Population-Based Evidence for the Use of Serum Neurofilaments as Individual Diagnostic and Prognostic Biomarkers in Amyotrophic Lateral Sclerosis.

OBJECTIVE: Neurofilament light chains (NfL) and phosphorylated neurofilament heavy chains (pNfH), established as diagnostic and prognostic biomarkers in hospital-based amyotrophic lateral sclerosis (ALS) cohorts, are now surrogate markers in clinical trials. This study extends their evaluation to a population level, with the aim of advancing their full establishment and assessing the transferability of biomarker findings from controlled cohorts to real-world ALS populations. METHODS: We measured serum NfL and pNfH levels in all ALS patients (n = 790) and general population controls (n = 570) with available baseline samples participating in the epidemiological ALS Registry Swabia, providing platform-specific (ELLA™) reference data and Z-scores for controls, as well as reference data, disease-specific Z-scores and longitudinal data in ALS. We evaluated the diagnostic and prognostic utility of neurofilaments and quantified the impact of ALS-related factors and non-ALS confounders. RESULTS: Neurofilaments showed high diagnostic and prognostic utility at the population level, with NfL superior to pNfH. The novel concept of a population-based ALS Z-score significantly improved the prognostic utility compared to absolute raw values. Both biomarkers increased more strongly with age in controls than in ALS, and age adjustment improved diagnostic accuracy. Our data show that disease progression rates, ALS phenotype, body mass index (BMI), and renal function need to be considered when interpreting neurofilament levels; longitudinal neurofilament levels were generally stable in individual patients, especially when adjusted for age and baseline levels. INTERPRETATION: Population-based assessment enhances the utility of particularly serum NfL as a diagnostic and prognostic biomarker in ALS and improves the translation of findings from controlled cohorts to real-world populations. ANN NEUROL 2024.

The Ecology of Human Sleep (EcoSleep) Cohort Study: Protocol for a longitudinal repeated measurement burst design study to assess the relationship between sleep determinants and outcomes under real-world conditions across time of year.

The interplay of daily life factors, including mood, physical activity, or light exposure, influences sleep architecture and quality. Laboratory-based studies often isolate these determinants to establish causality, thereby sacrificing ecological validity. Furthermore, little is known about time-of-year changes in sleep and circadian-related variables at high resolution, including the magnitude of individual change across time of year under real-world conditions. The Ecology of Human Sleep (EcoSleep) cohort study will investigate the combined impact of sleep determinants on individuals' daily sleep episodes to elucidate which waking events modify sleep patterns. A second goal is to describe high-resolution individual sleep and circadian-related changes across the year to understand intra- and inter-individual variability. This study is a prospective cohort study with a measurement-burst design. Healthy adults aged 18-35 years (N = 12) will be enrolled for 12 months. Participants will continuously wear actimeters and pendant-attached light loggers. A subgroup will also measure interstitial fluid glucose levels (six paticipants). Every 4 weeks, all participants will undergo three consecutive measurement days of four ecological momentary assessments each day ('bursts') to sample sleep determinants during wake. Participants will also continuously wear temperature loggers (iButtons) during the bursts. Body weight will be captured before and after the bursts in the laboratory. The bursts will be separated by two at-home electroencephalogram recordings each night. Circadian phase and amplitude will be estimated during the bursts from hair follicles, and habitual melatonin onset will be derived through saliva sampling. Environmental parameters (bedroom temperature, humidity, and air pressure) will be recorded continuously.

HBMIRT: A SAS macro for estimating uni- and multidimensional 1- and 2-parameter item response models in small (and large!) samples.

Item response theory (IRT) has evolved as a standard psychometric approach in recent years, in particular for test construction based on dichotomous (i.e., true/false) items. Unfortunately, large samples are typically needed for item refinement in unidimensional models and even more so in the multidimensional case. However, Bayesian IRT approaches with hierarchical priors have recently been shown to be promising for estimating even complex models in small samples. Still, it may be challenging for applied researchers to set up such IRT models in general purpose or specialized statistical computer programs. Therefore, we developed a user-friendly tool - a SAS macro called HBMIRT - that allows to estimate uni- and multidimensional IRT models with dichotomous items. We explain the capabilities and features of the macro and demonstrate the particular advantages of the implemented hierarchical priors in rather small samples over weakly informative priors and traditional maximum likelihood estimation with the help of a simulation study. The macro can also be used with the online version of SAS OnDemand for Academics that is freely accessible for academic researchers.

