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Light use is rising steeply, mainly because of the advent of light-emitting diode (LED) devices. LEDs are frequently blue-enriched light sources and may have different impacts on the non-image forming (NIF) system, which is maximally sensitive to blue-wavelength light. Most importantly, the timing of LED device use is widespread, leading to novel light exposure patterns on the NIF system. The goal of this narrative review is to discuss the multiple aspects that we think should be accounted for when attempting to predict how this situation will affect the NIF impact of light on brain functions. We first cover both the image-forming and NIF pathways of the brain. We then detail our current understanding of the impact of light on human cognition, sleep, alertness, and mood. Finally, we discuss questions concerning the adoption of LED lighting and screens, which offer new opportunities to improve well-being, but also raise concerns about increasing light exposure, which may be detrimental to health, particularly in the evening.

The Mousepost 1.0 online search tool, launched in 2017, allowed to search for variations in all protein-coding gene sequences of 36 sequenced mouse inbred strains, compared to the reference strain C57BL/6J, which could be linked to strain-specific phenotypes and modifier effects. Because recently these genome sequences have been significantly updated and sequences of 16 extra strains added by the Mouse Genomes Project, a profound update, correction and expansion of the Mousepost 1.0 database has been performed and is reported here. Moreover, we have added a new class of protein disturbing sequence polymorphisms (besides stop codon losses, stop codon gains, small insertions and deletions, and missense mutations), namely start codon mutations. The current version, Mousepost 2.0 (https://mousepost.be), therefore is a significantly updated and invaluable tool available to the community and is described here and foreseen by multiple examples.

Whether treatment response in patients with Parkinson disease depends on brain atrophy is insufficiently understood. The goal of this study is to identify specific atrophy patterns associated with response to dopaminergic therapy and deep brain stimulation.In this study, we analyzed the association of gray matter brain atrophy patterns, as identified by voxel-based morphometry, with acute response to levodopa (N = 118) and subthalamic nucleus deep brain stimulation (N = 39). Motor status was measured as a change in points on the Unified Parkinson's Disease Rating Scale III score. Baseline values were obtained before surgery, after cessation of dopaminergic medication for at least 12 hours; response to medication was assessed after administration of a standardized dose of levodopa. Response to deep brain stimulation was measured three months after surgery in the clinical condition after withdrawal of dopaminergic medication.Although frontoparietal brain gray matter loss was associated with subpar response to deep brain stimulation, there was no significant link between brain atrophy and response to levodopa.We conclude that response to deep brain stimulation relies on gray matter integrity; hence, gray matter loss may present a risk factor for poor response to deep brain stimulation and may be considered when making decision regarding clinical practice.

We report the detection of 5-vinyluridine (5-VUrd) in RNA at single nucleotide resolution via mutational profiling.

While multi-drug combinations and continuous treatment have become standard for multiple myeloma, the disease remains incurable. Repurposing drugs that are currently used for other indications could provide a novel approach to improve the therapeutic efficacy of standard multiple myeloma treatments. Here, we assessed the anti-tumor effects of cardiac drugs called β-blockers as a single agent and in combination with commonly used anti-myeloma therapies. Expression of the β 2-adrenergic receptor correlated with poor survival outcomes in patients with multiple myeloma. Targeting the β 2-adrenergic receptor (β 2AR) using either selective or non-selective β-blockers reduced multiple myeloma cell viability, and induced apoptosis and autophagy. Blockade of the β 2AR modulated cancer cell metabolism by reducing the mitochondrial respiration as well as the glycolytic activity. These effects were not observed by blockade of β 1-adrenergic receptors. Combining β 2AR blockade with the chemotherapy drug melphalan or the proteasome inhibitor bortezomib significantly increased apoptosis in multiple myeloma cells. These data identify the therapeutic potential of β 2AR-blockers as a complementary or additive approach in multiple myeloma treatment and support the future clinical evaluation of non-selective β-blockers in a randomized controlled trial.

