Risk of epilepsy after traumatic brain injury: a nationwide Norwegian matched cohort study.

Background: Post-traumatic epilepsy (PTE) is a well-known complication of traumatic brain injury (TBI). Although several risk factors have been identified, prediction of PTE is difficult. Changing demographics and advances in TBI treatment may affect the risk of PTE. Our aim was to provide an up-to-date estimate of the incidence of PTE by linking multiple nationwide registers. Methods: Patients with TBI admitted to hospital 2015-2018 were identified in the Norwegian Trauma Registry and matched to trauma-free controls on sex and birth year according to a matched cohort design. They were followed up for epilepsy in nationwide registers 2015-2020. Cumulative incidence of epilepsy in TBI patients and controls was estimated taking competing risks into account. Analyses stratified by the Abbreviated Injury Scale (AIS) severity score, Glasgow Coma Scale score and age were conducted for the TBI group. Occurrence of PTE in different injury types was visualized using UpSet plots. Results: In total, 8,660 patients and 84,024 controls were included in the study. Of the patients, 3,029 (35%) had moderate to severe TBI. The cumulative incidence of epilepsy in the TBI group was 3.1% (95% Confidence Interval [CI] 2.8-3.5%) after 2 years and 4.0% (3.6-4.5%) after 5 years. Corresponding cumulative incidences in the control group were 0.2% (95% CI 0.2-0.3%) and 0.5% (0.5-0.6%). The highest incidence was observed in patients with severe TBI according to AIS (11.8% [95% CI 9.7-14.4%] after 2 years and 13.2% [10.8-16.0%] after 5 years) and in patients >40 years of age. Conclusion: Patients with TBI have significantly higher risk of developing epilepsy compared to population controls. However, PTE incidence following moderate-severe TBI was notably lower than what has been reported in several previously published studies.

Gap Junctions May Have A Computational Function In The Cerebellum: A Hypothesis.

In the cerebellum, granule cells make parallel fibre contact on (and excite) Golgi cells and Golgi cells inhibit granule cells, forming an open feedback loop. Parallel fibres excite Golgi cells synaptically, each making a single contact. Golgi cells inhibit granule cells in a structure called a glomerulus almost exclusively by GABA spillover acting through extrasynaptic GABAA receptors. Golgi cells are connected dendritically by gap junctions. It has long been suspected that feedback contributes to homeostatic regulation of parallel fibre signals activity, causing the fraction of the population that are active to be maintained at a low level. We present a detailed neurophysiological and computationally-rendered model of functionally grouped Golgi cells which can infer the density of parallel fibre signals activity and convert it into proportional modulation of inhibition of granule cells. The conversion is unlearned and not actively computed; rather, output is simply the computational effect of cell morphology and network architecture. Unexpectedly, the conversion becomes more precise at low density, suggesting that self-regulation is attracted to sparse code, because it is stable. A computational function of gap junctions may not be confined to the cerebellum.

The Effect of Nucleo-Olivary Stimulation on Climbing Fiber EPSPs in Purkinje Cells.

Climbing fibers, connecting the inferior olive and Purkinje cells, form the nervous system's strongest neural connection. These fibers activate after critical events like motor errors or anticipation of rewards, leading to bursts of excitatory postsynaptic potentials (EPSPs) in Purkinje cells. The number of EPSPs is a crucial variable when the brain is learning a new motor skill. Yet, we do not know what determines the number of EPSPs. Here, we measured the effect of nucleo-olivary stimulation on periorbital elicited climbing fiber responses through in-vivo intracellular Purkinje cell recordings in decerebrated ferrets. The results show that while nucleo-olivary stimulation decreased the probability of a response occurring at all, it did not reduce the number of EPSPs. The results suggest that nucleo-olivary stimulation does not influence the number of EPSPs in climbing fiber bursts.

The ability to maintain rhythm is predictive of ADHD diagnosis and profile.