Modeling dynamic personality theories in a continuous-time framework: An illustration.

OBJECTIVE: Personality psychology has traditionally focused on stable between-person differences. Yet, recent theoretical developments and empirical insights have led to a new conceptualization of personality as a dynamic system (e.g., Cybernetic Big Five Theory). Such dynamic systems comprise several components that need to be conceptually distinguished and mapped to a statistical model for estimation. METHOD: In the current work, we illustrate how common components from these new dynamic personality theories may be implemented in a continuous time-modeling framework. RESULTS: As an empirical example, we reanalyze experience sampling data with N = 180 persons (with on average T = 40 [SD = 8] measurement occasions) to investigate four different effects between momentary happiness, momentary extraverted behavior, and the perception of a situation as social: (1) between-person effects, (2) contemporaneous effects, (3) autoregressive effects, and (4) cross-lagged effects. CONCLUSION: We highlight that these four effects must not necessarily point in the same direction, which is in line with assumptions from dynamic personality theories.

Comparing group means with the total mean in random samples, surveys, and large-scale assessments: A tutorial and software illustration.

In many disciplines of the social sciences, comparisons between a group mean and the total mean is a common but also challenging task. As one solution to this statistical testing problem, we propose using linear regression with weighted effect coding. For random samples, this procedure is straightforward and easy to implement by means of standard statistical software. However, for complex or clustered samples with imputed or weighted data, which are common in survey analyses, there is a lack of easy-to-use software solutions. In this paper, we discuss scenarios that are commonly encountered in the social sciences such as heterogeneous variances, weighted samples, and clustered samples, and we describe how group means can be compared to the total mean in these situations. We introduce the R package eatRep, which is a front end that makes the presented methods easily accessible for researchers. Two empirical examples, one using survey data (MIDUS 1) and the other using large-scale assessment data (PISA 2015), are given for illustration. Annotated R code to run group to total mean comparisons is provided.

A longitudinal investigation of bidirectional and time-dependent interrelationships between testosterone and training motivation in an elite rugby environment.

In sport, testosterone has been positioned as a substrate for motivation with both directional and time dependencies. However, evidence is scarce when considering the complexities of competitive sport and no work has explicitly modeled these dependencies. To address these gaps, we investigated the bidirectional and time-dependent interrelationships between testosterone and training motivation in an elite rugby environment. Thirty-six male athletes were monitored across training weeks before and after eight international rugby matches. Pre-breakfast measures of salivary testosterone and training motivation (1-10 rating) were taken on training, competition, and recovery days (up to 40 tests). Using a continuous-time (CT) model, within-person estimates of autoregressive effects (persistence) and cross-lagged effects (relationships) were derived. A stronger, more persistent temporal association was identified for testosterone than for motivation. Cross-lagged effects verified that training motivation was positively related to testosterone at latter time points (p < 0.001). Discrete-time analyses revealed a non-linear association; increasing in strength from a zero-time lag to peak after 2.83 days (standardized effect = 0.25), before dissipation over longer lagged intervals. The testosterone relationship with ensuing training motivation was also positive, but non-significant. Match effects also appeared (p < 0.001) with a predicted decline in training motivation, but a rise in testosterone, at match onset. In summary, a positive association emerged between within-person fluctuations in self-appraised motivation to train and testosterone concentration in an elite rugby environment. The lagged, non-linear nature of this relationship and match predictions on both outcomes support, and extend, theoretical models linking testosterone and competitive behaviors.

Institutional strategies related to test-taking behavior in low stakes assessment.

