Post-COVID-19 condition in the German working population: A cross-sectional study of 200,000 registered stem cell donors.

BACKGROUND: The SARS-CoV-2 pandemic has strained health systems worldwide, and infection numbers continue to rise. While previous data have already shown that many patients suffer from symptoms for months after an acute infection, data on risk factors and long-term outcomes are incomplete, particularly for the working population. OBJECTIVES: We aimed to provide information on the prevalence of post-COVID-19 conditions in a subset of the German working-age population (18-61 years old) and to analyze risk factors. METHODS: We conducted an online survey with a health questionnaire among registered potential stem cell donors with or without a self-reported history of polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection. Logistic regression models were used to examine the risks of severity of acute infection, sex, age, body mass index, diabetes mellitus, and arterial hypertension medication on post-COVID-19 symptoms. RESULTS: A total of 199,377 donors reported evaluable survey questionnaires-12,609 cases had a history of SARS-CoV-2 infection and 186,768 controls had none. Overall, cases reported physical, cognitive, and psychological complaints more frequently compared to controls. Increased rates of complaints persisted throughout 15 months postinfection, for example, 28.4%/19.3% of cases/controls reported fatigue (p <0.0001) and 9.5%/3.6% of cases/controls reported loss of concentration (p <0.0001). No significant differences were observed in the frequency of reported symptoms between 3 and 15 months postinfection. Multivariate analysis revealed a strong influence of the severity of the acute SARS-CoV-2 infection episode and age on the risk for post-COVID-19 conditions. CONCLUSION: We report the prevalence of post-COVID-19 conditions in mainly unvaccinated individuals with SARS-CoV-2 infections between February 2020 and August 2021. The severity of the acute course and age were major risk factors. Vaccinations may reduce the risk of post-COVID-19 conditions by reducing the risk of severe infections.

Individual HLA-A, -B, -C, and -DRB1 Genotypes Are No Major Factors Which Determine COVID-19 Severity.

HLA molecules are key restrictive elements to present intracellular antigens at the crossroads of an effective T-cell response against SARS-CoV-2. To determine the impact of the HLA genotype on the severity of SARS-CoV-2 courses, we investigated data from 6,919 infected individuals. HLA-A, -B, and -DRB1 allotypes grouped into HLA supertypes by functional or predicted structural similarities of the peptide-binding grooves did not predict COVID-19 severity. Further, we did not observe a heterozygote advantage or a benefit from HLA diplotypes with more divergent physicochemical peptide-binding properties. Finally, numbers of in silico predicted viral T-cell epitopes did not correlate with the severity of SARS-CoV-2 infections. These findings suggest that the HLA genotype is no major factor determining COVID-19 severity. Moreover, our data suggest that the spike glycoprotein alone may allow for abundant T-cell epitopes to mount robust T-cell responses not limited by the HLA genotype.

Reference Values of the QOLIBRI from General Population Samples in the United Kingdom and The Netherlands.

The Quality of Life after Traumatic Brain Injury (QOLIBRI) instrument is an internationally validated patient-reported outcome measure for assessing disease-specific health-related quality of life (HRQoL) in individuals after traumatic brain injury (TBI). However, no reference values for general populations are available yet for use in clinical practice and research in the field of TBI. The aim of the present study was, therefore, to establish these reference values for the United Kingdom (UK) and the Netherlands (NL). For this purpose, an online survey with a reworded version of the QOLIBRI for general populations was used to collect data on 4403 individuals in the UK and 3399 in the NL. This QOLIBRI version was validated by inspecting descriptive statistics, psychometric criteria, and comparability of the translations to the original version. In particular, measurement invariance (MI) was tested to examine whether the items of the instrument were understood in the same way by different individuals in the general population samples and in the TBI sample across the two countries, which is necessary in order to establish reference values. In the general population samples, the reworded QOLIBRI displayed good psychometric properties, including MI across countries and in the non-TBI and TBI samples. Therefore, differences in the QOLIBRI scores can be attributed to real differences in HRQoL. Individuals with and without a chronic health condition did differ significantly, with the latter reporting lower HRQoL. In conclusion, we provided reference values for healthy individuals and individuals with at least one chronic condition from general population samples in the UK and the NL. These can be used in the interpretation of disease-specific HRQoL assessments after TBI applying the QOLIBRI on the individual level in clinical as well as research contexts.

