroencephalographic spectral changes and clinical endpoints in propofol anesthesia.

BACKGROUND: Depth-of-anesthesia monitoring with the electroencephalogram has become widely used in anesthesia practice. Generally, the methods presented are based on the spectral changes of the electroencephalogram. In this study, the authors evaluate the influence of remifentanil on the relation of timely occurrence of clinical endpoints and the spectral behavior of the electroencephalogram. METHODS: Twenty-seven patients scheduled to undergo a surgical procedure were randomly assigned to three groups. Patients blindly received equal volumes of saline or remifentanil (7.5 or 30 microg.kg.h) 1 min before induction of anesthesia with infusion of propofol (30 mg.kg.h). The occurrence of loss of counting, loss of obeying verbal command, and loss of reaction to tetanic stimulation was assessed. The electroencephalogram was recorded from electrode Fz referenced to the common average, and an iterative algorithm was applied to solve the underlying frequency progression pattern. The positions of the clinical endpoints on the pattern were analyzed. RESULTS: The administration of remifentanil during induction of anesthesia with propofol led to an earlier occurrence of the clinical endpoints on the frequency progression pattern. A significant difference (P < 0.05) was observed between the saline and high-dose patient groups in all three endpoints. The effect of remifentanil was proportional to the infusion rate. CONCLUSIONS: The infusion of remifentanil during propofol anesthesia significantly modifies the mutual relations of the electroencephalographic spectral characteristics and the endpoints in a predictable and quantifiable manner. This finding suggests that the electroencephalographic phenomena and the endpoints may not be identical but rather to some extent separate manifestations of hypnotic drug effect.

EEG spectral changes and onset of burst suppression pattern in propofol/remifentanil anesthesia.

This paper studies how remifentanil, a commonly used intraoperative opioid, affects the relation of the onset of burst suppression pattern (BSP) and the spectral changes of EEG during anesthesia. The onsets of BSP were detected using both manual and the automatic method proposed from the EEGs of twenty-seven patients who had received different amount of remifentanil with the anesthetic. The spectral changes were determined by calculating the frequency progression patterns of the EEGs. The results showed that remifentanil significantly affects the relation of EEG spectral changes and the onset of BSP. The finding is important since the current EEG-based assessment of the depth of anesthesia basically relies on the analysis of the spectral features and BSP.

Removal of ballistocardiogram artifact from EEG data acquired in the MRI scanner: selection of ICA components.

The removal of ballistocardiogram (BCG) artifact from the EEG recorded in the MRI scanner is challenging. Few studies have utilized independent component analysis (ICA) in this task. A drawback of ICA has been the proper selection of the BCG related components. The key idea in this work is to use the difference between the power spectrum of the artifact-processed data and the spectrum of data recorded outside the scanner as a cost function in the selection of the BCG related independent components. Forward floating selection algorithm was implemented to find the components to minimize this criterion. Also, the typical component selection criteria based on the correlation with electrocardiogram (ECG) signal and on explained variance were compared in this respect. The correlation criterion was least successful leaving considerable residual artifact in the signal. With the first few removed components the variance criterion performed as well as the minimum spectral difference criterion. With the variance criterion alone, however, the number of the components to be removed cannot be determined. The suggested methods may provide objective means to validate residual artifact or the possible loss of physiological signal due to artifact removal and to help selecting the proper artifact-related components.

EEG frequency progression during induction of anesthesia: from start of infusion to onset of burst suppression pattern.

The anesthetic infusion with propofol influences EEG activity rather smoothly by changing the amplitude activity in different frequency bands. This results in a frequency progression pattern (FPP) which can be related to the depth of anesthesia. An iterative algorithm is proposed for the estimation of the shape of this pattern. The presented method is applied to the data recorded from the start of the propofol anesthetic infusion to the onset of the burst suppression pattern (BSP) with nine patients. The results reveal the underlying FPP and how the onset of the BSP is related to it. The proposed method offers potential for the development of automatic assessment systems for the depth of anesthesia.