Attention deficit hyperactivity disorder (ADHD) is the most prevalent neuropsychiatric disorder in the world. Currently, the diagnosis is based mainly on interviews, resulting in uncertainties in the clinical assessment. While some neuropsychological tests are used, their specificity and selectivity are low, and more reliable biomarkers are desirable. Previous research indicates that ADHD is associated with morphological changes in the cerebellum, which is essential for motor ability and timing. Here, we compared 29 children diagnosed with ADHD to 96 age-matched controls on prism adaptation, eyeblink conditioning, and timed motor performance in a finger tapping task. Prism adaptation and timing precision in the finger tapping task, but not performance on eyeblink conditioning, differed between the ADHD and control groups, as well as between children with and without Deficits in Attention, Motor control, and Perception (DAMP) - a more severe form of ADHD. The results suggest finger tapping can be used as a cheap, objective, and unbiased biomarker to complement current diagnostic procedures.

Predicting COVID-19 Incidence Using Wastewater Surveillance Data, Denmark, October 2021-June 2022.

Analysis of wastewater is used in many settings for surveillance of SARS-CoV-2, but it remains unclear how well wastewater testing results reflect incidence. Denmark has had an extensive wastewater analysis system that conducts 3 weekly tests in ≈200 sites and has 85% population coverage; the country also offers free SARS-CoV-2 PCR tests to all residents. Using time series analysis for modeling, we found that wastewater data, combined with information on circulating variants and the number of human tests performed, closely fitted the incidence curve of persons testing positive. The results were consistent at a regional level and among a subpopulation of frequently tested healthcare personnel. We used wastewater analysis data to estimate incidence after testing was reduced to a minimum after March 2022. These results imply that data from a large-scale wastewater surveillance system can serve as a good proxy for COVID-19 incidence and for epidemic control.

Neurocognitive and cerebellar function in ADHD, autism and spinocerebellar ataxia.

The cerebellum plays a major role in balance, motor control and sensorimotor integration, but also in cognition, language, and emotional regulation. Several neuropsychiatric disorders such as attention deficit-hyperactivity disorder (ADHD), autism spectrum disorder (ASD), as well as neurological diseases such as spinocerebellar ataxia type 3 (SCA3) are associated with differences in cerebellar function. Morphological abnormalities in different cerebellar subregions produce distinct behavioral symptoms related to the functional disruption of specific cerebro-cerebellar circuits. The specific contribution of the cerebellum to typical development may therefore involve the optimization of the structure and function of cerebro-cerebellar circuits underlying skill acquisition in multiple domains. Here, we review cerebellar structural and functional differences between healthy and patients with ADHD, ASD, and SCA3, and explore how disruption of cerebellar networks affects the neurocognitive functions in these conditions. We discuss how cerebellar computations contribute to performance on cognitive and motor tasks and how cerebellar signals are interfaced with signals from other brain regions during normal and dysfunctional behavior. We conclude that the cerebellum plays a role in many cognitive functions. Still, more clinical studies with the support of neuroimaging are needed to clarify the cerebellum's role in normal and dysfunctional behavior and cognitive functioning.

Effects of working memory load and CS-US intervals on delay eyeblink conditioning.

Eyeblink conditioning is used in many species to study motor learning and make inferences about cerebellar function. However, the discrepancies in performance between humans and other species combined with evidence that volition and awareness can modulate learning suggest that eyeblink conditioning is not merely a passive form of learning that relies on only the cerebellum. Here we explored two ways to reduce the influence of volition and awareness on eyeblink conditioning: (1) using a short interstimulus interval, and (2) having participants do working memory tasks during the conditioning. Our results show that participants trained with short interstimulus intervals (150 ms and 250 ms) produce very few conditioned responses after 100 trials. Participants trained with a longer interstimulus interval (500 ms) who simultaneously did working memory tasks produced fewer conditioned responses than participants who watched a movie during the training. Our results suggest that having participants perform working memory tasks during eyeblink conditioning can be a viable strategy for studying cerebellar learning that is absent of influences from awareness and volition. This could enhance the comparability of the results obtained in human studies with those in animal models.