OBJECTIVE The treatment of symptomatic, progressive or recurrent acquired intracerebral cysts is challenging, especially when they are localized in eloquent structures. In addition to resection, endoscopic fenestration, or stereotactic puncture, the implantation of a cystoventricular shunt by stereotactic guidance (SCVS) has been reported as a minimally invasive procedure; however, only scarce data are available regarding its feasibility and efficacy. Here, the authors evaluated the feasibility and efficacy of frame-based SCVS in patients with acquired intracranial cysts. METHODS In this single-center retrospective analysis, the authors included all patients with acquired intracerebral cysts treated by SCVS following a standardized prospective protocol between 2012 and 2020. They analyzed clinical symptoms, complications, and radiological outcome with regard to cyst volume reduction by 3D volumetry. RESULTS Thirty-four patients (17 females and 17 males; median age 44 years, range 5–77 years) were identified. The median initial cyst volume was 11.5 cm3 (range 1.6–71.6 cm3), and the mean follow-up was 20 months (range 1–82 months). At the last follow-up, 27 of 34 patients (79%) showed a cyst volume reduction of more than 50%. Initial symptoms improved or resolved in 74% (n = 25) and remained stable in 24% (n = 8). No permanent clinical deterioration after treatment was observed. The total complication rate was 5.9%, comprising transient neurological deterioration (n = 1) and ventriculitis (n = 1). There were no deaths. The overall recurrence rate was 11.8%. CONCLUSIONS In this study, SCVS proved to be a safe, minimally invasive, and effective treatment with reliable long-term volume reduction, resulting in clinical improvement and a minor complication rate.

The genetic characteristics of neutral loci in natural populations are shaped by the interplay between genetic drift and gene flow that themselves result from key ecological and evolutionary processes. Because of their influence on population size, habitats characteristics may influence substantially populations' genetic characteristics. However, past studies focused primarily on variables related to habitat quantity while habitat quality was largely overlooked. We therefore combined genetic data to detailed habitat descriptions of three sympatric butterfly species having different ecological needs to quantify the relative contribution of geographic distance and habitat quality/quantity on their genetic characteristics. In all species, the genetic diversity was greater in larger and good quality patches. The genetic differentiation of Lycaena helle (specialist species with limited dispersal) was mostly explained by geographical distances. This effect was dampened by habitat quality as populations inhabiting low quality patches had higher genetic differentiations indicating that the constraints set by local environmental factors increased genetic drift. In Boloria eunomia (specialist species with greater dispersal), the genetic differentiation was only influenced by geographic distance. Finally, in Brenthis ino (more generalist species with greater dispersal), isolation-by-distance was weak and habitat characteristics were unrelated to genetic differentiation. The different effect of habitat quality on these species' genetic characteristics suggests that fundamental ecological traits underpin their response to habitat degradation. In L. helle, a species with major conservation concerns, these results show that preserving habitat quality and connectivity among populations' are important to ensure the maintenance of fully functional metapopulations.

The Couffo basin is not well known, and neither are its aquatic living resources, such as fish fauna, which are subjected to high exploitation rates. The objectives of this study were to establish length-weight ratios (LWRs) and length-length ratios (LLRs) for the most important species in the catches and those of certain economic value. A total of 12,191 specimens belonging to 40 commercial species of actinopterygian fishes were caught with several fishing gears and methods between February 2018 and March 2021. Allometric coefficient b of the LWRs (BW = a × TL b ) ranged from 2.194 for Enteromius callipterus to 3.673 for Protopterus annectens with a mean of 2.902 ± 0.315. The growth of thirteen species was isometric, that of fourteen species was negatively allometric, and that of the remaining thirteen species was positively allometric. Coefficient of determination r2 for the LLRs of 39 of the 40 selected species mentioned above was significant and ranged from 0.781 in Gobionellus occidentalis to 0.997 in Elops senegalensis with a mean value of 0.951 ± 0.049. The results will be useful for further studies on assessments of population dynamics and the sustainable conservation of the already limited fish stocks in the Couffo River basin.

ObjectiveThis study aims to shed light on structural networks associated with stimulation-induced dysarthria (SID) and to derive a data-driven model to predict SID in patients with Parkinson’s Disease (PD) and deep brain stimulation (DBS) of the subthalamic nucleus (STN).MethodsRandomized, double-blinded monopolar reviews determining SID thresholds were conducted in 25 patients with PD and STN-DBS. A fiber-based mapping approach, based on the calculation of fiber-wise Odds Ratios for SID, was employed to identify the distributional pattern of SID in the STN’s vicinity. The ability of the data-driven model to classify stimulation volumes as “causing SID” or “not causing SID” was validated by calculating receiver operating characteristics (ROC) in an independent out-of-sample cohort comprising 14 patients with PD and STN-DBS.ResultsLocal fiber-based stimulation maps showed an involvement of fibers running lateral and postero-medial to the STN in the pathogenesis of SID, independent of the investigated hemisphere. ROC-analysis in the independent out-of-sample cohort resulted in a good fit of the data-driven model for both hemispheres (AUCleft= 0.88, AUCright= 0.88).InterpretationThis study reveals an involvement of both, cerebello-thalamic fibers, as well as the pyramidal tract, in the pathogenesis of SID in STN-DBS. The results may impact future postoperative programming strategies to avoid SID in patients with PD and STN-DBS.