Factorial Structure and Validity of Depression (PHQ-9) and Anxiety (GAD-7) Scales after Traumatic Brain Injury.

BACKGROUND: The dimensionality of depression and anxiety instruments have recently been a source of controversy. OBJECTIVES AND DESIGN: In a European-wide sample of patients after Traumatic Brain Injury (TBI), we aim to examine the factorial structure, validity, and association of the Patient Health Questionnaire for depression (PHQ-9) and the Generalized Anxiety Disorder (GAD-7) instruments. This study is based on longitudinal observational data. We conducted analyses of factorial structure and discriminant validity of outcomes six-months after TBI. We also examined the prevalence, co-occurrence, and changes of scores on the PHQ-9 and GAD-7 at 3-, 6-, and 12-month post-TBI assessments. PARTICIPANTS: At six-months post-TBI assessment, 2137 (738 (34.5%) women) participants completed the PHQ-9 and GAD-7 questionnaires. For the longitudinal analysis, we had 1922 participants (672 (35.0%) women). RESULTS: The results of exploratory factor analysis suggested a general latent construct underlying both PHQ-9 and GAD-7 measures. Confirmatory factor analyses showed a slight improvement in the fit indices for the bifactorial model. The Omega hierarchical test clearly differentiated two subfactors of PHQ-9 and GAD-7 items over and above the underlying general factor; however, most of the variance (85.0%) was explained by the general factor and the explained variance of the subfactors was small. The PHQ-9 and GAD-7 performed similarly in detecting post-traumatic stress disorder (PTSD). As defined by conventional cut-offs, depression and anxiety have different prevalence rates in the sample. The scales also differed in their relationships with the short form of health survey (SF-36v2) subscales. The longitudinal analysis showed high stability of depression and anxiety symptoms: 49-67% of the post-TBI patients with comorbid depression and anxiety reported the persistence of the symptoms over time. DISCUSSION: The factorial structure analysis favors a general latent construct underlying both depression and anxiety scales among patients after TBI. We discuss the implications our findings and future research directions.

Measurement invariance of assessments of depression (PHQ-9) and anxiety (GAD-7) across sex, strata and linguistic backgrounds in a European-wide sample of patients after Traumatic Brain Injury.

BACKGROUND: The Patient Health Questionnaire-9 (PHQ-9) and the Generalized Anxiety Disorder (GAD-7) are two widely used instruments to screen patients for depression and anxiety. Comparable psychometric properties across different demographic and linguistic groups are necessary for multiple group comparison and international research on depression and anxiety. OBJECTIVES AND METHOD: We examine measurement invariance for the PHQ-9 and GAD-7 by: (a) the sex of the participants, (b) recruitment stratum, and (c) linguistic background. This study is based on non-randomized observational data six months after Traumatic Brain Injury (TBI) that were collected in 18 countries. We used multiple methods to detect Differential Item Functioning (DIF) including Item Response Theory, logistic regression, and the Mantel-Haenszel method. RESULTS: At the 6-month post-injury, 2137 (738 [34.5%] women) participants completed the PHQ-9 and GAD-7 questionnaires: 885 [41.4%] patients were primarily admitted to the Intensive Care Unit (ICU), 805 [37.7%] were admitted to hospital ward, and 447 [20.9%] were evaluated in the Emergency Room and discharged. Results supported the invariance of PHQ-9 and GAD-7 across sex, patient strata and linguistic background. For different strata three PHQ-9 items and one GAD-7 item and for different linguistic groups only two GAD-7 items were flagged as showing differences in two out of four DIF tests. However, the magnitude of the DIF effect was negligible. LIMITATION: Despite high number of participants from ICU, patients have mostly mild TBI. CONCLUSION: The findings demonstrate adequate psychometric properties for PHQ-9 and GAD-7, allowing direct multigroup comparison across sex, strata, and linguistic background.