An Indirect Comparison of Basal Insulin Plus Once-Weekly Semaglutide and Fully Optimised Basal-Bolus Insulin in Type 2 Diabetes.

INTRODUCTION: To date, there have been few head-to-head comparisons between semaglutide once-weekly (OW) and short-acting meal-time insulin in participants with type 2 diabetes (T2D) treated with basal insulin and requiring treatment intensification. This indirect comparison evaluated the effects of these regimens on glycated haemoglobin (HbA1c), body weight, hypoglycaemia, and other clinically relevant outcomes. METHODS: A post-hoc, unanchored, individual participant data meta-analysis was conducted on the basis of data from single treatment arms in the SUSTAIN 5 and DUAL 7 trials. Semaglutide 0.5 mg OW and 1.0 mg OW plus basal insulin were compared with an optimised (treat-to-target) basal-bolus regimen of insulin glargine and insulin aspart over 26 weeks, using regression adjustment to account for baseline differences between the trials. RESULTS: Over 26 weeks, semaglutide 1.0 mg OW plus basal insulin reduced mean HbA1c by significantly more than the basal-bolus regimen (treatment difference: - 0.36%; p = 0.003), while semaglutide 0.5 mg OW plus basal insulin was comparable with basal-bolus insulin (treatment difference: 0.08%, p = 0.53). Both doses of semaglutide were associated with significant weight loss relative to insulin intensification (treatment differences: 6.8-9.4 kg; p < 0.001). At both doses, semaglutide intensification required less basal insulin per day than bolus intensification, and more participants on semaglutide met HbA1c targets of < 7.0% and ≤ 6.5% without hypoglycaemia or weight gain (odds ratio [OR] for < 7.0%, 21.9; OR for ≤ 6.5%, 16.2; both p < 0.001). CONCLUSIONS: In T2D uncontrolled by basal insulin, intensification with semaglutide 1.0 mg OW was associated with better glycaemic control, weight loss, and reduced hypoglycaemia versus a basal-bolus regimen, while limiting the treatment burden associated with frequent injections. Clinicians could consider treatment intensification with semaglutide when T2D is uncontrolled by basal insulin, especially when weight management is a priority. Effective glycaemic control coupled with weight management can alleviate the burden of diabetes-associated complications.

Quantitative properties of the creation and activation of a cell-intrinsic duration-encoding engram.

The engram encoding the interval between the conditional stimulus (CS) and the unconditional stimulus (US) in eyeblink conditioning resides within a small population of cerebellar Purkinje cells. CSs activate this engram to produce a pause in the spontaneous firing rate of the cell, which times the CS-conditional blink. We developed a Bayesian algorithm that finds pause onsets and offsets in the records from individual CS-alone trials. We find that the pause consists of a single unusually long interspike interval. Its onset and offset latencies and their trial-to-trial variability are proportional to the CS-US interval. The coefficient of variation (CoV = σ/µ) are comparable to the CoVs for the conditional eye blink. The average trial-to-trial correlation between the onset latencies and the offset latencies is close to 0, implying that the onsets and offsets are mediated by two stochastically independent readings of the engram. The onset of the pause is step-like; there is no decline in firing rate between the onset of the CS and the onset of the pause. A single presynaptic spike volley suffices to trigger the reading of the engram; and the pause parameters are unaffected by subsequent volleys. The Fano factors for trial-to-trial variations in the distribution of interspike intervals within the intertrial intervals indicate pronounced non-stationarity in the endogenous spontaneous spiking rate, on which the CS-triggered firing pause supervenes. These properties of the spontaneous firing and of the engram read out may prove useful in finding the cell-intrinsic, molecular-level structure that encodes the CS-US interval.

Fast tipping point sensitivity analyses in clinical trials with missing continuous outcomes under multiple imputation.

