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The aim of the present study was to examine gender and age-specific effects on subjective daytime sleepiness (as measured by the Epworth Sleepiness Scale), body weight and eating behaviour in patients with central disorders of hypersomnolence. Based on the European Narcolepsy Network database, we compared 1035 patients with narcolepsy type I and 505 patients with other central disorders of hypersomnolence ("narcoleptic borderland"), including narcolepsy type II (N = 308) and idiopathic hypersomnia (N = 174), using logistic regression and general linear models. In the entire study population, the Epworth Sleepiness Scale was higher in women (N = 735, mean age = 30 years, mean Epworth Sleepiness Scale = 16.6 ± SD 3.9) than in men (N = 805, mean age = 32 years, mean Epworth Sleepiness Scale = 15.8 ± SD 4.4). In women with narcolepsy type I (N = 475), both Epworth Sleepiness Scale and body mass index increased in parallel with age. In women of the narcoleptic borderland (N = 260), the Epworth Sleepiness Scale markedly peaked in their early 30s, while body mass index only started to rise at that age. This rise in body mass index following the Epworth Sleepiness Scale peak cannot be explained by sleepiness-induced uncontrolled eating, as self-reported uncontrolled eating was negatively associated with the Epworth Sleepiness Scale in this group. We propose that the narcoleptic borderland harbours a unique cluster of women in their fertile years with an unexplored aetiology requiring further investigation towards tailored interventions., (© 2024 The Author(s). Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

Improved neural understanding of posttraumatic growth (PTG) is required for effective trauma care. PTG is the advantageous psychological change some individuals derive from their struggle to overcome trauma. This comprehensive review critically examined the limited neural PTG research, to identify electrophysiological training targets for future research examining neurofeedback to enhance PTG, and provides novel insights into the emerging neural theory of PTG. PRISMA-ScR (Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews) informed the process. Findings from the studies N=8 (participants N=765) revealed PTG was correlated with left-lateralised alpha frequency power patterns. Specifically, PTG was associated with lower left frontal alpha power, higher left central alpha power, and lower parietal alpha power. Differences between studies may identify different components of PTG-related neural circuitry, or represent variations in PTG and sub-factor strength, mechanistic differences between studies, or the potential confounding presence of posttraumatic stress disorder (PTSD). While lower alpha power has been associated with higher PTSD in existing literature, higher left central alpha power was associated with lower PTSD. Therefore, alpha upregulation neurofeedback delivered over the sensorimotor cortex of the brain, around left central EEG electrode C3, presented the most promising neurofeedback target., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Presence of psychiatric comorbidities is well documented in narcolepsy type-1 (NT1) but there are limited data on patients with 'other central disorders of hypersomnolence' (OCH). This study aimed to investigate frequency of psychiatric comorbidities in patients with NT1 and OCH, and to evaluate their impact on quality of life and sleep as an additive factor in combination with hypersomnolence-related symptoms. This study was conducted within the scope of the international Swiss Primary Hypersomnolence and Narcolepsy Cohort Study (iSPHYNCS), which aims to find new biomarkers in central disorders of hypersomnolence (CDH). Study participants underwent Mini International Neuropsychiatric Interview and completed questionnaires related to quality of life and sleep. Comparative analysis was conducted to investigate group differences, and multivariable regression models were used to reveal the impact of psychiatric comorbidities. Among a total of 90 patients, 26 were diagnosed with NT1 and 64 with OCH. In all, 38 patients showed at least one psychiatric disorder, 27% of NT1 and 48% of OCH, with female dominance (50% in females versus 23% in males, p < 0.02). Major depressive episodes (n = 29) were most common, followed by suicidality (n = 13). Patients with a psychiatric diagnosis were more fatigued (β = 0.70, p < 0.05), apathic (β = -5.41, p < 0.002), had more disturbed sleep (β = 0.55, p < 0.02), worse sleep (β = 1.89, p < 0.001) and general health (β = -12.55, p < 0.02) quality. Comorbid psychiatric disorders are frequent in patients with CDH and worsen the impact of hypersomnolence-related symptoms on daily activities regardless of the type of CDH. Psychiatric comorbidities may create a vicious circle with fatigue and avoidance of physical activities, which aggravates hypersomnolence-related symptoms., (© 2024 The Author(s). Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

The Swiss Primary Hypersomnolence and Narcolepsy Cohort Study (SPHYNCS) is a multicenter research initiative to identify new biomarkers in central disorders of hypersomnolence (CDH). Whereas narcolepsy type 1 (NT1) is well characterized, other CDH disorders lack precise biomarkers. In SPHYNCS, we utilized Fitbit smartwatches to monitor physical activity, heart rate, and sleep parameters over 1 year. We examined the feasibility of long-term ambulatory monitoring using the wearable device. We then explored digital biomarkers differentiating patients with NT1 from healthy controls (HC). A total of 115 participants received a Fitbit smartwatch. Using a adherence metric to evaluate the usability of the wearable device, we found an overall adherence rate of 80% over 1 year. We calculated daily physical activity, heart rate, and sleep parameters from 2 weeks of greatest adherence to compare NT1 (n = 20) and HC (n = 9) participants. Compared to controls, NT1 patients demonstrated findings consistent with increased sleep fragmentation, including significantly greater wake-after-sleep onset (p = .007) and awakening index (p = .025), as well as standard deviation of time in bed (p = .044). Moreover, NT1 patients exhibited a significantly shorter REM latency (p = .019), and sleep latency (p = .001), as well as a lower peak heart rate (p = .008), heart rate standard deviation (p = .039) and high-intensity activity (p = .009) compared to HC. This ongoing study demonstrates the feasibility of long-term monitoring with wearable technology in patients with CDH and potentially identifies a digital biomarker profile for NT1. While further validation is needed in larger datasets, these data suggest that long-term wearable technology may play a future role in diagnosing and managing narcolepsy., (© The Author(s) 2024. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background & Aims: Colonoscopy-based surveillance to prevent colorectal cancer (CRC) causes substantial burden for patients and health care. Stool tests may help to reduce surveillance colonoscopies by limiting colonoscopies to individuals at increased risk of advanced neoplasia., Methods: This cross-sectional observational study included individuals aged 50-75 years with surveillance indication. Before bowel preparation, participants collected samples for a multitarget stool DNA test and 2 fecal immunochemical tests (FITs). Test accuracy was calculated for all surveillance indications. For the post-polypectomy indication only, which is the most common and is associated with a relatively low CRC risk, long-term impact of stool-based surveillance was evaluated with the Adenoma and Serrated Pathway to Colorectal Cancer (ASCCA) model. Stool-based strategies were simulated to tune each test's positivity threshold to obtain strategies at least as effective as colonoscopy surveillance., Results: There were 3453 individuals with results for all stool tests and colonoscopy; 2226 had previous polypectomy, 1003 had previous CRC, and 224 had a familial risk. Areas under the receiver operating characteristic curve for advanced neoplasia were 0.72 (95% CI, 0.69-0.75) for the multitarget stool DNA test, 0.61 (95% CI, 0.58-0.64) for the FIT OC-SENSOR (Eiken Chemical Co, Tokyo, Japan) and 0.59 (95% CI, 0.56-0.61) for the FIT FOB-Gold (Sentinel, Milan, Italy). Stool-based post-polypectomy surveillance strategies at least as effective as colonoscopy surveillance reduced the number of colonoscopies by 15%-41% and required 5.6-9.5 stool tests over a person's lifetime. Multitarget stool DNA-based surveillance was more costly than colonoscopy surveillance, whereas FIT-based surveillance saved costs., Conclusions: This study found that stool-based post-polypectomy surveillance strategies can be safe and cost-effective, with potential to reduce the number of colonoscopies by up to 41%., Clinicaltrials: gov, Number: NCT02715141., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The laws of thermodynamics apply to biophysical systems on the nanoscale as described by the framework of stochastic thermodynamics. This theory provides universal, exact relations for quantities like work, which have been verified in experiments where a fully resolved description allows direct access to such quantities. Complementary studies consider partially hidden, coarse-grained descriptions, in which the mean entropy production typically is not directly accessible but can be bounded in terms of observable quantities. Going beyond the mean, we introduce a fluctuating entropy production that applies to individual trajectories in a coarse-grained description under time-dependent driving. Thus, this concept is applicable to the broad and experimentally significant class of driven systems in which not all relevant states can be resolved. We provide a paradigmatic example by studying an experimentally verified protein unfolding process. As a consequence, the entire distribution of the coarse-grained entropy production rather than merely its mean retains spatial and temporal information about the microscopic process. In particular, we obtain a bound on the distribution of the physical entropy production of individual unfolding events., Competing Interests: Competing interests statement:The authors declare no competing interest.