Exposure to blue wavelength light stimulates alertness and performance by modulating a widespread set of task-dependent cortical and subcortical areas. How light affects the crosstalk between brain areas to trigger this stimulating effect is not established. We recorded the brain activity of 19 healthy young participants (24.05±2.63; 12 women) while they completed an auditory attentional task in darkness or under an active (blue-enriched) or a control (orange) light, in an ultra-high-field 7 Tesla MRI scanner. We tested if light modulated the effective connectivity between an area of the posterior associative thalamus, encompassing the pulvinar, and the intraparietal sulcus (IPS), key areas in the regulation of attention. We found that only the blue-enriched light strengthened the connection from the posterior thalamus to the IPS. Our results provide the first empirical data supporting that blue wavelength light affects ongoing non-visual cognitive activity by modulating task-dependent information flow from subcortical to cortical areas.

Light triggers numerous non-image forming (NIF), or non-visual, biological effects. The brain correlates of these NIF effects have been investigated, notably using Magnetic Resonance Imaging (MRI) and short light exposures varying in irradiance and spectral quality. However, it is not clear whether having light in subsequent blocks may induce carry over effects of one light block onto the next, thus biasing the study. We reasoned that pupil light reflex (PLR) was an easy readout of one of the NIF effects of light that could be used to address this issue. We characterized the sustained PLR in 13 to 16 healthy young individuals under short light exposures during three distinct cognitive processes (executive, emotional and attentional). Light conditions pseudo-randomly alternated between monochromatic orange light [0.16 melanopic Equivalent Daylight Illuminance (mel EDI) lux] and polychromatic blue-enriched white light of three different levels [37, 92, 190 mel EDI lux]. As expected, higher melanopic irradiance was associated with larger sustained PLR in each cognitive domain. This result was stable over the light block sequence under higher melanopic irradiance levels as compared to lower ones. Exploratory frequency-domain analyses further revealed that PLR was more variable within a light block under lower melanopic irradiance levels. Importantly, PLR varied across tasks independently of the light condition pointing to a potential impact of the light history and/or cognitive context on PLR. Together, our results emphasize that the distinct contribution and adaptation of the different retinal photoreceptors influence the NIF effects of light and therefore potentially their brain correlates.

Light has many non-image-forming functions including modulation of pupil size and stimulation of alertness and cognition. Part of these non-image-forming effects may be mediated by the brainstem locus coeruleus. The processing of sensory inputs can be associated with a transient pupil dilation that is likely driven in part by the phasic activity of the locus coeruleus. Here, we aimed to characterise the task-evoked pupil response associated with auditory inputs under different light levels and across two cognitive tasks. We continuously monitored the pupil of 20 young healthy participants (24.05y ±4.0; 14 women) while they completed an attentional and an emotional auditory task whilst exposed to repeated 30-to-40s-blocks of light interleaved with darkness periods. Blocks could either consist of monochromatic orange light [0.16 melanopic Equivalent Daylight Illuminance (EDI) lux] or blue-enriched white light of three different levels [37, 92, 190 melanopic EDI lux; 6500K]. For the analysis 15 and then 14 participants were included in the attentional and emotional tasks respectively. Generalized Linear Mixed Models showed a significant main effect of light level on the task-evoked pupil responses triggered by the attentional and emotional tasks (p≤.0001). The impact of light was different for the target vs. non-target stimulus of the attentional task but was not different for the emotional and neutral stimulus of the emotional task. Despite a smaller sustained pupil size during brighter light blocks, a higher light level triggers a stronger task-evoked pupil response to auditory stimulation, presumably through the recruitment of the locus coeruleus.