The psychometric validation of the Dutch version of the Rivermead Post-Concussion Symptoms Questionnaire (RPQ) after traumatic brain injury (TBI).

BACKGROUND: Traumatic brain injury (TBI) is one of the most common neurological conditions. It can have wide-ranging physical, cognitive and psychosocial effects. Most people recover within weeks to months after the injury, but a substantial proportion are at risk of developing lasting post-concussion symptoms. The Rivermead Post-Concussion Syndrome Questionnaire (RPQ) is a short validated 16-items self-report instrument to evaluate post-concussive symptoms. The aim of this study was to test psychometrics characteristics of the current Dutch translation of the RPQ. METHODS: To determine the psychometric characteristics of the Dutch RPQ, 472 consecutive patients six months after they presented with a traumatic brain injury in seven medical centers in the Netherlands (N = 397), and in two in Belgium (Flanders) (N = 75) took part in the study which is part of the large prospective longitudinal observational CENTER-TBI-EU-study. Psychometric properties at six months post TBI, were assessed using exploratory and confirmatory factor analyses. Sensitivity was analyzed by comparing RPQ scores and self-reported recovery status of patients with mild vs. moderate and severe TBI. FINDINGS: The Dutch version of RPQ proved good, showing excellent psychometric characteristics: high internal consistency (Cronbach's α .93), and good construct validity, being sensitive to self-reported recovery status at six months post TBI. Moreover, data showed a good fit to the three dimensional structure of separate cognitive, emotional and somatic factors (Chi2 = 119; df = 117; p = .4; CFI = .99; RMSEA = .006), reported earlier in the literature. DISCUSSION: Psychometric characteristics of the Dutch version of RPQ proved excellent to good, and can the instrument therefore be applied for research purposes and in daily clinical practice.

Prevalence of post-concussion-like symptoms in the general population in Italy, The Netherlands and the United Kingdom.

Objectives: To evaluate the frequency of post-concussion symptoms and prevalence and risk factors of post-concussion syndrome (PCS) in the general population, investigate the association between the Rivermead Post-Concussion Symptoms Questionnaire (RPQ) and self-perceived health, and evaluate differences between three European countries. Methods: A web-based survey including the RPQ and EQ-5D was conducted among representative samples in three European countries. Results: A total of 11,759 respondents completed the questionnaire. The most frequently reported symptom was fatigue (49.9%). Almost half (45.1%) of the respondents were classified as having PCS considering rating score 2 (three RPQ items with score ≥ 2) as a cut-off. Chronic health complaints were found as a significant risk factor for PCS. All items of the RPQ were positively correlated with the EQ-5D and the strongest positive correlation (0.633, p<0.001) was between RPQ item 'feeling depressed or tearful' and EQ-5D domain 'anxiety/depression'. Conclusions: We found a high frequency of post-concussion-like symptoms and PCS in the general population, indicating that these symptoms are not specific for patients with traumatic brain injury (TBI), and PCS is not a unique syndrome after TBI. Therefore, the use of post-concussion symptoms and PCS as outcome following mild TBI should be interpreted with caution.

Quality of Life After Brain Injury: Psychometric Properties of the Spanish Translation of the QoLIBRI.

Traumatic brain injury (TBI) is frequently followed by a variety of physical, emotional, and cognitive symptoms, which affect the patient's daily life, their social relations, and their work/educational status. In addition to function measures, health-related quality of life (HRQoL) has received increasing attention as an important outcome after TBI, as it may guide rehabilitation and evaluate treatment success. Here, we report on psychometric properties of a Spanish translation of the quality of life after brain injury (QoLIBRI) questionnaire, a disease-specific instrument to assess HRQoL in patients after TBI. Classical test theory, item response theory, and structural equation modeling were used to evaluate psychometric properties of the Spanish QoLIBRI translation in a convenience sample of N = 155 patients with TBI. A subset of n = 23 patients were tested twice with a test-retest interval of ≤2 weeks. Internal consistency and test-retest reliabilities were high (Cronbach's α: 0.78-0.96; ICCs: 0.81-0.96). Rasch analysis infit (range 0.52-1.20) and outfit indices (range 0.50-1.17) supported unidimensionality of subscales, whereas SEM analysis tended to support a correlated six-factor model (CFI = .88, RMSEA = .068, 95% confidence interval [.061, .075]). Results show favorable psychometric properties of the Spanish translation of the QoLIBRI, comparable to the international version. It is, thus, a useful instrument for clinicians and researchers assessing the impact of TBI on quality of life, the outcomes of rehabilitation, and may be included in epidemiological surveys.