Purpose: This study aims to enhance the clinical use of automated sleep-scoring algorithms by incorporating an uncertainty estimation approach to efficiently assist clinicians in the manual review of predicted hypnograms, a necessity due to the notable inter-scorer variability inherent in polysomnography (PSG) databases. Our efforts target the extent of review required to achieve predefined agreement levels, examining both in-domain (ID) and out-of-domain (OOD) data, and considering subjects' diagnoses., Patients and Methods: A total of 19,578 PSGs from 13 open-access databases were used to train U-Sleep, a state-of-the-art sleep-scoring algorithm. We leveraged a comprehensive clinical database of an additional 8832 PSGs, covering a full spectrum of ages (0-91 years) and sleep-disorders, to refine the U-Sleep, and to evaluate different uncertainty-quantification approaches, including our novel confidence network. The ID data consisted of PSGs scored by over 50 physicians, and the two OOD sets comprised recordings each scored by a unique senior physician., Results: U-Sleep demonstrated robust performance, with Cohen's kappa (K) at 76.2% on ID and 73.8-78.8% on OOD data. The confidence network excelled at identifying uncertain predictions, achieving AUROC scores of 85.7% on ID and 82.5-85.6% on OOD data. Independently of sleep-disorder status, statistical evaluations revealed significant differences in confidence scores between aligning vs discording predictions, and significant correlations of confidence scores with classification performance metrics. To achieve κ ≥ 90% with physician intervention, examining less than 29.0% of uncertain epochs was required, substantially reducing physicians' workload, and facilitating near-perfect agreement., Conclusion: Inter-scorer variability limits the accuracy of the scoring algorithms to ~80%. By integrating an uncertainty estimation with U-Sleep, we enhance the review of predicted hypnograms, to align with the scoring taste of a responsible physician. Validated across ID and OOD data and various sleep-disorders, our approach offers a strategy to boost automated scoring tools' usability in clinical settings., Competing Interests: Mrs Francesca Faraci reports grants from Eurostar Eureka, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2024 Bechny et al.)

An Elimination Diet (ED) may be effective in reducing symptoms of Attention-Deficit/Hyperactivity Disorder (ADHD), but has never been compared to an active control condition [i.e., Healthy Diet (HD)]. In a two-armed RCT, a total of N = 165 children (5-12 years) with ADHD were randomized by means of minimization (1:1) to either an ED (N = 84) or HD (N = 81) within two Dutch child and adolescent psychiatry centers. The design included a non-randomized comparator arm including N = 58 children being treated with Care as Usual (CAU). Treatment allocation was unblinded. The primary outcome was a 5-point ordinal measure of respondership based on a combination of parent and teacher ratings on ADHD and emotion regulation, determined after 5 weeks of treatment. Ordinal regression analyses were done on an intention-to-treat basis. Fewer ED (35%) than HD (51%) participants showed a partial to full response, despite overall good-to-excellent treatment adherence (> 88%) and comparable high parental prior believes. A younger age and higher problem severity predicted a better respondership. CAU-preferring participants responded more often favorably (56%) compared to ED-but not HD-participants. Small-to-medium improvements in physical health (blood pressure, heart rate, and somatic complaints) were found in response to ED/HD versus decrements in response to CAU (74% received psychostimulants). The lack of superiority of the ED versus HD suggests that for the majority of children, dietary treatment response is not rooted in food-allergies/-sensitivities. The comparable results for treatment with HD and CAU are remarkable given that CAU participants were probably 'easier to treat' than HD (and ED) participants with proportionally fewer with a (suboptimal/non-response to) prior treatment with medication (4% versus 20%). Further assessment of long-term effects is needed to evaluate the potential place of dietary treatment within clinical guidelines. The trial is closed and registered in the Dutch trial registry, number NL5324 ( https://www.onderzoekmetmensen.nl/en/trial/25997 )., (© 2023. The Author(s).)

Childhood adversity, a prevalent experience, is related to a higher risk for externalizing and internalizing psychopathology. Alterations in the development of cognitive processes, for example in the attention-interference domain may link childhood adversity and psychopathology. Interfering stimuli can vary in their salience, i.e. ability to capture attentional focus, and valence. However, it is not known if interference by salience or valence is associated with self-reported adversity. In two independent study samples of healthy men (Study 1: n = 44; mean age [standard deviation (SD)] = 25.9 [3.4] years; Study 2: n = 37; 43.5 [9.7] years) we used the attention modulation task (AMT) that probed interference by two attention-modulating conditions, salience and valence separately across repeated target stimuli. The AMT measures the effects of visual distractors (pictures) on the performance of auditory discrimination tasks (target stimuli). We hypothesized that participants reporting higher levels of childhood adversity, measured with the childhood trauma questionnaire, would show sustained interference in trials with lower salience. Due to conflicting reports on the valence-modulation, we tested the valence condition in an exploratory manner. Linear mixed models revealed an interaction between reported childhood adversity and the salience condition across tone presentations in both study samples (Sample 1: p = .03; Sample 2: p = .04), while there were no effects for the valence condition across both studies. Our study suggests that higher self-reported childhood adversity is related to faster processing of target cues during high salience, but slower during low salience conditions. These results hint to the mechanisms linking childhood adversity and psychopathological symptoms in the attentional domain., (© 2024. The Author(s).)

Among the ecological functions and services of biodiversity is the potential buffering of diseases through dilution effects where increased biodiversity results in a reduction in disease risk for humans and wildlife hosts. Whether such effects are a universal phenomenon is still under intense debate and diversity effects are little studied in cases when non-host organisms remove free-living parasite stages during their transmission from one host to the next by consumption or physical obstruction. Here, we investigated non-host diversity effects on the removal of cercarial stages of trematodes, ubiquitous parasites in aquatic ecosystems. In laboratory experiments using response surface designs, varying both diversity and density at same time, we compared three combinations of two non-hosts at four density levels: predatory crabs that actively remove cercariae from the water column via their mouth parts and gills, filter feeding oysters that passively filter cercariae from the water column while not becoming infected themselves, and seaweed which physically obstructs cercariae. The addition of a second non-host did not generally result in increased parasite removal but neutralised, amplified or reduced the parasite removal exerted by the first non-host, depending on the density and non-host combination. These non-linear non-host diversity effects were probably driven by intra- and interspecific interactions and suggest the need to integrate non-host diversity effects in understanding the links between community diversity and infection risk., (© 2024. The Author(s).)

Background and Purpose: The diagnosis of sleep-wake disorders (SWDs) is challenging because of the existence of only few accurate biomarkers and the frequent coexistence of multiple SWDs and/or other comorbidities. The aim of this study was to assess in a large cohort of well-characterized SWD patients the potential of a data-driven approach for the identification of SWDs., Methods: We included 6958 patients from the Bernese Sleep Registry and 300 variables/biomarkers including questionnaires, results of polysomnography/vigilance tests, and final clinical diagnoses. A pipeline, based on machine learning, was created to extract and cluster the clinical data. Our analysis was performed on three cohorts: patients with central disorders of hypersomnolence (CDHs), a full cohort of patients with SWDs, and a clean cohort without coexisting SWDs., Results: A first analysis focused on the cohort of patients with CDHs and revealed four patient clusters: two clusters for narcolepsy type 1 (NT1) but not for narcolepsy type 2 or idiopathic hypersomnia. In the full cohort of SWDs, nine clusters were found: four contained patients with obstructive and central sleep apnea syndrome, one with NT1, and four with intermixed SWDs. In the cohort of patients without coexisting SWDs, an additional cluster of patients with chronic insomnia disorder was identified., Conclusions: This study confirms the existence of clear clusters of NT1 in CDHs, but mainly intermixed groups in the full spectrum of SWDs, with the exception of sleep apnea syndromes and NT1. New biomarkers are needed for better phenotyping and diagnosis of SWDs., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Allogeneic natural killer (NK) cell-based immunotherapy is a promising, well-tolerated adjuvant therapeutic approach for acute myeloid leukemia (AML). For reproducible NK cell immunotherapy, a homogenous, pure and scalable NK cell product is preferred. Therefore, we developed a good manufacturing practice (GMP)-compliant, cytokine-based ex vivo manufacturing process for generating NK cells from CD34 + hematopoietic stem and progenitor cells (HSPC). This manufacturing process combines amongst others IL15 and IL12 and the aryl hydrocarbon receptor antagonist StemRegenin-1 (SR1) to generate a consistent and active NK cell product that fits the requirements for NK cell immunotherapy well. The cell culture protocol was first optimized to generate NK cells with required expansion and differentiation capacity in GMP-compliant closed system cell culture bags. In addition, phenotype, antitumor potency, proliferative and metabolic capacity were evaluated to characterize the HSPC-NK product. Subsequently, seven batches were manufactured for qualification of the process. All seven runs demonstrated consistent results for proliferation, differentiation and antitumor potency, and preliminary specifications for the investigational medicinal product for early clinical phase trials were set. This GMP-compliant manufacturing process for HSPC-NK cells (named RNK001 cells) is used to produce NK cell batches applied in the clinical trial 'Infusion of ex vivo-generated allogeneic natural killer cells in combination with subcutaneous IL2 in patients with acute myeloid leukemia' approved by the Dutch Ethics Committee (EudraCT 2019-001929-27)., (© 2023. The Author(s).)