IntroductionPolymicrobial sepsis causes acute anorexia (loss of appetite), leading to lipolysis in white adipose tissue and proteolysis in muscle, and thus release of free fatty acids (FFAs), glycerol and gluconeogenic amino acids. Since hepatic peroxisome proliferator-activated receptor alpha (PPARα) and glucocorticoid receptor (GR) quickly lose function in sepsis, these metabolites accumulate (causing toxicity) and fail to yield energy-rich molecules such as ketone bodies (KBs) and glucose. The mechanism of PPARα and GR dysfunction is not known.Methods & resultsWe investigated the hypothesis that hypoxia and/or activation of hypoxia inducible factors (HIFs) might play a role in these issues with PPARα and GR. After cecal ligation and puncture (CLP) in mice, leading to lethal polymicrobial sepsis, bulk liver RNA sequencing illustrated the induction of the genes encoding HIF1α and HIF2α, and an enrichment of HIF-dependent gene signatures. Therefore, we generated hepatocyte-specific knock-out mice for HIF1α, HIF2α or both, and a new HRE-luciferase reporter mouse line. After CLP, these HRE-luciferase reporter mice show signals in several tissues, including the liver. Hydrodynamic injection of an HRE-luciferase reporter plasmid also led to (liver-specific) signals in hypoxia and CLP. Despite these encouraging data, however, hepatocyte-specific HIF1α and/or HIF2α knock-out mice suggest that survival after CLP was not dependent on the hepatocyte-specific presence of HIF proteins, which was supported by measuring blood levels of glucose, FFAs, and KBs. The HIF proteins were also irrelevant in the CLP-induced glucocorticoid resistance, but we found indications that the absence of HIF1α in hepatocytes causes less inactivation of PPARα transcriptional function.ConclusionWe conclude that HIF1α and HIF2α are activated in hepatocytes in sepsis, but their contribution to the mechanisms leading to lethality are minimal.

IntroductionDeep brain stimulation (DBS) is an established treatment in patients with pharmaco-resistant neurological disorders of different ages. Surgical targeting and postoperative programming of DBS depend on the spatial location of the stimulating electrodes in relation to the surrounding anatomical structures and on electrode connectivity to a specific distributed pattern of brain networks. Such information is usually collected using group-level analysis which relies on the availability normative imaging-resources (atlases and connectomes). To this end, analyzing DBS data of children with debilitating neurological disorders like dystonia would make benefit from such resources, especially given the developmental differences between adults and children neuroimaging data. We assembled pediatric, normative neuroimaging-resources from open-access neuroimaging datasets and illustrated their utility on a cohort of children with dystonia treated with pallidal DBS. We aimed to derive a local pallidal sweetspot and explore a connectivity fingerprint associated with pallidal stimulation to exemplify the utility of the assembled imaging resources.MethodsA pediatric average brain template was implemented and used to localize DBS electrodes of twenty patients of the GEPESTIM registry cohort. Next, a pediatric subcortical atlas was also employed to highlight anatomical structures of interest. Local pallidal sweetspot was modeled and its degree of overlap with stimulation volumes was calculated as a correlate of individual clinical outcome. Additionally, a pediatric functional connectome of neurotypical subjects was built to allow network-based analyses and decipher a connectivity fingerprint responsible for clinical improvement in our cohort.ResultsWe successfully implemented a pediatric neuroimaging dataset that will be made available to public use as a tool for DBS-analyses. Overlap of stimulation volumes with the identified DBS-sweetspot model correlated significantly with improvement on a local spatial level (R = 0.46,permuted p= 0.019). Functional connectivity fingerprint of DBS-outcome was determined as a network correlate of therapeutic pallidal stimulation in children with dystonia (R = 0.30,permuted p= 0.003).ConclusionsLocal sweetspot and distributed network models provide neuroanatomical substrates for DBS-associated clinical outcome in dystonia using pediatric neuroimaging surrogate data. The current implementation of pediatric neuroimaging dataset might help improving the practice of DBS-neuroimaging analyses in pediatric patients.

The locus coeruleus (LC) is the primary source of norepinephrine (NE) in the brain, and the LC-NE system is involved in regulating arousal and sleep. It plays key roles in the transition between sleep and wakefulness, and between slow wave sleep (SWS) and rapid eye movement sleep (REMS). However, it is not clear whether the LC activity during the day predicts sleep quality and sleep properties during the night, and how this varies as a function of age. Here, we used 7 Tesla functional Magnetic Resonance Imaging (7T fMRI), sleep electroencephalography (EEG) and a sleep questionnaire to test whether the LC activity during wakefulness was associated with sleep quality in 52 healthy younger (N=33; ~22y; 28 women) and older (N=19; ~61y; 14 women) individuals. We find that, in older, but not in younger participants, higher LC activity, as probed during an auditory mismatch negativity task, is associated with worse subjective sleep quality and with lower power over the EEG theta band during REMS (4-8Hz), which are two sleep parameters significantly correlated in our sample of older individuals. The results remain robust even when accounting for the age-related changes in the integrity of the LC. These findings suggest that the activity of the LC may contribute to the perception of the sleep quality and to an essential oscillatory mode of REMS, and that the LC may be an important target in the treatment of sleep disorders and age-related diseases.