Low stakes assessment without grading the performance of students in educational systems has received increasing attention in recent years. It is used in formative assessments to guide the learning process as well as in large-scales assessments to monitor educational programs. Yet, such assessments suffer from high variation in students' test-taking effort. We aimed to identify institutional strategies related to serious test-taking behavior in low stakes assessment to provide medical schools with practical recommendations on how test-taking effort might be increased. First, we identified strategies that were already used by medical schools to increase the serious test-taking behavior on the low stakes Berlin Progress Test (BPT). Strategies which could be assigned to self-determination theory of Ryan and Deci were chosen for analysis. We conducted the study at nine medical schools in Germany and Austria with a total of 108,140 observations in an established low stakes assessment. A generalized linear-mixed effects model was used to assess the association between institutional strategies and the odds that students will take the BPT seriously. Overall, two institutional strategies were found to be positively related to more serious test-taking behavior: discussing low test performance with the mentor and consequences for not participating. Giving choice was negatively related to more serious test-taking behavior. At medical schools that presented the BPT as evaluation, this effect was larger in comparison to medical schools that presented the BPT as assessment.

How sure can we be that a student really failed? On the measurement precision of individual pass-fail decisions from the perspective of Item Response Theory.

BACKGROUND: In high-stakes assessments in medical education, the decision to let a particular participant pass or fail has far-reaching consequences. Reliability coefficients are usually used to support the trustworthiness of assessments and their accompanying decisions. However, coefficients such as Cronbach's Alpha do not indicate the precision with which an individual's performance was measured. OBJECTIVE: Since estimates of precision need to be aligned with the level on which inferences are made, we illustrate how to adequately report the precision of pass-fail decisions for single individuals. METHOD: We show how to calculate the precision of individual pass-fail decisions using Item Response Theory and illustrate that approach using a real exam. In total, 70 students sat this exam (110 items). Reliability coefficients were above recommendations for high stakes test (> 0.80). At the same time, pass-fail decisions around the cut score were expected to show low accuracy. CONCLUSIONS: Our results illustrate that the most important decisions-i.e. those based on scores near the pass-fail cut-score-are often ambiguous, and that reporting a traditional reliability coefficient is not an adequate description of the uncertainty encountered on an individual level.

Why assessment in medical education needs a solid foundation in modern test theory.

Despite the frequent use of state-of-the-art psychometric models in the field of medical education, there is a growing body of literature that questions their usefulness in the assessment of medical competence. Essentially, a number of authors raised doubt about the appropriateness of psychometric models as a guiding framework to secure and refine current approaches to the assessment of medical competence. In addition, an intriguing phenomenon known as case specificity is specific to the controversy on the use of psychometric models for the assessment of medical competence. Broadly speaking, case specificity is the finding of instability of performances across clinical cases, tasks, or problems. As stability of performances is, generally speaking, a central assumption in psychometric models, case specificity may limit their applicability. This has probably fueled critiques of the field of psychometrics with a substantial amount of potential empirical evidence. This article aimed to explain the fundamental ideas employed in psychometric theory, and how they might be problematic in the context of assessing medical competence. We further aimed to show why and how some critiques do not hold for the field of psychometrics as a whole, but rather only for specific psychometric approaches. Hence, we highlight approaches that, from our perspective, seem to offer promising possibilities when applied in the assessment of medical competence. In conclusion, we advocate for a more differentiated view on psychometric models and their usage.

A Novel Variant in the HINT1 Gene in a Girl with Autosomal Recessive Axonal Neuropathy with Neuromyotonia: Thorough Neurological Examination Gives the Clue.

We report a girl with autosomal recessive axonal neuropathy with neuromyotonia (ARAN-NM) who presented with asymmetric gait impairment, foot drop, and action myotonia on fast handgrip. Electrophysiological studies showed symmetrical axonal motor greater than sensory neuropathy, and neuromyotonic discharges on needle electromyography. ARAN-NM was confirmed by molecular genetic testing, which revealed a novel homozygous missense variant c.100G > A [p.(Glu34Lys)] in HINT1. This case shows that the diagnosis of ARAN-NM, as a new entity, has to be considered in the differential diagnosis of polyneuropathy in combination with neuromyotonia/action myotonia in children, even with asymmetric clinical presentation.

The role of environmental and individual characteristics in the development of student achievement: a comparison between a traditional and a problem-based-learning curriculum.