When dealing with missing data in clinical trials, it is often convenient to work under simplifying assumptions, such as missing at random (MAR), and follow up with sensitivity analyses to address unverifiable missing data assumptions. One such sensitivity analysis, routinely requested by regulatory agencies, is the so-called tipping point analysis, in which the treatment effect is re-evaluated after adding a successively more extreme shift parameter to the predicted values among subjects with missing data. If the shift parameter needed to overturn the conclusion is so extreme that it is considered clinically implausible, then this indicates robustness to missing data assumptions. Tipping point analyses are frequently used in the context of continuous outcome data under multiple imputation. While simple to implement, computation can be cumbersome in the two-way setting where both comparator and active arms are shifted, essentially requiring the evaluation of a two-dimensional grid of models. We describe a computationally efficient approach to performing two-way tipping point analysis in the setting of continuous outcome data with multiple imputation. We show how geometric properties can lead to further simplification when exploring the impact of missing data. Lastly, we propose a novel extension to a multi-way setting which yields simple and general sufficient conditions for robustness to missing data assumptions.

No evidence of conditioning of pupillary constriction despite overtraining.

Eyeblink conditioning is the most popular paradigm for studying classical conditioning in humans. But the fact that eyelids are under voluntary control means it is ultimately impossible to ascertain whether a blink response is 'conditioned' or a timed 'voluntary' blink response. In contrast, the pupillary response is an autonomic response, not under voluntary control. By conditioning the pupillary response, one might avoid potential volition-related confounds. Several attempts have been made to condition the pupillary constriction and dilation responses, with the earliest published attempts dating back to the beginning of the 20th century. While a few early studies reported successful conditioning of pupillary constriction, later studies have failed to replicate this. The apparatus for recording pupil size, the type of stimuli used and the interval between the stimuli has varied in previous attempts-which may explain the inconsistent results. Moreover, measuring the pupil size used to be cumbersome compared with today when an eyetracker can continuously measure pupil size non-invasively. Here we used an eyetracker to test whether it is possible to condition the autonomic pupillary constriction response by pairing a tone (CS) and a light (US) with a 1s CS-US interval. Unlike in previous studies, our subjects went through multiple training sessions to ensure that any potential lack of conditioning would not be due to too little training. A total of 10 participants went through 2-12 conditioning sessions, each lasting approximately 20 min. One training session consisted of 75 paired, tone + light, trials and 25 randomly interspersed CS alone trials. The eyetracker (Tobii Pro Nano), continuously measured participants' pupil size. To test statistically whether conditioning of the pupillary response occurred we compared the pupil size after the tone on the first session and the last session. The results showed a complete lack of evidence of conditioning. Though the pupil size varied slightly between participants, the size did not change as a result of the training-irrespective of the number of training sessions. The data replicate previous findings that pupillary constriction does not show conditioning. We conclude that it is not possible to condition pupillary constriction-at least not by pairing a tone and a light. One hypothesis is that when pupillary conditioning has been observed in previous studies, it has been mediated by conditioning of an emotional response.

Continuous Glucose Monitoring Sensor Glucose Levels and Insulin Pump Infusion Set Wear-Time During Treatment with Fast-Acting Insulin Aspart: A Post Hoc Analysis of Onset 5.

Background: In the onset 5 trial, fast-acting insulin aspart (faster aspart) was noninferior to insulin aspart (IAsp) for change from baseline glycated hemoglobin at 16 weeks, when used in continuous subcutaneous insulin infusion by participants with type 1 diabetes. The aim of this post hoc analysis was to investigate whether infusion set wear-time was associated with changes in sensor glucose, measured using continuous glucose monitoring (CGM). Materials and Methods: This was a post hoc analysis of onset 5 data. Mean infusion set wear-time and duration of CGM-wearing period were assessed. Mean CGM sensor glucose 24 h before and 24 h after were used to calculate the before-after difference (CGM sensor glucose drift). Results: Mean infusion set wear-time was 2.9 and 3.0 days in the faster aspart and IAsp arms, respectively. At 16 weeks, the average duration of the CGM wearing period was 13.7 and 13.8 days, respectively. Mean CGM sensor glucose before versus after an infusion set change, at week 16, was 10.14 versus 9.39 mmol/L with faster aspart and 9.48 versus 9.47 mmol/L with IAsp. The estimated treatment difference in CGM sensor glucose drift at 16 weeks for faster aspart versus IAsp was +0.72 mmol/L (95% confidence interval: 0.48-0.96, P < 0.001). Conclusions: Mean infusion set wear-time and duration of CGM-wearing period were similar for faster aspart and IAsp. A significantly greater upward drift in CGM sensor glucose values measured during an infusion set wearing period was observed with faster aspart versus IAsp. Clinical trial registration: NCT02825251.