ZusammenfassungAufgrund steigender Fallzahlen der Alzheimer-Erkrankung und bislang eher mäßigem Erfolg der verfügbaren symptomatischen und kausalen pharmakologischen Therapien besteht ein erheblicher Bedarf, nicht-pharmakologische Behandlungsmöglichkeiten zu erforschen. Im Bereich der nicht-invasiven Hirnstimulation (non-invasive brain stimulation; NIBS) wurden verschiedene Verfahren untersucht, insbesondere die transkranielle Magnetstimulation und die transkranielle elektrische Stimulation. Zusätzlich wird derzeit die Tiefe Hirnstimulation (deep brain stimulation; DBS) als innovatives Verfahren zur gezielten Neuromodulation erforscht. Nicht-invasiven und invasiven Ansätzen gemein ist der Versuch, neuronale Aktivität zu modulieren und kognitiv-mnestische Funktionen zu verbessern. Durch sekundäre Mechanismen wie die Langzeit-Potenzierung bei NIBS oder Neurogenese bei DBS könnten auch längerfristige positive Effekte erzielt werden. Präklinische und klinische Studien ergaben bereits vielversprechende Ergebnisse bei Patientinnen und Patienten in frühen Stadien der Alzheimer-Erkrankung. Inkonsistente Studien- und Stimulationsprotokolle sowie kleine Stichproben erschweren jedoch die Bewertung der Wirksamkeit. Weitere Forschungsbemühungen sind angebracht, um einen zeitnahen Einzug nicht-invasiver oder invasiver neuromodulatorischer Ansätze in die klinische Praxis zu ermöglichen.

OBJECTIVE To obtain individual clinical and neuroimaging data of patients undergoing Deep Brain Stimulation for essential tremor from five different European centers to identify predictors of outcome and to identify an optimal stimulation site. METHODS We analysed retrospectively baseline covariates, pre- and postoperative clinical tremor scores (12-month) as well as individual imaging data from 119 patients to obtain individual electrode positions and stimulation volumes. Individual imaging and clinical data was used to calculate a probabilistic stimulation map in normalized space using voxel-wise statistical analysis. Finally, we used this map to train a classifier to predict tremor improvement. RESULTS Probabilistic mapping of stimulation effects yielded a statistically significant cluster that was associated with a tremor improvement greater than 50%. This cluster of optimal stimulation extended from the posterior subthalamic area to the ventralis intermedius nucleus and coincided with a normative structural-connectivity-based cerebello-thalamic tract (CTT). The combined features "distance between the stimulation volume and the significant cluster" and "CTT activation" were used as a predictor of tremor improvement. This correctly classified a greater than 50% tremor improvement with a sensitivity of 89% and a specificity of 57%. INTERPRETATION Our multicentre ET probabilistic stimulation map identified an area of optimal stimulation along the course of the CTT. The results of this study are mainly descriptive until confirmed in independent datasets, ideally through prospective testing. This target will be made openly available and may be used to guide surgical planning and for computer-assisted programming of deep brain stimulation in the future. This article is protected by copyright. All rights reserved.

BACKGROUND: The majority of opioid overdose admissions in pediatric patients are associated with prescription opioids. Post-operative prescriptions are an addressable source of opioids in the household. This study aims to assess for sustained reduction in opioid prescribing after implementation of provider-based education at nine centers. METHODS: Opioid prescribing information was collected for pediatric patients undergoing umbilical hernia repair at nine centers between December 2018 and January 2019, one year after the start of an education intervention. This was compared to prescribing patterns in the immediate pre- and post-intervention periods at each of the nine centers. RESULTS: In the current study period, 29/127 (22.8%) patients received opioid prescriptions (median 8 doses) following surgery. There were no medication refills, emergency department returns or readmissions related to the procedure. There was sustained reduction in opioid prescribing compared to pre-intervention (22.8% vs 75.8% of patients, p