In medical education, the effect of the educational environment on student achievement has primarily been investigated in comparisons between traditional and problem-based learning (PBL) curricula. As many of these studies have reached no clear conclusions on the superiority of the PBL approach, the effect of curricular reform on student performance remains an issue. We employed a theoretical framework that integrates antecedents of student achievement from various psychosocial domains to examine how students interact with their curricular environment. In a longitudinal study with N = 1,646 participants, we assessed students in a traditional and a PBL-centered curriculum. The measures administered included students' perception of the learning environment, self-efficacy beliefs, positive study-related affect, social support, indicators of self-regulated learning, and academic achievement assessed through progress tests. We compared the relations between these characteristics in the two curricular environments. The results are two-fold. First, substantial relations of various psychosocial domains and their associations with achievement were identified. Second, our analyses indicated that there are no substantial differences between traditional and PBL-based curricula concerning the relational structure of psychosocial variables and achievement. Drawing definite conclusions on the role of curricular-level interventions in the development of student's academic achievement is constrained by the quasi-experimental design as wells as the selection of variables included. However, in the specific context described here, our results may still support the view of student activity as the key ingredient in the acquisition of achievement and performance.

Spasticity treatment with onabotulinumtoxin A: data from a prospective German real-life patient registry.

This study aimed at providing real-life baseline, injection and outcome data for the treatment of various forms of spasticity with onabotulinumtoxin A in Germany. Prospective data were collected in an open multicenter patient registry from 2005 until 2010, encompassing the experience of ten specialized German centers in the treatment of spasticity using onabotulinumtoxin A in 508 patients with a total of 2005 treatment sessions. Disease entities comprised spasticity following stroke (both ischemic and hemorrhagic), traumatic brain injury, multiple sclerosis, cerebral palsy, and anoxia. Sustained improvement was observed in a variety of outcome parameters including goal attainment and motor performance scores for up to five repeated injection sessions. No significant differences between disease entities or between upper and lower limb treatment were observed with regard to efficacy and safety following onabotulinumtoxin A treatment. Minor to moderate side effects were reported in <1 % of the study population. We conclude that repetitive treatment of focal and multifocal spasticity with onabotulinumtoxin A provides a safe and efficacious therapeutic strategy for patients with different disease entities of the central nervous system.

Training-related improvements in mental well-being through reduction in negative interpretation bias: A randomized trial of online socio-emotional dyadic and mindfulness interventions.

BACKGROUND: Effects of online contemplative practices, especially partner-based practices, on psychological well-being remain mixed, with sparse understanding of potential affective-cognitive mechanisms. The study aimed to assess the efficacy of two online contemplative interventions in improving depression, anxiety, emotion regulation (ER), and resilience, and to evaluate the mechanistic role of negative attention and interpretation biases. METHODS: Employing a randomized controlled design (n = 285), we compared the efficacy of 10-week online mindfulness-based and partner-based socio-emotional dyadic interventions, both supported by weekly coaching sessions. Mental health aspects were assessed using validated self-report measures and negative biases using the mouse-contingent Scrambled Sentences Task. RESULTS: Both interventions, compared to waitlist control, led to reductions in depression and ER difficulties, while trait anxiety decreased only after mindfulness training. Increases in multidimensional resilience were observed only after socio-emotional training and in stress recovery only after mindfulness-based training, both compared to waitlist control. Socio-emotional training led to significant reductions in negative interpretation bias and this mediated reductions in depression and trait anxiety. Neither training led to reductions in state anxiety or negative attention bias. LIMITATIONS: The subclinical nature and overrepresentation of females in the sample limits generalizability. CONCLUSIONS: Findings indicate that online mindfulness-based and socio-emotional partner-based interventions, supported by online coaching sessions, can reduce depression and ER difficulties. Though mindfulness practice reduced trait anxiety and enhanced stress recovery, socio-emotional training increased multidimensional resilience. Socio-emotional training reduced negative interpretation bias, which emerged as an intervention-specific mechanism. These findings highlight the potential benefits of online contemplative intervention approaches for psychological well-being.

Reducing Loneliness through the Power of Practicing Together: A Randomized Controlled Trial of Online Dyadic Socio-Emotional vs. Mindfulness-Based Training.