This exploratory study investigates a human agent's evolving judgements of reliability when interacting with an AI system. Two aims drove this investigation: (1) compare the predictive performance of quantum vs. Markov random walk models regarding human reliability judgements of an AI system and (2) identify a neural correlate of the perturbation of a human agent's judgement of the AI's reliability. As AI becomes more prevalent, it is important to understand how humans trust these technologies and how trust evolves when interacting with them. A mixed-methods experiment was developed for exploring reliability calibration in human-AI interactions. The behavioural data collected were used as a baseline to assess the predictive performance of the quantum and Markov models. We found the quantum model to better predict the evolving reliability ratings than the Markov model. This may be due to the quantum model being more amenable to represent the sometimes pronounced within-subject variability of reliability ratings. Additionally, a clear event-related potential response was found in the electroencephalographic (EEG) data, which is attributed to the expectations of reliability being perturbed. The identification of a trust-related EEG-based measure opens the door to explore how it could be used to adapt the parameters of the quantum model in real time.

Temporal neural synchrony disruption can be linked to a variety of symptoms of major depressive disorder (MDD), including mood rigidity and the inability to break the cycle of negative emotion or attention biases. This might imply that altered dynamic neural synchrony may play a role in the persistence and exacerbation of MDD symptoms. Our study aimed to investigate the changes in whole-brain dynamic patterns of the brain functional connectivity and activity related to depression using the hidden Markov model (HMM) on resting-state functional magnetic resonance imaging (rs-fMRI) data. We compared the patterns of brain functional dynamics in a large sample of 314 patients with MDD (65.9% female; age (mean ± standard deviation): 35.9 ± 13.4) and 498 healthy controls (59.4% female; age: 34.0 ± 12.8). The HMM model was used to explain variations in rs-fMRI functional connectivity and averaged functional activity across the whole-brain by using a set of six unique recurring states. This study compared the proportion of time spent in each state and the average duration of visits to each state to assess stability between different groups. Compared to healthy controls, patients with MDD showed significantly higher proportional time spent and temporal stability in a state characterized by weak functional connectivity within and between all brain networks and relatively strong averaged functional activity of regions located in the somatosensory motor (SMN), salience (SN), and dorsal attention (DAN) networks. Both proportional time spent and temporal stability of this brain state was significantly associated with depression severity. Healthy controls, in contrast to the MDD group, showed proportional time spent and temporal stability in a state with relatively strong functional connectivity within and between all brain networks but weak averaged functional activity across the whole brain. These findings suggest that disrupted brain functional synchrony across time is present in MDD and associated with current depression severity., (© 2023. The Author(s).)

Irreversibility is commonly quantified by entropy production. An external observer can estimate it through measuring an observable that is antisymmetric under time reversal like a current. We introduce a general framework that allows us to infer a lower bound on entropy production through measuring the time-resolved statistics of events with any symmetry under time reversal, in particular, time-symmetric instantaneous events. We emphasize Markovianity as a property of certain events rather than of the full system and introduce an operationally accessible criterion for this weakened Markov property. Conceptually, the approach is based on snippets as particular sections of trajectories between two Markovian events, for which a generalized detailed balance relation is discussed.

Objectives: Standard once-daily dosing of ceftriaxone may not lead to adequate antibiotic exposure in all cases of Staphylococcus aureus bacteraemia (SAB). Therefore, we compared clinical effectiveness of empirical antibiotic treatment with flucloxacillin, cefuroxime and ceftriaxone in adult patients with MSSA bacteraemia., Methods: We analysed data from the Improved Diagnostic Strategies in Staphylococcus aureus bacteraemia (IDISA) study, a multicentre prospective cohort study of adult patients with MSSA bacteraemia. Duration of bacteraemia and 30 day SAB-related mortality were compared between the three groups using multivariable mixed-effects Cox regression analyses., Results: In total, 268 patients with MSSA bacteraemia were included in the analyses. Median duration of empirical antibiotic therapy was 3 (IQR 2-3) days in the total study population. Median duration of bacteraemia was 1.0 (IQR 1.0-3.0) day in the flucloxacillin, cefuroxime and ceftriaxone groups. In multivariable analyses, neither ceftriaxone nor cefuroxime was associated with increased duration of bacteraemia compared with flucloxacillin (HR 1.08, 95% CI 0.73-1.60 and HR 1.22, 95% CI 0.88-1.71). In multivariable analysis, neither cefuroxime nor ceftriaxone was associated with higher 30 day SAB-related mortality compared with flucloxacillin [subdistribution HR (sHR) 1.37, 95% CI 0.42-4.52 and sHR 1.93, 95% CI 0.67-5.60]., Conclusions: In this study, we could not demonstrate a difference in duration of bacteraemia and 30 day SAB-related mortality between patients with SAB empirically treated with flucloxacillin, cefuroxime or ceftriaxone. Since sample size was limited, it is possible the study was underpowered to find a clinically relevant effect., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Introduction: A major knowledge gap in the treatment of complicated Staphylococcus aureus bacteraemia (SAB) is the optimal duration of antibiotic therapy. Safe shortening of antibiotic therapy has the potential to reduce adverse drug events, length of hospital stay and costs. The objective of the SAFE trial is to evaluate whether 4 weeks of antibiotic therapy is non-inferior to 6 weeks in patients with complicated SAB., Methods and Analysis: The SAFE-trial is a multicentre, non-inferiority, open-label, parallel group, randomised controlled trial evaluating 4 versus 6 weeks of antibiotic therapy for complicated SAB. The study is performed in 15 university hospitals and general hospitals in the Netherlands. Eligible patients are adults with methicillin-susceptible SAB with evidence of deep-seated or metastatic infection and/or predictors of complicated SAB. Only patients with a satisfactory clinical response to initial antibiotic treatment are included. Patients with infected prosthetic material or an undrained abscess of 5 cm or more at day 14 of adequate antibiotic treatment are excluded. Primary outcome is success of therapy after 180 days, a combined endpoint of survival without evidence of microbiologically confirmed disease relapse. Assuming a primary endpoint occurrence of 90% in the 6 weeks group, a non-inferiority margin of 7.5% is used. Enrolment of 396 patients in total is required to demonstrate non-inferiority of shorter antibiotic therapy with a power of 80%. Currently, 152 patients are enrolled in the study., Ethics and Dissemination: This is the first randomised controlled trial evaluating duration of antibiotic therapy for complicated SAB. Non-inferiority of 4 weeks of treatment would allow shortening of treatment duration in selected patients with complicated SAB. This study is approved by the Medical Ethics Committee VUmc (Amsterdam, the Netherlands) and registered under NL8347 (the Netherlands Trial Register). Results of the study will be published in a peer-reviewed journal., Trial Registration Number: NL8347 (the Netherlands Trial Register)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

In single-molecule experiments, the dynamics of molecular motors are often observed indirectly by measuring the trajectory of an attached bead in a motor-bead assay. In this work, we propose a method to extract the step size and stalling force for a molecular motor without relying on external control parameters. We discuss this method for a generic hybrid model that describes bead and motor via continuous and discrete degrees of freedom, respectively. Our deductions are solely based on the observation of waiting times and transition statistics of the observable bead trajectory. Thus, the method is non-invasive, operationally accessible in experiments and can, in principle, be applied to any model describing the dynamics of molecular motors. We briefly discuss the relation of our results to recent advances in stochastic thermodynamics on inference from observable transitions. Our results are confirmed by extensive numerical simulations for parameters values of an experimentally realized F1-ATPase assay.