A Multidimensional Approach to Post-concussion Symptoms in Mild Traumatic Brain Injury.

Mild traumatic brain injury (mTBI) presents a substantial burden to patients, families, and health care systems. Whereas, recovery can be expected in the majority of patients, a subset continues to report persisting somatic, cognitive, emotional, and/or behavioral problems, generally referred to as post-concussion syndrome (PCS). However, this term has been the subject of debate since the mechanisms underlying post-concussion symptoms and the role of pre- and post-injury-related factors are still poorly understood. We review current evidence and controversies concerning the use of the terms post-concussion symptoms vs. syndrome, its diagnosis, etiology, prevalence, assessment, and treatment in both adults and children. Prevalence rates of post-concussion symptoms vary between 11 and 82%, depending on diagnostic criteria, population and timing of assessment. Post-concussion symptoms are dependent on complex interactions between somatic, psychological, and social factors. Progress in understanding has been hampered by inconsistent classification and variable assessment procedures. There are substantial limitations in research to date, resulting in gaps in our understanding, leading to uncertainty regarding epidemiology, etiology, prognosis, and treatment. Future directions including the identification of potential mechanisms, new imaging techniques, comprehensive, multidisciplinary assessment and treatment options are discussed. Treatment of post-concussion symptoms is highly variable, and primarily directed at symptom relief, rather than at modifying the underlying pathology. Longitudinal studies applying standardized assessment strategies, diagnoses, and evidence-based interventions are required in adult and pediatric mTBI populations to optimize recovery and reduce the substantial socio-economic burden of post-concussion symptoms.

German validation of Quality of Life after Brain Injury (QOLIBRI) assessment and associated factors.

The consequences of traumatic brain injury (TBI) for health-related quality of life (HRQoL) are still poorly understood, and no TBI-specific instrument has hitherto been available. This paper describes in detail the psychometrics and validity of the German version of an internationally developed, self-rated HRQoL tool after TBI-the QOLIBRI (Quality of Life after Brain Injury). Factors associated with HRQoL, such as the impact of cognitive status and awareness, are specifically reported. One-hundred seventy-two participants after TBI were recruited from the records of acute clinics, most of whom having a Glasgow Coma Scale (GCS) 24-hour worst score and a Glasgow Outcome Scale (GOSE) score. Participants had severe (24%), moderate (11%) and mild (56%) injuries as assessed on the GCS, 3 months to 15 years post-injury. The QOLIBRI uses 37 items to measure "satisfaction" in the areas of "Cognition", "Self", "Daily Life and Autonomy", and "Social Relationships", and "feeling bothered" by "Emotions"and "Physical Problems". The scales meet standard psychometric criteria (α = .84 to .96; intra-class correlation-ICC = .72 to .91). ICCs (0.68 to 0.90) and αs (.83 to .96) were also good in a subgroup of participants with lower cognitive performance. The six-subscale structure of the international sample was reproduced for the German version using confirmatory factor analyses and Rasch analysis. Scale validity was supported by systematic relationships observed between the QOLIBRI and the GOSE, Patient Competency Rating Scale for Neurorehabilitation (PCRS-NR), Hospital Anxiety and Depression Scale (HADS), Profile of Mood States (POMS), Short Form 36 (SF-36), and Satisfaction with Life Scale (SWLS). The German QOLIBRI contains novel information not provided by other currently available measures and has good psychometric criteria. It is potentially useful for clinicians and researchers, in post-acute and rehabilitation studies, on a group and individual level.

Basic discriminative and semantic processing in patients in the vegetative and minimally conscious state.