Background: The satisfaction with life and, in particular, with treatment in Parkinson’s disease (PD) is understudied. Objective: To explore a new 7-item rating tool assessing satisfaction with life and treatment (SLTS-7) in PD. Methods: In this cross-sectional, multi-center study, including patients screened for advanced therapies, psychometric characteristics of the SLTS-7 were analyzed. An exploratory factor analysis identified the underlying factorial structure of the SLTS-7. Results: 117 patients were included, and the data quality of the SLTS-7 was excellent (computable data 100%), and acceptability measures satisfied standard criteria. Besides the global assessment (item 1), the exploratory factor analysis produced item 2 (physical satisfaction) as an independent item and two factors among the remaining items: items 3–5 (psycho-social satisfaction), and items 6 and 7 (treatment satisfaction). Cronbach’s alpha was 0.89, indicative of high internal consistency. The SLTS-7 total score correlated moderately with motor symptoms and weakly with non-motor symptoms total scores. SLTS-7 showed the highest correlations with the European Quality of Life with 5 items (EQ-5D) visual analog scale (0.43–0.58, p

We investigate the parameter estimation of regression models with fixed group effects, when the group variable is missing while group related variables are available. This problem involves clustering to infer the missing group variable based on the group related variables, and regression to build a model on the target variable given the group and eventually additional variables. Thus, this problem can be formulated as the joint distribution modeling of the target and of the group related variables. The usual parameter estimation strategy for this joint model is a two-step approach starting by learning the group variable (clustering step) and then plugging in its estimator for fitting the regression model (regression step). However, this approach is suboptimal (providing in particular biased regression estimates) since it does not make use of the target variable for clustering. Thus, we claim for a simultaneous estimation approach of both clustering and regression, in a semi-parametric framework. Numerical experiments illustrate the benefits of our proposition by considering wide ranges of distributions and regression models. The relevance of our new method is illustrated on real data dealing with problems associated with high blood pressure prevention.

The brainstem locus coeruleus (LC) influences a broad range of brain processes, including cognition. The so-called LC contrast is an accepted marker of the integrity of the LC that consists of a local hyperintensity on specific Magnetic Resonance Imaging (MRI) structural images. The small size of the LC has, however, rendered its functional characterization difficult in humans, including in aging. A full characterization of the structural and functional characteristics of the LC in healthy young and late middle-aged individuals is needed to determine to potential roles of the LC in different medical conditions. Here, we wanted to determine whether the activation of the LC in a mismatch negativity task changes in aging and whether the LC functional response was associated to the LC contrast. We used Ultra-High Field (UHF) 7-Tesla functional MRI (fMRI) to record brain response during an auditory oddball task in 53 healthy volunteers, including 34 younger (age: 22.15y ± 3.27; 29 women) and 19 late middle-aged (age: 61.05y ± 5.3; 14 women) individuals. Whole-brain analyses confirmed brain responses in the typical cortical and subcortical regions previously associated with mismatch negativity. When focusing on the brainstem, we found a significant response in the rostral part of the LC probability mask generated based on individual LC images. Although bilateral, the activation was more extensive in the left LC. Individual LC activity was not significantly different between young and late middle-aged individuals. Critically, while the LC contrast was higher in older individuals, the functional response of the LC was not associated with its contrast. These findings show that the age-related alterations of the LC structural integrity may not necessarily be related to changes in its functional response. The results further indicate that LC responses could remain stable in healthy individuals aged 20 to 70.

In the framework of model-based clustering, a model, called multi-partitions clustering, allowing several latent class variables has been proposed. This model assumes that the distribution of the observed data can be factorized into several independent blocks of variables, each block following its own mixture model. In this paper, we assume that each block follows a non parametric latent class model, {\it i.e.} independence of the variables in each component of the mixture with no parametric assumption on their class conditional distribution. The purpose is to deduce, from the observation of a sample, the number of blocks, the partition of the variables into the blocks and the number of components in each block, which characterise the proposed model. By following recent literature on model and variable selection in non-parametric mixture models, we propose to discretize the data into bins. This permits to apply the classical multi-partition clustering procedure for parametric multinomials, which are based on a penalized likelihood method (\emph{e.g.} BIC). The consistency of the procedure is obtained and an efficient optimization is proposed. The performances of the model are investigated on simulated data.