The aim of the present study was to re-evaluate 457 renal cell carcinoma (RCC) cases from the Netherlands Cohort Study on Diet and Cancer (NLCS), a large population-based cohort, according to the new 2022 ISUP, Genitourinary Pathology Society and World Health Organisation (WHO) classifications to assess whether newly recognized subtypes of RCC could be found among these cases. These cases were initially evaluated according to the 2004 WHO classification, the Fuhrman grading system and the 3rd version of the Tumor-Node-Metastasis (TNM). Data on tumor size, laterality and date of diagnosis, among other clinicopathological characteristics, were obtained through record linkage with the Netherlands Cancer Registry and the Pathologisch-Anatomisch Landelijk Geautomatiseerd Archief. Digital slides from the NLCS were reviewed by two urogenital pathologists according to the new ISUP grading and the 2022 WHO classification (5th edition). Immunohistochemistry staining for carbonic anhydrase IX was performed on cases with ambiguous morphology. A total of 373 cases of clear cell RCC (ccRCC), 61 cases of papillary RCC (pRCC), 13 cases of chromophobe RCC, 3 cases of collecting duct carcinoma and 4 cases of oncocytoma were identified. The subtyping showed no discrepancy with the previous diagnoses. A comparison of the WHO/ISUP grading to the original Fuhrman grading showed a similar grading in 245 (56.5%) cases of the total ccRCC and pRCC cases. The staging according to the novel TNM classification 8th edition showed a restaging in 286 cases (65.5%). Lymphovascular (microvascular) invasion (LVI) and tumor necrosis (TN) were present in 14.4% and 33.5% of the total number of cases, respectively. Furthermore, the presence of sarcomatoid differentiation in 5.1% and rhabdoid differentiation in 4.2% of the cases was observed. In conclusion, none of the newly accepted and emerging/provisional RCC entities were identified in the NLCS cases, which could be attributed to the high mean age (71.4 years) at diagnosis of the patients included in the present study. A restaging of the NLCS cases using the TNM 8th edition and regrading using ISUP grading was performed, which showed that it is possible to report on newer features, such as sarcomatoid differentiation and LVI, even in an old sample collection., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Odeh et al.)

AASM guidelines are the result of decades of efforts aiming at standardizing sleep scoring procedure, with the final goal of sharing a worldwide common methodology. The guidelines cover several aspects from the technical/digital specifications, e.g., recommended EEG derivations, to detailed sleep scoring rules accordingly to age. Automated sleep scoring systems have always largely exploited the standards as fundamental guidelines. In this context, deep learning has demonstrated better performance compared to classical machine learning. Our present work shows that a deep learning-based sleep scoring algorithm may not need to fully exploit the clinical knowledge or to strictly adhere to the AASM guidelines. Specifically, we demonstrate that U-Sleep, a state-of-the-art sleep scoring algorithm, can be strong enough to solve the scoring task even using clinically non-recommended or non-conventional derivations, and with no need to exploit information about the chronological age of the subjects. We finally strengthen a well-known finding that using data from multiple data centers always results in a better performing model compared with training on a single cohort. Indeed, we show that this latter statement is still valid even by increasing the size and the heterogeneity of the single data cohort. In all our experiments we used 28528 polysomnography studies from 13 different clinical studies., (© 2023. The Author(s).)

Background: Supporting wellbeing beyond symptom reduction is necessary in trauma care. Research suggests increased posttraumatic growth (PTG) may promote wellbeing more effectively than posttraumatic stress disorder (PTSD) symptom reduction alone. Understanding neurobiological mechanisms of PTG would support PTG intervention development. However, most PTG research to-date has been cross-sectional data self-reported through surveys or interviews. Objective: Neural evidence of PTG and its coexistence with resilience and PTSD is limited. To advance neural PTG literature and contribute translational neuroscientific knowledge necessary to develop future objectively measurable neural-based PTG interventions. Method: Alpha frequency EEG and validated psychological inventories measuring PTG, resilience, and PTSD symptoms were collected from 30 trauma-exposed healthy adults amidst the COVID-19 pandemic. EEG data were collected using custom MNE-Python software, and a wireless OpenBCI 16-channel dry electrode EEG headset. Psychological inventory scores were analysed in SPSS Statistics and used to categorise the EEG data. Power spectral density analyses, t -tests and ANOVAs were conducted within EEGLab to identify brain activity differentiating high and low PTG, resilience, and PTSD symptoms. Results: Higher PTG was significantly differentiated from low PTG by higher alpha power in the left centro-temporal brain area around EEG electrode C3. A trend differentiating high PTG from PTSD was also indicated in this same location. Whole-scalp spectral topographies revealed alpha power EEG correlates of PTG, resilience and PTSD symptoms shared limited, but potentially meaningful similarities. Conclusion: This research provides the first comparative neural topographies of PTG, resilience and PTSD symptoms in the known literature. Results provide objective neural evidence supporting existing theory depicting PTG, resilience and PTSD as independent, yet co-occurring constructs. PTG neuromarker alpha C3 significantly delineated high from low PTG and warrants further investigation for potential clinical application. Findings provide foundation for future neural-based interventions and research for enhancing PTG in trauma-exposed individuals.

Introduction: This prospective controlled study evaluates volumetric, length, and average cross-sectional area (aCSA) airway changes in growing patients with unilateral complete cleft lip and palate after 1.5 years of bone-anchored maxillary protraction therapy., Methods: Thirty-five growing unilateral complete cleft lip and palate patients with maxillary deficiency were included (aged 11.3 ± 0.5 years). Cone-beam computed tomography scans were obtained before bone-anchored maxillary protraction (BAMP) therapy and after 1.5 years. A growing group without cleft (n = 18) patients served as a control group at 1.5 years posttreatment (aged 13.1 ± 1.2 years). Volumetric, length, and aCSA changes of the total airway, nasopharynx (NP), middle pharynx, and inferior pharynx airway were evaluated., Results: After 1.5 years of BAMP therapy, a significant increase was observed in the total airway volume and the NP (P <0.01). The middle and inferior pharynx showed an insignificant tendency of volumetric increase. Compared with the control group, a significantly larger airway volume could be observed in the total airway and NP (P <0.05). The aCSA of the NP increased significantly compared with pretreatment., Conclusions: The total airway and NP volumes significantly increased in growing subjects with cleft lip and palate after 1.5 years of BAMP therapy to a level comparable to a control group without cleft. Volumetric increase in the NP in the BAMP group is mainly attributed to the increase in its cross-sectional area. BAMP can therefore be recommended as an effective therapy for patients with cleft lip and palate with positive effects on airway development., (Copyright © 2022. Published by Elsevier Inc.)

Background: The multicomponent drug Neurexan (Nx4) was shown to reduce the neural stress network activation. We now investigated its effects on stress-induced resting state functional connectivity (RSFC) in dependence of trait anxiety (TA), an acknowledged vulnerability factor for stress-induced psychopathologies., Methods: Nx4 was tested in a randomized placebo-controlled crossover trial. Resting state fMRI scans were performed before and after a psychosocial stress task and exploratively analyzed for amygdala centered RSFC. Effects of Nx4 on stress-induced RSFC changes were evaluated and correlated to TA levels. A subgroup analysis based on TA scores was performed., Results: Multiple linear regression analysis revealed a significant correlation between TA and Nx4 effect on stress-induced RSFC changes between right amygdala and pregenual anterior cingulate cortex (pgACC) and ventro-medial prefrontal cortex (vmPFC). For participants with above average TA, a significant amelioration of the stress-induced RSFC changes was observed., Conclusions: The data add evidence to the hypothesis that Nx4's clinical efficacy is based on a dampened activation of the neural stress network, with a greater neural response in subjects with anxious personality traits. Further studies assessing clinically relevant outcome measures in parallel to fMRI are encouraged to evaluate the real-world benefit of Nx4. Trial registration NCT02602275., (© 2022. The Author(s).)