Patients who survive injuries to the brain following accidents or diseases often acquire a disorder of consciousness (DOC). Assessment of the state of consciousness in these patients is difficult since they are usually incapable of reproducible motor movements. The application of event-related potentials (ERP) recorded via EEG constitutes one promising approach to complement the assessment of cognitive functions in DOC patients. For these assessments, a hierarchical approach was suggested which means that paradigms aiming at higher order ERPs are only presented if early responses were found. In this study, 19 behaviorally unresponsive or low-responsive DOC patients were presented with three auditory paradigms using passive instructions. The paradigms aimed at eliciting the Mismatch Negativity (MMN) and N400 and were applied at two time points. One oddball paradigm (MMN) and two semantic paradigms (word-pairs: N400 Words; sentences: N400 Sentences) were included. The majority of patients (n=15) did not show any response to the stimulation. In the MMN paradigm, an MMN was identified in two patients, in the N400 Words paradigm, only an N1 was identified in one patient, and in the N400 Sentences paradigm, a late positive complex (LPC) was identified in two patients. These data contradict the hierarchical approach since the LPC was identified in patients who did not exhibit an MMN. They further support the notion that even higher information processing as addressed with the N400 paradigms is preserved in a minority of DOC patients. Thus, in this sample, around 10% of the DOC patients exhibited indicators of preserved consciousness.

Circadian course of the P300 ERP in patients with amyotrophic lateral sclerosis - implications for brain-computer interfaces (BCI).

BACKGROUND: Accidents or neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) can lead to progressing, extensive, and complete paralysis leaving patients aware but unable to communicate (locked-in state). Brain-computer interfaces (BCI) based on electroencephalography represent an important approach to establish communication with these patients. The most common BCI for communication rely on the P300, a positive deflection arising in response to rare events. To foster broader application of BCIs for restoring lost function, also for end-users with impaired vision, we explored whether there were specific time windows during the day in which a P300 driven BCI should be preferably applied. METHODS: The present study investigated the influence of time of the day and modality (visual vs. auditory) on P300 amplitude and latency. A sample of 14 patients (end-users) with ALS and 14 healthy age matched volunteers participated in the study and P300 event-related potentials (ERP) were recorded at four different times (10, 12 am, 2, & 4 pm) during the day. RESULTS: Results indicated no differences in P300 amplitudes or latencies between groups (ALS patients v. healthy participants) or time of measurement. In the auditory condition, latencies were shorter and amplitudes smaller as compared to the visual condition. CONCLUSION: Our findings suggest applicability of EEG/BCI sessions in patients with ALS throughout normal waking hours. Future studies using actual BCI systems are needed to generalize these findings with regard to BCI effectiveness/efficiency and other times of day.

Cognitive Processing in Non-Communicative Patients: What Can Event-Related Potentials Tell Us?

Event-related potentials (ERP) have been proposed to improve the differential diagnosis of non-responsive patients. We investigated the potential of the P300 as a reliable marker of conscious processing in patients with locked-in syndrome (LIS). Eleven chronic LIS patients and 10 healthy subjects (HS) listened to a complex-tone auditory oddball paradigm, first in a passive condition (listen to the sounds) and then in an active condition (counting the deviant tones). Seven out of nine HS displayed a P300 waveform in the passive condition and all in the active condition. HS showed statistically significant changes in peak and area amplitude between conditions. Three out of seven LIS patients showed the P3 waveform in the passive condition and five of seven in the active condition. No changes in peak amplitude and only a significant difference at one electrode in area amplitude were observed in this group between conditions. We conclude that, in spite of keeping full consciousness and intact or nearly intact cortical functions, compared to HS, LIS patients present less reliable results when testing with ERP, specifically in the passive condition. We thus strongly recommend applying ERP paradigms in an active condition when evaluating consciousness in non-responsive patients.

Information processing in patients in vegetative and minimally conscious states.