Loneliness has become a pressing topic, especially among young adults and during the COVID-19 pandemic. In a randomized controlled trial with 253 healthy adults, we evaluated the differential efficacy of two 10-week app-delivered mental training programs: one based on classic mindfulness and one on an innovative partner-based socio-emotional practice (Affect Dyad). We show that the partner-based training resulted in greater reductions in loneliness than the mindfulness-based training. This effect was shown on three measures of loneliness: general loneliness assessed with the 20-item UCLA Loneliness Scale, state loneliness queried over an 8-day ecological momentary assessment in participants' daily lives, and loneliness ratings required before and after daily practice. Our study provides evidence for the higher efficacy of a mental training approach based on a 12 min practice conducted with a partner in reducing loneliness and provides a novel, scalable online approach to reduce the increasing problem of loneliness in society.

An evaluation of the performance of stopping rules in AI-aided screening for psychological meta-analytical research.

Several AI-aided screening tools have emerged to tackle the ever-expanding body of literature. These tools employ active learning, where algorithms sort abstracts based on human feedback. However, researchers using these tools face a crucial dilemma: When should they stop screening without knowing the proportion of relevant studies? Although numerous stopping rules have been proposed to guide users in this decision, they have yet to undergo comprehensive evaluation. In this study, we evaluated the performance of three stopping rules: the knee method, a data-driven heuristic, and a prevalence estimation technique. We measured performance via sensitivity, specificity, and screening cost and explored the influence of the prevalence of relevant studies and the choice of the learning algorithm. We curated a dataset of abstract collections from meta-analyses across five psychological research domains. Our findings revealed performance differences between stopping rules regarding all performance measures and variations in the performance of stopping rules across different prevalence ratios. Moreover, despite the relatively minor impact of the learning algorithm, we found that specific combinations of stopping rules and learning algorithms were most effective for certain prevalence ratios of relevant abstracts. Based on these results, we derived practical recommendations for users of AI-aided screening tools. Furthermore, we discuss possible implications and offer suggestions for future research.

Coping as a resource to allow for psychosocial adjustment in fatal disease: results from patients with amyotrophic lateral sclerosis.

Background: Amyotrophic lateral sclerosis (ALS) is a fatal disorder, which imposes a severe emotional burden on patients. Appropriate coping mechanisms may alleviate this burden and facilitate wellbeing, with social support known to be a successful coping strategy. This observational study aimed to determine the interplay of general coping traits of hope for success and fear of failure, coping behavior of social activity, and patients' wellbeing. Methods: In this cross-sectional study, patients with ALS from a clinical-epidemiological registry in Southwestern Germany were interviewed regarding coping traits (achievement-motivated behavior: hope for success and fear of failure), coping behavior of social activity, and psychosocial adjustment, determined using measures of depressiveness, anxiety [both measured by Hospital Anxiety and Depression Scale (HADS)], and quality of life [Anamnestic Comparative Self-Assessment (ACSA)]. Demographics, clinical [ALS Functional Rating Scale revised version (ALSFRS-R)], and survival data were recorded. Results: A total of 868 patients [60.70% male patients, mean age: 64.70 (±10.83) years, mean ALSFRS-R: 37.36 ± 7.07] were interviewed. Anxiety in patients was found to be associated with a high fear of failure. In contrast, a generally positive attitude in patients exemplified in high hopes for success was associated with better wellbeing. Finally, coping behavior of social activity explained up to 65% of the variance of depressiveness among the patients with ALS. Conclusion: In this study, we present evidence that the wellbeing of patients with ALS is not an immediate fatalistic consequence of physical degradation but rather determined by coping traits and behavior, which may be trained to substantially increase the wellbeing of patients with ALS.

On the role of biomedical knowledge in the acquisition of clinical knowledge.