Waking Up in Pain: a prospective unselected cohort study of pain in 3702 patients immediately after surgery in the Danish Realm.

BACKGROUND: Acute and persistent pain after surgery is well described. However, no large-scale studies on immediate postoperative pain in the operating room (OR) exist, hindering potential areas of research to improve clinical outcomes. Thus, we aimed to describe the occurrence and severity of immediate postoperative pain in a large, unselected cohort. METHODS: This was a prospective cohort study, encompassing all procedures in 31 public hospitals in the Danish Realm, during a 5-day period including the weekend. Data on procedures and anesthesia were collected and the main outcome was occurrence of moderate or severe pain in the OR. Secondary outcomes included pain, sedation and nausea in the OR or during the first 15 min in the postanesthesia care unit (PACU) including relevant risk factors. Descriptive and logistic regression statistics were used. RESULTS: A total of 3675 procedures were included for analysis (87% inclusion rate). Moderate or severe pain occurred in 7.4% (95% CI 6.5% to 8.3%) of cases in the OR immediately after awakening, rising to 20.2% in the OR and/or PACU. Large intraprocedure and interprocedure variations occurred (0.0%-37.5%), and in 20% of cases with epidural-general anesthesia patients experienced moderate or severe pain. Independent risk factors were female sex, younger age, preoperative pain, daily opioid use and major surgical procedures. CONCLUSION: Moderate or severe pain in the immediate postoperative phase occurred in 20% of all cases with procedure and anesthesiological technique variations, suggesting a need for identification of relevant procedure-specific risk factors and development of preventive treatments. TRIAL REGISTRATION NUMBER: RoPR ID 43191.

An indirect treatment comparison of the efficacy of semaglutide 1.0 mg versus dulaglutide 3.0 and 4.5 mg.

AIM: To compare the effects of semaglutide 1.0 mg versus dulaglutide 3.0 and 4.5 mg on HbA1c and body weight in patients with type 2 diabetes. MATERIALS AND METHODS: A Bucher indirect comparison was conducted to compare efficacy outcomes of semaglutide 1.0 mg versus dulaglutide 3.0 and 4.5 mg using published results from the SUSTAIN 7 and AWARD-11 trials. Sensitivity analyses using individual patient data from SUSTAIN 7 and aggregate data from AWARD-11 were conducted to explore the impact of adjustment for cross-trial imbalances in baseline characteristics. RESULTS: Semaglutide 1.0 mg significantly reduced HbA1c versus dulaglutide 3.0 mg, with an estimated treatment difference (ETD) of -0.24%-points (95% confidence interval [CI] -0.43, -0.05), with comparable reductions in HbA1c versus dulaglutide 4.5 mg with an ETD of -0.07%-points (95% CI -0.26, 0.12). Semaglutide 1.0 mg significantly reduced body weight versus dulaglutide 3.0 and 4.5 mg with an ETD of -2.65 kg (95% CI -3.57, -1.73) and -1.95 kg (95% CI -2.87, -1.03), respectively. Sensitivity analyses supported the primary analysis findings. CONCLUSIONS: This indirect comparison showed significantly greater reductions in HbA1c with semaglutide 1.0 mg versus dulaglutide 3.0 mg and comparable HbA1c reductions versus dulaglutide 4.5 mg. Semaglutide 1.0 mg significantly reduced body weight versus both dulaglutide 3.0 and 4.5 mg. With several glucagon-like peptide-1 receptor agonists available, information regarding their comparative efficacy can be valuable to clinicians.