Ubiquitin-specific protease 7 (USP7) has been implicated in cancer progression and neurodevelopment. However, its molecular targets remain poorly characterized. We combined quantitative proteomics, transcriptomics, and epigenomics to define the core USP7 network. Our multi-omics analysis reveals USP7 as a control hub that links genome regulation, tumor suppression, and histone H2A ubiquitylation (H2AK119ub1) by noncanonical Polycomb-repressive complexes (ncPRC1s). USP7 strongly stabilizes ncPRC1.6 and, to a lesser extent, ncPRC1.1. Moreover, USP7 represses expression of AUTS2, which suppresses H2A ubiquitylation by ncPRC1.3/5. Collectively, these USP7 activities promote the genomic deposition of H2AK119ub1 by ncPRC1, especially at transcriptionally repressed loci. Notably, USP7-dependent changes in H2AK119ub1 levels are uncoupled from H3K27me3. Even complete loss of the PRC1 catalytic core and H2AK119ub1 has only a limited effect on H3K27me3. Besides defining the USP7 regulome, our results reveal that H2AK119ub1 dosage is largely disconnected from H3K27me3.

Background: The basic functional organization of the resting brain, assessed as resting-state functional connectivity (rsFC), can be affected by previous stress experience and it represents the basis on which subsequent stress experience develops. Notably, the rsFC between the amygdala and the cortical regions associated with emotion regulation and anxiety are affected during stress. The multicomponent drug Neurexan ® (Nx4) has previously demonstrated a reduction in amygdala activation in an emotional face matching task and it ameliorated stress-related symptoms. We, thus, investigated the effect of Nx4 on rsFC of the amygdala before stress induction compared with baseline in mildly to moderately stressed participants. Methods: In a randomized, placebo-controlled, double-blind, crossover trial 39 participants received a single dose of placebo or Nx4. Resting-state functional magnetic resonance imaging scans were performed pre-dose and 40 to 60 min post-dose, before any stress induction. First, highly connected functional hubs were identified by global functional connectivity density (gFCD) analysis. Second, by using a seed-based approach, rsFC maps of the left centromedial amygdala (CeMA) were created. The effect of Nx4 on both was evaluated. Results: The medial prefrontal cortex was identified as a relevant functional hub affected by Nx4 in an explorative whole brain gFCD analysis. Using the seed-based approach, we then demonstrated that Nx4 significantly enhanced the negative connectivity between the left CeMA and two cortical regions: the dorsolateral and medial prefrontal cortices. Conclusions: In a resting-state condition, Nx4 reduced the prefrontal cortex gFCD and strengthened the functional coupling between the amygdala and the prefrontal cortex that is relevant for emotion regulation and the stress response. Further studies should elaborate whether this mechanism represents enhanced regulatory control of the amygdala at rest and, consequently, to a diminished susceptibility to stress. ClinicalTrials.gov ID: NCT02602275.

Objective: Stress-related symptoms are associated with significant health and economic burden. Several studies suggest Nx4 for the pharmacological management of the stress response and investigated the underlying neural processes. Here we hypothesized that Nx4 can directly affect the stress response in a predefined stress network, including the anterior cingulate cortex (ACC), which is linked to various stress-related symptoms in patients., Methods: In a randomized, placebo-controlled, double-blind, crossover trial, 39 healthy males took a single dose of placebo or Nx4. Psychosocial stress was induced by the ScanSTRESS paradigm inside an MRI scanner, and stress network activation was analyzed in brain regions defined a priori., Results: Using the placebo data only, we could validate the activation of a distinct neural stress pattern by the ScanSTRESS paradigm. For Nx4, we provide evidence of an attenuating effect on this stress response. A statistically significant reduction in differential stress-induced activation in the right supracallosal ACC was observed for the rotation stress task of the ScanSTRESS paradigm. The results add to previously published results of Nx4 effects on emotion regulation., Conclusions: Our results strengthen the hypothesis that Nx4 modulates the stress response by reducing the activation in parts of the neural stress network, particularly in the ACC., Trial Registration: NCT02602275; ClinicalTrials.gov., (© 2022 The Authors. Human Psychopharmacology: Clinical and Experimental published by John Wiley & Sons Ltd.)

A minimum stoichiometric carbon and nitrogen model of an entire ecosystem based on Dynamic Energy Budget (DEB) theory is presented. The ecosystem contains nutrients, producers, consumers, decomposers and detritus. All three living groups consist of somatic structure and either one (consumers and decomposers) or two (producers) reserve compartments, hence the living matter is described by seven state variables. Four types of detritus are distinguished. As the system is closed for matter, the dynamics of the nutrients carbon dioxide and ammonium follow automatically from the dynamics of the other 11 state variables. All DEB organisms in the model are V1-morphs, which means that surface area of each organism is proportional to volume. The resulting ontogenetic symmetry implies that complicated modelling of size structure is not required. The DEB V1-morph model is explained in detail, and the same holds for the idea of synthesizing units, which plays a key role in DEB modelling. First results of system dynamics are presented., (© The Author(s) 2022. Published by Oxford University Press and the Society for Experimental Biology.)

Semi-Markov processes generalize Markov processes by adding temporal memory effects as expressed by a semi-Markov kernel. We recall the path weight for a semi-Markov trajectory and the fact that thermodynamic consistency in equilibrium imposes a crucial condition called direction-time independence for which we present an alternative derivation. We prove a thermodynamic uncertainty relation that formally resembles the one for a discrete-time Markov process. The result relates the entropy production of the semi-Markov process to mean and variance of steady-state currents. We prove a further thermodynamic uncertainty relation valid for semi-Markov descriptions of coarse-grained Markov processes that emerge by grouping states together. A violation of this inequality can be used as an inference tool to conclude that a given semi-Markov process cannot result from coarse graining an underlying Markov one. We illustrate these results with representative examples.

Chinese hamster ovary (CHO) cells are known not to express appreciable levels of the sialic acid residue N-glycolylneuraminic acid (NGNA) on monoclonal antibodies. However, we actually have identified a recombinant CHO cell line expressing an IgG with unusually high levels of NGNA sialylation (>30%). Comprehensive multi-OMICs based experimental analyses unraveled the root cause of this atypical sialylation: (1) expression of the cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH) gene was spontaneously switched on, (2) CMAH mRNA showed an anti-correlated expression to the newly discovered Cricetulus griseus (cgr) specific microRNA cgr-miR-111 and exhibits two putative miR-111 binding sites, (3) miR-111 expression depends on the transcription of its host gene SDK1, and (4) a single point mutation within the promoter region of the sidekick cell adhesion molecule 1 (SDK1) gene generated a binding site for the transcriptional repressor histone H4 transcription factor HINF-P. The resulting transcriptional repression of SDK1 led to a downregulation of its co-expressed miR-111 and hence to a spontaneous upregulation of CMAH expression finally increasing NGNA protein sialylation., (© 2021 Boehringer Ingelheim Pharma GmbH & Co.KG. Biotechnology and Bioengineering published by Wiley Periodicals LLC.)