OBJECTIVE: Evaluation of a short two-tone oddball paradigm to discriminate between the vegetative state (VS) and minimal consciousness state (MCS) in a sample of patients with severe disorders of consciousness (DOC). METHOD: EEG was recorded from 45 DOC patients and 14 healthy participants while listening to an auditory oddball paradigm presented in a passive - just listen - and an active - count the odd tones - condition. In patients, the experiment was repeated after a minimum of one week. RESULTS: Prevalence of the P300 was higher in healthy participants (71%) than in patients, but did not discriminate between VS (T1: ∼10%; T2: ∼11%) and MCS (T1: ∼13%; T2: 25%) patients. CONCLUSION: Results cast doubt on whether this simple auditory stimulation paradigm, which requires cognitive action from the listener, is sensitive enough to discriminate between patients with DOC. SIGNIFICANCE: The sensitivity of the P300 ERP obtained in a short two-tone oddball paradigm presented in a passive and an active condition appears to be too low for routine application in a clinical setting aiming at distinguishing between VS and MCS patients.

Studentized continuous wavelet transform (t-CWT) in the analysis of individual ERPs: real and simulated EEG data.

This study aimed at evaluating the performance of the Studentized Continuous Wavelet Transform (t-CWT) as a method for the extraction and assessment of event-related brain potentials (ERP) in data from a single subject. Sensitivity, specificity, positive (PPV) and negative predictive values (NPV) of the t-CWT were assessed and compared to a variety of competing procedures using simulated EEG data at six low signal-to-noise ratios. Results show that the t-CWT combines high sensitivity and specificity with favorable PPV and NPV. Applying the t-CWT to authentic EEG data obtained from 14 healthy participants confirmed its high sensitivity. The t-CWT may thus be well suited for the assessment of weak ERPs in single-subject settings.

Well-being in amyotrophic lateral sclerosis: a pilot experience sampling study.

OBJECTIVE: The aim of this longitudinal study was to identify predictors of instantaneous well-being in patients with amyotrophic lateral sclerosis (ALS). Based on flow theory well-being was expected to be highest when perceived demands and perceived control were in balance, and that thinking about the past would be a risk factor for rumination which would in turn reduce well-being. METHODS: Using the experience sampling method, data on current activities, associated aspects of perceived demands, control, and well-being were collected from 10 patients with ALS three times a day for two weeks. RESULTS: RESULTS show that perceived control was uniformly and positively associated with well-being, but that demands were only positively associated with well-being when they were perceived as controllable. Mediation analysis confirmed thinking about the past, but not thinking about the future, to be a risk factor for rumination and reduced well-being. DISCUSSION: Findings extend our knowledge of factors contributing to well-being in ALS as not only perceived control but also perceived demands can contribute to well-being. They further show that a focus on present experiences might contribute to increased well-being.

The auditory P300-based single-switch brain-computer interface: paradigm transition from healthy subjects to minimally conscious patients.

OBJECTIVE: Within this work an auditory P300 brain-computer interface based on tone stream segregation, which allows for binary decisions, was developed and evaluated. METHODS AND MATERIALS: Two tone streams consisting of short beep tones with infrequently appearing deviant tones at random positions were used as stimuli. This paradigm was evaluated in 10 healthy subjects and applied to 12 patients in a minimally conscious state (MCS) at clinics in Graz, Würzburg, Rome, and Liège. A stepwise linear discriminant analysis classifier with 10×10 cross-validation was used to detect the presence of any P300 and to investigate attentional modulation of the P300 amplitude. RESULTS: The results for healthy subjects were promising and most classification results were better than random. In 8 of the 10 subjects, focused attention on at least one of the tone streams could be detected on a single-trial basis. By averaging 10 data segments, classification accuracies up to 90.6% could be reached. However, for MCS patients only a small number of classification results were above chance level and none of the results were sufficient for communication purposes. Nevertheless, signs of consciousness were detected in 9 of the 12 patients, not on a single-trial basis, but after averaging of all corresponding data segments and computing significant differences. These significant results, however, strongly varied across sessions and conditions. CONCLUSION: This work shows the transition of a paradigm from healthy subjects to MCS patients. Promising results with healthy subjects are, however, no guarantee of good results with patients. Therefore, more investigations are required before any definite conclusions about the usability of this paradigm for MCS patients can be drawn. Nevertheless, this paradigm might offer an opportunity to support bedside clinical assessment of MCS patients and eventually, to provide them with a means of communication.