CONTEXT: Basic science teaching in undergraduate medical education faces several challenges. One prominent discussion is focused on the relevance of biomedical knowledge to the development and integration of clinical knowledge. Although the value of basic science knowledge is generally emphasised, theoretical positions on the relative role of this knowledge and the optimal approach to its instruction differ. The present paper addresses whether and to what extent biomedical knowledge is related to the development of clinical knowledge. METHODS: We analysed repeated-measures data for performances on basic science and clinical knowledge assessments. A sample of 598 medical students on a traditional curriculum participated in the study. The entire study covered a developmental phase of 2 years of medical education. Structural equation modelling was used to analyse the temporal relationship between biomedical knowledge and the acquisition of clinical knowledge. RESULTS: At the point at which formal basic science education ends and clinical training begins, students show the highest levels of biomedical knowledge. The present data suggest a decline in basic science knowledge that is complemented by a growth in clinical knowledge. Statistical comparison of several structural equation models revealed that the model to best explain the data specified unidirectional relationships between earlier states of biomedical knowledge and subsequent changes in clinical knowledge. However, the parameter estimates indicate that this association is negative. DISCUSSION: Our analysis suggests a negative relationship between earlier levels of basic science knowledge and subsequent gains in clinical knowledge. We discuss the limitations of the present study, such as the educational context in which it was conducted and its non-experimental nature. Although the present results do not necessarily contradict the relevance of basic sciences, we speculate on mechanisms that might be related to our findings. We conclude that our results hint at possibly critical issues in basic science education that have been rarely addressed thus far.

Heterogeneous Mental Health Responses to the COVID-19 Pandemic in Germany: An Examination of Long-Term Trajectories, Risk Factors, and Vulnerable Groups.

Abundant studies have examined mental health in the early periods of the COVID-19 pandemic. However, empirical work examining the mental health impact of the pandemic's subsequent phases remains limited. In the present study, we investigated how mental vulnerability and resilience evolved over the various phases of the pandemic in 2020 and 2021 in Germany. Data were collected (n = 3522) across seven measurement occasions using validated and self-generated measures of vulnerability and resilience. We found evidence for an immediate increase in vulnerability during the first lockdown in Germany, a trend towards recovery when lockdown measures were eased, and an increase in vulnerability with each passing month of the second lockdown. Four different latent trajectories of resilience-vulnerability emerged, with the majority of participants displaying a rather resilient trajectory, but nearly 30% of the sample fell into the more vulnerable groups. Females, younger individuals, those with a history of psychiatric disorders, lower income groups, and those with high trait vulnerability and low trait social belonging were more likely to exhibit trajectories associated with poorer mental well-being. Our findings indicate that resilience-vulnerability responses in Germany during the COVID-19 pandemic may have been more complex than previously thought, identifying risk groups that could benefit from greater support.

Day-to-day coordination of the stress and reproductive axes: A continuous-time analysis of within-person testosterone and cortisol relationships in athletic and healthy men.

Day-to-day coordination of the stress (i.e., hypothalamic-pituitary-adrenal [HPA]) and reproductive (i.e., hypothalamic-pituitary-gonadal [HPG]) axes is central to allostatic regulation, reproductive success, and survival. Reports of positive, within-person testosterone and cortisol relationships (or coupling) suggest cross-talk of a facilitative nature, but longitudinal evidence is scarce and has methodological and analytical limitations. To address this, we used a continuous-time (CT) model to investigate day-to-day, within-person coupling of testosterone and cortisol in two male cohorts. Salivary testosterone and cortisol fluctuations were monitored in 35 athletic men across two international tournaments (M = 19.3 tests) and in 41 healthy men during normal daily living (M = 27.9 tests). Bayesian CT analysis revealed a diminishing effect of each hormone on itself as time-interval length or lag increased. In both groups, cortisol had a negative lagged effect on testosterone that persisted for around three days. The cortisol effect on testosterone peaked after 0.71 and 0.51 days in athletic (standardized estimate = -0.13) and healthy men (standardized estimate = -0.11), respectively. Further estimates of non-lagged, contemporaneous correlations revealed positive testosterone and cortisol relationships (athlete r = 0.04, healthy r = 0.46). In summary, complex within-person HPA and HPG interplay emerged in two independent male cohorts. Specifically, a rising cortisol concentration was linked to a fall in testosterone concentration at later time points, but concurrently these hormones tended to rise and fall together. Our results suggest that inhibitory and facilitatory hormonal actions coexist on varying timescales, thereby expanding knowledge of HPG and HPA cross-talk in everyday life.