Objectives: To examine the association between the use of oral antibiotics and subsequent colorectal cancer risk., Design: Matched case-control study., Setting: General practice centres participating in the Integrated Computerised Network database in Flanders, Belgium., Participants: In total, 1705 cases of colorectal cancer diagnosed between 01 January 2010 and 31 December 2015 were matched to 6749 controls by age, sex, comorbidity and general practice centre., Primary Outcome Measure: The association between the number of prescriptions for oral antibiotics and the incidence of colorectal cancer over a period of 1-10 years, estimated by a conditional logistic regression model., Results: A significantly increased risk of colorectal cancer (OR 1.25, 95% CI 1.10 to 1.44) was found in subjects with one or more prescriptions compared with those with none after correction for diabetes mellitus. No dose-response relationship was found., Conclusions: This study resulted in a modestly higher risk of having colorectal cancer diagnosed after antibiotic exposure. The main limitation was missing data on known risk factors, in particular smoking behaviour. This study did not allow us to examine the causality of the relationship, indicating the need of further investigation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Depending on geographic location, causes of encephalitis, meningoencephalitis and meningitis vary substantially. We aimed to identify the most frequent causes, clinical presentation and long-term outcome of encephalitis, meningoencephalitis and meningitis cases treated in the Inselspital University Hospital Bern, Switzerland., Methods: In this monocentric, observational study, we performed a retrospective review of clinical patient records for all patients treated within a 3-year period. Patients were contacted for a telephone follow-up interview and to fill out questionnaires, especially related to disturbances of sleep and wakefulness., Results: We included 258 patients with the following conditions: encephalitis (18%), nonbacterial meningoencephalitis (42%), nonbacterial meningitis (27%) and bacterial meningoencephalitis/meningitis (13%). Herpes simplex virus (HSV) was the most common cause of encephalitis (18%); tick-borne encephalitis virus (TBEV) was the most common cause of nonbacterial meningoencephalitis (46%), enterovirus was the most common cause of nonbacterial meningitis (21%) and Streptococcus pneumoniae was the most common cause of bacterial meningoencephalitis/meningitis (49%). Overall, 35% patients remained without a known cause. After a median time of 16 months, 162 patients participated in the follow-up interview; 56% reported suffering from neurological long-term sequelae such as fatigue and/or excessive daytime sleepiness (34%), cognitive impairment and memory deficits (22%), headache (14%) and epileptic seizures (11%)., Conclusions: In the Bern region, Switzerland, TBEV was the overall most frequently detected infectious cause, with a clinical manifestation of meningoencephalitis in the majority of cases. Long-term neurological sequelae, most importantly cognitive impairment, fatigue and headache, were frequently self-reported not only in encephalitis and meningoencephalitis survivors but also in viral meningitis survivors up to 40 months after acute infection., (© 2021. The Author(s).)

Background: Stress adversely affects the attentional focus, the active concentration on stimuli, and increases susceptibility to distraction. To experimentally explore the susceptibility to distraction, the Attention Modulation by Salience Task (AMST) is a validated paradigm measuring reaction times (RT) for processing auditory information while presenting task-irrelevant visual distractors of high or low salience. We extended the AMST by an emotional dimension of distractors and an EEG-based evaluation. We then investigated the effect of the stress-relieving medication Neurexan (Nx4) on the participants' susceptibility to distraction. Methods: Data from a randomized, placebo-controlled, crossover trial (NEURIM study; ClinicalTrials.gov: NCT02602275) were exploratively reanalyzed post-hoc . In this trial, 39 participants received a single dose of placebo or Nx4 immediately before the AMST. Participants had to discriminate two different tone modulations (ascending or descending) while simultaneously perceiving task-irrelevant pictures of different salience (high or low) or valence (negative or positive) as distractors. Using EEG recordings, RT and the event-related potential (ERP) components N1, N2, and N3 were analyzed as markers for susceptibility to distraction. Results: In the placebo condition, we could replicate the previously reported task effects of salient distractors with longer RT for high salient distractors on the behavioral level. On the electrophysiological level, we observed significantly increased amplitudes of the N2 and N3 ERP components for positive emotional pictures. In terms of drug effect, we found evidence that Nx4 reduced distractibility by emotional distractors. The effect was shown by significantly reduced amplitudes of N2 and N3 ERP components and reduced RT for the positive valence domain under Nx4 compared to placebo. The Nx4 effects on RT and ERP components also showed a significant correlation. Conclusion: Emotional distractors in addition to the previously used salience distractors and the EEG based evaluation of ERPs valuably complement the AMST. Salient distractors were affecting attentional processes earlier, while valent distractors show modulatory effects later. Our results suggest that Nx4 has beneficial effects on attention by inhibiting the effect of task-irrelevant information and reducing susceptibility to emotionally distracting stimuli. The observation of a beneficial impact of Nx4 on attention regulation is supportive of Nx4's claim as a stress-relieving medication., Competing Interests: BN and MS were employed by Biologische Heilmittel Heel GmbH. MW received institutional research support from Heel paid to his institution for this study, and from BrainWaveBank, H. Lundbeck A/S and LivaNova Belgium N.V., LivaNova PLC outside the submitted work. The University of Tübingen received institutional fees for advisory services by MW from Heel GmbH, Servier Deutschland GmbH, Bayer AG and Janssen-Cilag GmbH. The University of Tübingen received financial support for conference attendance of KM, MK, SA, and HJ from Heel for presenting data of this study not reported in this article for this study. JV is a senior biometric consultant of idv Datenanalyse & Versuchsplanung (conceptualization, methodology, formal analysis, writing–original draft, writing–review, and editing) and received personal fees for biometric services from the Foundation of the Society for the Study of Neuroprotection and Neuroplasticity (SSNN) outside the submitted work, and idv Datenanalyse & Versuchsplanung received payments for biometric services from Heel, University Medical Center Göttigen, IgNova GmbH, Abnoba GmbH, AOP Orphan Pharmaceuticals AG, IDEA AG, PBB Entrepreneur Ltd., Tillots Pharma AG, STORZ Medical AG, EVER Neuro Pharma GmbH, MUCOS Pharma GmbH & Co. KG, Steigerwald Arzneimittelwerk GmbH outside the submitted work. MS and BN are employed by Heel (conceptualization, project administration, methodology, validation, writing–review, editing, and supervision). KM, MK, SA, HJ, and JM were part of MW team for this study and declare no other conflict of interest outside the submitted work. All investigators followed the institutional guidelines for COI management in full compliance with the regulations of the Otto v. Guericke University, Magdeburg., (Copyright © 2021 Mayer, Krylova, Alizadeh, Jamalabadi, van der Meer, Vester, Naschold, Schultz and Walter.)

Background and Objectives: The pathophysiology of chronic fatigue syndrome (CFS) and Q fever fatigue syndrome (QFS) remains elusive. Recent data suggest a role for neuroinflammation as defined by increased expression of translocator protein (TSPO). In the present study, we investigated whether there are signs of neuroinflammation in female patients with CFS and QFS compared with healthy women, using PET with the TSPO ligand 11 C-( R )-(2-chlorophenyl)- N -methyl- N -(1-methylpropyl)-3-isoquinoline-carbox-amide ([ 11 C]-PK11195)., Methods: The study population consisted of patients with CFS (n = 9), patients with QFS (n = 10), and healthy subjects (HSs) (n = 9). All subjects were women, matched for age (±5 years) and neighborhood, aged between 18 and 59 years, who did not use any medication other than paracetamol or oral contraceptives, and were not vaccinated in the last 6 months. None of the subjects reported substance abuse in the past 3 months or reported signs of underlying psychiatric disease on the Mini-International Neuropsychiatric Interview. All subjects underwent a [ 11 C]-PK11195 PET scan, and the [ 11 C]-PK11195 binding potential (BP ND ) was calculated., Results: No statistically significant differences in BP ND were found for patients with CFS or patients with QFS compared with HSs. BP ND of [ 11 C]-PK11195 correlated with symptom severity scores in patients with QFS, but a negative correlation was found in patients with CFS., Discussion: In contrast to what was previously reported for CFS, we found no significant difference in BP ND of [ 11 C]-PK11195 when comparing patients with CFS or QFS with healthy neighborhood controls. In this small series, we were unable to find signs of neuroinflammation in patients with CFS and QFS., Trial Registration Information: EudraCT number 2014-004448-37., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Narcolepsy type 1 (NT1) is a disorder with well-established markers and a suspected autoimmune aetiology. Conversely, the narcoleptic borderland (NBL) disorders, including narcolepsy type 2, idiopathic hypersomnia, insufficient sleep syndrome and hypersomnia associated with a psychiatric disorder, lack well-defined markers and remain controversial in terms of aetiology, diagnosis and management. The Swiss Primary Hypersomnolence and Narcolepsy Cohort Study (SPHYNCS) is a comprehensive multicentre cohort study, which will investigate the clinical picture, pathophysiology and long-term course of NT1 and the NBL. The primary aim is to validate new and reappraise well-known markers for the characterization of the NBL, facilitating the diagnostic process. Seven Swiss sleep centres, belonging to the Swiss Narcolepsy Network (SNaNe), joined the study and will prospectively enrol over 500 patients with recent onset of excessive daytime sleepiness (EDS), hypersomnia or a suspected central disorder of hypersomnolence (CDH) during a 3-year recruitment phase. Healthy controls and patients with EDS due to severe sleep-disordered breathing, improving after therapy, will represent two control groups of over 50 patients each. Clinical and electrophysiological (polysomnography, multiple sleep latency test, maintenance of wakefulness test) information, and information on psychomotor vigilance and a sustained attention to response task, actigraphy and wearable devices (long-term monitoring), and responses to questionnaires will be collected at baseline and after 6, 12, 24 and 36 months. Potential disease markers will be searched for in blood, cerebrospinal fluid and stool. Analyses will include quantitative hypocretin measurements, proteomics/peptidomics, and immunological, genetic and microbiota studies. SPHYNCS will increase our understanding of CDH and the relationship between NT1 and the NBL. The identification of new disease markers is expected to lead to better and earlier diagnosis, better prognosis and personalized management of CDH., (© 2021 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