Feedback from HTC Vive Sensors Results in Transient Performance Enhancements on a Juggling Task in Virtual Reality.

Virtual reality headsets, such as the HTC Vive, can be used to model objects, forces, and interactions between objects with high perceived realism and accuracy. Moreover, they can accurately track movements of the head and the hands. This combination makes it possible to provide subjects with precise quantitative feedback on their performance while they are learning a motor task. Juggling is a challenging motor task that requires precise coordination of both hands. Professional jugglers throw objects so that the arc peaks just above head height, and they time their throws so that the second ball is thrown when the first ball reaches its peak. Here, we examined whether it is possible to learn to juggle in virtual reality and whether the height and the timing of the throws can be improved by providing immediate feedback derived from the motion sensors. Almost all participants became better at juggling in the ~30 min session: the height and timing of their throws improved and they dropped fewer balls. Feedback on height, but not timing, improved performance, albeit only temporarily.

Weak correlations between cerebellar tests.

Eyeblink conditioning, finger tapping, and prism adaptation are three tasks that have been linked to the cerebellum. Previous research suggests that these tasks recruit distinct but partially overlapping parts of the cerebellum, as well as different extra-cerebellar networks. However, the relationships between the performances on these tasks remain unclear. Here we tested eyeblink conditioning, finger tapping, and prism adaptation in 42 children and 44 adults and estimated the degree of correlation between the performance measures. The results show that performance on all three tasks improves with age in typically developing school-aged children. However, the correlations between the performance measures of the different tasks were consistently weak and without any consistent directions. This reinforces the view that eyeblink conditioning, finger tapping, and prism adaptation rely on distinct mechanisms. Consequently, performance on these tasks cannot be used separately to assess a common cerebellar function or to make general conclusions about cerebellar dysfunction. However, together, these three behavioral tasks have the potential to contribute to a nuanced picture of human cerebellar functions during development.

[Inflammatory spinal arthritis].

Spondyloarthritis (SpA) is an inflammatory arthritis mainly affecting the axial skeleton and large peripheral joints. Age of onset is typically 20-35 years. However, symptoms of SpA is often overlooked or interpreted as common low back pain, postponing an effective treatment. In this review, symptoms of SpA with emphasis on inflammatory pain and clinical findings are summed-up. Furthermore, diagnostic challenges, and treatments are covered.

[Narrative medicine as a new, interdisciplinary field].

This article presents narrative medicine as a new field of medical humanities. Narrative medicine has become influential over the world as well as in Denmark in recent years. Narrative medicine aims to counter the often reductionist way patients are perceived and treated in biomedicine and argues for the importance of seeing and hearing patients in the clinical practice as whole, complex persons. Through close reading of literary narratives about illness the medical students are assumed to become less unemphatic, more attuned to self-care and more tolerant towards ambiguity in the clinic.

Characterizing chromatin landscape from aggregate and single-cell genomic assays using flexible duration modeling.

ATAC-seq has become a leading technology for probing the chromatin landscape of single and aggregated cells. Distilling functional regions from ATAC-seq presents diverse analysis challenges. Methods commonly used to analyze chromatin accessibility datasets are adapted from algorithms designed to process different experimental technologies, disregarding the statistical and biological differences intrinsic to the ATAC-seq technology. Here, we present a Bayesian statistical approach that uses latent space models to better model accessible regions, termed ChromA. ChromA annotates chromatin landscape by integrating information from replicates, producing a consensus de-noised annotation of chromatin accessibility. ChromA can analyze single cell ATAC-seq data, correcting many biases generated by the sparse sampling inherent in single cell technologies. We validate ChromA on multiple technologies and biological systems, including mouse and human immune cells, establishing ChromA as a top performing general platform for mapping the chromatin landscape in different cellular populations from diverse experimental designs.