Objectives: Vigilance is characterized by alertness and sustained attention. The hyper-vigilance states are indicators of stress experience in the resting brain. Neurexan (Nx4) has been shown to modulate the neuroendocrine stress response. Here, we hypothesized that the intake of Nx4 would alter brain vigilance states at rest., Method: In this post-hoc analysis of the NEURIM study, EEG recordings of three, 12 min resting-state conditions in 39 healthy male volunteers were examined in a randomized, placebo-controlled, double-blind, cross-over clinical trial. EEG was recorded at three resting-state sessions: at baseline (RS0), after single-dose treatment with Nx4 or placebo (RS1), and subsequently after a psychosocial stress task (RS2). During each resting-state session, each 2-s segment of the consecutive EEG epochs was classified into one of seven different brain states along a wake-sleep continuum using the VIGALL 2.1 algorithm., Results: In the post-stress resting-state, subjects exhibited a hyper-stable vigilance regulation characterized by an increase in the mean vigilance level and by more rigidity in the higher vigilance states for a longer period of time. Importantly, Nx4-treated participants exhibited significantly lower mean vigilance level compared to placebo-treated ones. Also, Nx4- compared to placebo-treated participants spent comparably less time in higher vigilance states and more time in lower vigilance states in the post-stress resting-state., Conclusion: Study participants showed a significantly lower mean vigilance level in the post-stress resting-state condition and tended to stay longer in lower vigilance states after treatment with Nx4. These findings support the known stress attenuation effect of Nx4., Competing Interests: M.W. received institutional research support from Heel paid to his institution for this study, and from BrainWaveBank, H. Lundbeck A/S and LivaNova Belgium N.V., LivaNova PLC outside the submitted work. The University of Tübingen received institutional fees for advisory services by Prof. Walter from Heel GmbH, Servier Deutschland GmbH, Bayer AG and Janssen-Cilag GmbH. The University of Tübingen received financial support for conference attendance of T.C., S.A., L.H., M.K. and H.J. from Heel for presenting data of this study not reported in this article. L.H., J.V.M., T.C., S.A., H.J., and M.K. were part of M.W. team for this study, and declare no other conflict of interest outside the submitted work. All investigators followed the institutional guidelines for COI management in full compliance with the regulations of the Otto v. Guericke University, Magdeburg., (© 2021 The Authors.)

Allogeneic natural killer (NK) cell transfer is a potential immunotherapy to eliminate and control cancer. A promising source are CD34 + hematopoietic progenitor cells (HPCs), since large numbers of cytotoxic NK cells can be generated. Effective boosting of NK cell function can be achieved by interleukin (IL)-15. However, its in vivo half-life is short and potent trans-presentation by IL-15 receptor α (IL-15Rα) is absent. Therefore, ImmunityBio developed IL-15 superagonist N-803, which combines IL-15 with an activating mutation, an IL-15Rα sushi domain for trans-presentation, and IgG1-Fc for increased half-life. Here, we investigated whether and how N-803 improves HPC-NK cell functionality in leukemia and ovarian cancer (OC) models in vitro and in vivo in OC-bearing immunodeficient mice. We used flow cytometry-based assays, enzyme-linked immunosorbent assay, microscopy-based serial killing assays, and bioluminescence imaging, for in vitro and in vivo experiments. N-803 increased HPC-NK cell proliferation and interferon (IFN)γ production. On leukemia cells, co-culture with HPC-NK cells and N-803 increased ICAM-1 expression. Furthermore, N-803 improved HPC-NK cell-mediated (serial) leukemia killing. Treating OC spheroids with HPC-NK cells and N-803 increased IFNγ-induced CXCL10 secretion, and target killing after prolonged exposure. In immunodeficient mice bearing human OC, N-803 supported HPC-NK cell persistence in combination with total human immunoglobulins to prevent Fc-mediated HPC-NK cell depletion. Moreover, this combination treatment decreased tumor growth. In conclusion,  N-803 is a promising IL-15-based compound that boosts HPC-NK cell expansion and functionality in vitro and in vivo. Adding N-803 to HPC-NK cell therapy could improve cancer immunotherapy.

Background: In case-control studies most algorithms allow the controls to be sampled several times, which is not always optimal. If many controls are available and adjustment for several covariates is necessary, matching without replacement might increase statistical efficiency. Comparing similar units when having observational data is of utter importance, since confounding and selection bias is present. The aim was twofold, firstly to create a method that accommodates the option that a control is not resampled, and second, to display several scenarios that identify changes of Odds Ratios (ORs) while increasing the balance of the matched sample., Methods: The algorithm was derived in an iterative way starting from the pre-processing steps to derive the data until its application in a study to investigate the risk of antibiotics on colorectal cancer in the INTEGO registry (Flanders, Belgium). Different scenarios were developed to investigate the fluctuation of ORs using the combination of exact and varying variables with or without replacement of controls. To achieve balance in the population, we introduced the Comorbidity Index (CI) variable, which is the sum of chronic diseases as a means to have comparable units for drawing valid associations., Results: This algorithm is fast and optimal. We simulated data and demonstrated that the run-time of matching even with millions of patients is minimal. Optimal, since the closest controls is always captured (using the appropriate ordering and by creating some auxiliary variables), and in the scenario that a case has only one control, we assure that this control will be matched to this case, thus maximizing the cases to be used in the analysis. In total, 72 different scenarios were displayed indicating the fluctuation of ORs, and revealing patterns, especially a drop when balancing the population., Conclusions: We created an optimal and computationally efficient algorithm to derive a matched case-control sample with and without replacement of controls. The code and the functions are publicly available as an open source in an R package. Finally, we emphasize the importance of displaying several scenarios and assess the difference of ORs while using an index to balance population in observational data.

Compound biodegradability tests with natural microbial communities form an important keystone in the ecological assessment of chemicals. However, biodegradability tests are frequently limited by a singular focus either on the chemical and potential transformation products or on the individual microbial species degrading the compound. Here, we investigated a methodology to simultaneously analyze community compositional changes and biomass growth on dosed test compound from flow cytometry (FCM) data coupled to machine-learned cell type recognition. We quantified the growth of freshwater microbial communities on a range of carbon dosages of three readily biodegradable reference compounds, phenol, 1-octanol, and benzoate, in comparison to three fragrances, methyl jasmonate, myrcene, and musk xylene (as a nonbiodegradable control). Compound mass balances with between 0.1 to 10 mg C · liter -1 phenol or 1-octanol, inferred from cell numbers, parent compound analysis, and CO 2 evolution, as well as use of 14 C-labeled compounds, showed between 6 and 25% mg C · mg C -1 substrate incorporation into biomass within 2 to 4 days and 25 to 45% released as CO 2 In contrast, similar dosage of methyl jasmonate and myrcene supported slower (4 to 10 days) and less (2.6 to 6.6% mg C · mg C -1 with 4.9 to 22% CO 2 ) community growth. Community compositions inferred from machine-learned cell type recognition and 16S rRNA amplicon sequencing showed substrate- and concentration-dependent changes, with visible enrichment of microbial subgroups already at 0.1 mg C · liter -1 phenol and 1-octanol. In general, community compositions were similar at the start and after the stationary phase of the microbial growth, except at the highest used substrate concentrations of 100 to 1,000 mg C · liter -1 Flow cytometry cell counting coupled to deconvolution of communities into subgroups is thus suitable to infer biodegradability of organic chemicals, permitting biomass balances and near-real-time assessment of relevant subgroup changes. IMPORTANCE The manifold effects of potentially toxic compounds on microbial communities are often difficult to discern. Some compounds may be transformed or completely degraded by few or multiple strains in the community, whereas others may present inhibitory effects. In this study, we benchmark a new method based on machine-learned microbial cell recognition to rapidly follow dynamic changes in aquatic communities. We further determine productive biodegradation upon dosing of a number of well-known readily biodegradable tester compounds at a variety of concentrations. Microbial community growth was quantified using flow cytometry, and the multiple cell parameters measured were used in parallel to deconvolute the community on the basis of similarity to previously standardized cell types. Biodegradation was further confirmed by chemical analysis, showing how distinct changes in specific populations correlate to degradation. The method holds great promise for near-real-time community composition changes and deduction of compound biodegradation in natural microbial communities., (Copyright © 2021 Özel Duygan et al.)

The momentary global functional state of the brain is reflected in its electric field configuration and cluster analytical approaches have consistently shown four configurations, referred to as EEG microstate classes A to D. Changes in microstate parameters are associated with a number of neuropsychiatric disorders, task performance, and mental state establishing their relevance for cognition. However, the common practice to use eye-closed resting state data to assess the temporal dynamics of microstate parameters might induce systematic confounds related to vigilance levels. Here, we studied the dynamics of microstate parameters in two independent data sets and showed that the parameters of microstates are strongly associated with vigilance level assessed both by EEG power analysis and fMRI global signal. We found that the duration and contribution of microstate class C, as well as transition probabilities towards microstate class C were positively associated with vigilance, whereas the sign was reversed for microstate classes A and B. Furthermore, in looking for the origins of the correspondence between microstates and vigilance level, we found Granger-causal effects of vigilance levels on microstate sequence parameters. Collectively, our findings suggest that duration and occurrence of microstates have a different origin and possibly reflect different physiological processes. Finally, our findings indicate the need for taking vigilance levels into consideration in resting-sate EEG investigations., (Copyright © 2020. Published by Elsevier Inc.)

Because the occurrence of infective endocarditis (IE) continues to be associated with high mortality, a working group was created by the Dutch Society of Cardiology to examine how the most recent European Society of Cardiology (ESC) guidelines for IE management could be implemented most effectively in the Netherlands. In order to investigate current Dutch IE practices, the working group conducted a country-wide survey. Based on the results obtained, it was concluded that most ESC recommendations could be endorsed, albeit with some adjustments. For instance, the suggested pre-operative screening and treatment of nasal carriers of Staphylococcus aureus as formulated in the ESC guideline was found to be dissimilar to current Dutch practice, and was therefore made less restrictive. The recently adapted ESC diagnostic criteria for IE were endorsed, while the practical employment of the relevant diagnostic techniques was simplified in an adapted flowchart. In addition, the presence of a multidisciplinary, so-called 'endocarditis team' in tertiary centres was proposed as a quality indicator. An adapted flowchart specifically tailored to Dutch practice for microbiological diagnostic purposes was constructed. Lastly, the working group recommended the Stichting Werkgroep Antibioticabeleid (SWAB; Dutch Working Party on Antibiotic Policy) guidelines for IE treatment instead of the antibiotic regimens proposed by the ESC.

The temporal pole (TP) is an associative cortical region required for complex cognitive functions such as social and emotional cognition. However, mapping the TP with functional magnetic resonance imaging is technically challenging and thus understanding its interaction with other key emotional circuitry, such as the amygdala, remains elusive. We exploited the unique advantages of stereo-electroencephalography (sEEG) to assess the responses of the TP and the amygdala during the perception of emotionally salient stimuli of pictures, music and movies. These stimuli consistently elicited high gamma responses (70-140 Hz) in both the TP and the amygdala, accompanied by functional connectivity in the low frequency range (2-12 Hz). Computational analyses suggested that the TP drove this effect in the theta frequency range, modulated by the emotional valence of the stimuli. Notably, cross-frequency analysis indicated the phase of theta oscillations in the TP modulated the amplitude of high gamma activity in the amygdala. These results were reproducible across three types of sensory inputs including naturalistic stimuli. Our results suggest that multimodal emotional stimuli induce a hierarchical influence of the TP over the amygdala., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Obligate anaerobic bacteria from the genus Pectinatus have been known to cause beer spoilage for over 40 years. Whole genome sequencing was performed on eleven beer spoilage strains (nine Pectinatus frisingensis, one Pectinatus cerevisiiphilus and one Pectinatus haikarae isolate), as well as two pickle spoilage species (Pectinatus brassicae MB591 and Pectinatus sottacetonis MB620) and the tolerance of all species to a range of environmental conditions was tested. Exploration of metabolic pathways for carbohydrates, amino acids and vitamins showed little difference between beer spoilage- and pickle spoilage-associated strains. However, genes for certain carbohydrate- and sulphur-containing amino acid-associated enzymes were only present in the beer spoilage group and genes for specific transporters and regulatory genes were uniquely found in the pickle spoilage group. Transporters for compatible solutes, only present in pickle-associated strains, likely explain their experimentally observed higher halotolerance compared to the beer spoilers. Genes involved in biofilm formation and ATP Binding Cassette (ABC) transporters potentially capable of exporting hop-derived antimicrobial compounds were found in all strains. All species grew in the presence of alcohol up to 5% alcohol by volume (ABV) and hops extract up to 80 ppm of iso-α-acids. Therefore, the species isolated from pickle processes may pose novel hazards in brewing., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Food may trigger Attention-Deficit/Hyperactivity Disorder (ADHD) symptoms. Therefore, an elimination diet (ED) might be an effective treatment for children with ADHD. However, earlier studies were criticized for the nature of the control group, potential confounders explaining the observed effects, unsatisfactory blinding, potential risks of nutritional deficiencies and unknown long term and cost-effectiveness. To address these issues, this paper describes the rationale, study design and methods of an ongoing two arm randomized controlled trial (RCT) comparing the short (5 week) and long term (1 year) effects of an elimination diet and a healthy diet compared with care as usual (CAU) in children with ADHD., Methods: A total of N = 162 children (5-12 years) with ADHD will be randomized to either an ED or a healthy diet. A comparator arm including N = 60 children being solely treated with CAU (e.g. medication) is used to compare the effects found in both dietary groups. The two armed RCT is performed in two youth psychiatry centers in the Netherlands, with randomization within each participating center. The primary outcome measure is response to treatment defined as a ≥ 30% reduction on an ADHD DSM-5 rating scale (SWAN) and/or on an emotion dysregulation rating scale (SDQ: dysregulation profile). This is assessed after 5 weeks of dietary treatment, after which participants continue the diet or not. Secondary outcome measures include the Disruptive Behavior Diagnostic Observational Schedule (DB-DOS), parent and teacher ratings of comorbid symptoms, cognitive assessment (e.g. executive functions), school functioning, physical measurements (e.g. weight), motor activity, sleep pattern, food consumption, nutritional quality of the diet, adherence, parental wellbeing, use of health care resources and cost-effectiveness. Assessments take place at the start of the study (T0), after five weeks (T1), four months (T2), eight months (T3) and 12 months of treatment (T4). T0, T1 and T4 assessments take place at one of the psychiatric centers. T2 and T3 assessments consist of filling out online questionnaires by the parents only., Discussion: This RCT will likely contribute significantly to clinical practice for ADHD by offering insight into the feasibility, nutritional quality, (cost-)effectiveness and long term effects of dietary treatments for ADHD., Trial Registration: www.trialregister.nl, NTR5434. Registered at October 11th, 2015.

Viruses are the most abundant biological entities in marine environments, however, despite its potential ecological implications, little is known about virus removal by ambient non-host organisms. Here, we examined the effects of a variety of non-host organisms on the removal of viruses. The marine algal virus PgV-07T (infective to Phaeocystis globosa) can be discriminated from bacteriophages using flow cytometry, facilitating its use as a representative model system. Of all the non-host organisms tested, anemones, polychaete larvae, sea squirts, crabs, cockles, oysters and sponges significantly reduced viral abundance. The latter four species reduced viral abundance the most, by 90, 43, 12 and 98% over 24 h, respectively. Breadcrumb sponges instantly removed viruses at high rates (176 mL h -1 g tissue dry wt -1 ) which continued over an extended period of time. The variety of non-host organisms capable of reducing viral abundance highlights that viral loss by ambient organisms is an overlooked avenue of viral ecology. Moreover, our finding that temperate sponges have the huge potential for constant and effective removal of viruses from the water column demonstrates that natural viral loss has, thus far, been underestimated.