Obsessive-compulsive disorder is among the most disabling psychiatric disorders. Although deep brain stimulation is considered an effective treatment, its use in clinical practice is not fully established. This is, at least in part, due to ambiguity about the best suited target and insufficient knowledge about underlying mechanisms. Recent advances suggest that changes in broader brain networks are responsible for improvement of obsessions and compulsions, rather than local impact at the stimulation site. These findings were fueled by innovative methodological approaches using brain connectivity analyses in combination with neuromodulatory interventions. Such a connectomic approach for neuromodulation constitutes an integrative account that aims to characterize optimal target networks. In this critical review, we integrate findings from connectomic studies and deep brain stimulation interventions to characterize a neural network presumably effective in reducing obsessions and compulsions. To this end, we scrutinize methodologies and seemingly conflicting findings with the aim to merge observations to identify common and diverse pathways for treating obsessive-compulsive disorder. Ultimately, we propose a unified network that-when modulated by means of cortical or subcortical interventions-alleviates obsessive-compulsive symptoms. https://doi.org/10.1016/j.biopsych.2021.07.010

Sleep is essential for the maintenance of human physical health (Grandner et al., 2012; Reid et al., 2006), cognitive performance (Ferrie et al., 2011; Leng et al., 2017), and mental health (Freeman et al., 2017; Joao et al., 2018). Experimental sleep deprivation and different degrees of sleep restriction permit the characterization of human sleep behaviors and brain's responses to inadequate sleep (Durmer and Dinges, 2005; Elmenhorst et al., 2017; Elmenhorst et al., 2018; Van Dongen et al., 2003). Sleep disruption is known to impact not only brain functions but also affects brain anatomy; earlier studies found that sleep deprivation is associated with lower volumes of gray matter across various brain regions (Åkerstedt et al., 2020; Liu et al., 2014; Long et al., 2020; Sun et al., 2020), however with inconsistent localization of effects. Other studies reported alterations in white matter microstructure (Elvsåshagen et al., 2015; Voldsbekk et al., 2021), increased ventricles size, and cognitive decline (Lo et al., 2014). In addition, one-night sleep deprivation was found to increase the Aβ burden in the right hippocampus and thalamus of healthy controls (Shokri-Kojori 2018), suggesting an interrupted clearance pathway due to sleep deprivation. These prior studies suggest that sleep deprivation may impact anatomical features of the brain, but there is a need for large-scale replications and extensions of previous work. Increased brain age compared to chronological age is a risk factor for several neurodegenerative and psychiatric disorders (Wyss-Coray, 2016). Brain-age prediction is a widely studied topic that aims to estimate the trajectory of brain aging (Franke et al., 2019), and its association with pathological conditions. MRI-derived features used to predict individuals’ brain age have proven to constitute a proxy for overall health (Habes et al., 2016, Koutsouleris et al., 2014, Cole et al., 2018). Sleep patterns also change with aging. In particular, older adults tend to sleep less, and present a more fragmented sleep with lower slow-wave sleep. They also present a reduced sleep rebound following sleep deprivation, report less sleepiness under acute sleep deprivation conditions, and report a smaller increase in lapses of attention after sleep deprivation [23]. However, little is known on whether brain-age models reflect the impact of sleep deprivation on the brain structure - i.e., the difference between predicted age and real age (so-called brain-age delta) using MRI data. We hypothesized that the morphological alterations associated with sleep deprivation would lead to an increased brain-delta score.

In the standard toolkit for recombinant protein expression, the yeast known in biotechnology asPichia pastoris(formally:Komagataella phaffii) takes up the position betweenE. coliand HEK293 or CHO mammalian cells, and is used by thousands of laboratories both in academia and industry. The organism is eukaryotic yet microbial, and grows to extremely high cell densities while secreting proteins into its fully defined growth medium, using very well established strong inducible or constitutive promoters. Many products made inPichiaare in the clinic and in industrial markets.Pichiais also a favoured host for the rapidly emerging area of ‘precision fermentation’ for the manufacturing of food proteins. However, the earliest steps in the development of the industrial strain (NRRL Y-11430/CBS 7435) that is used throughout the world were performed prior to 1985 in industry (Phillips Petroleum Company) and are not in the public domain. Moreover, despite the long expiry of associated patents, the patent deposit NRRL Y-11430/CBS 7435 that is the parent to all commonly used industrial strains, is not or no longer made freely available through the resp. culture collections. This situation is far from ideal for what is a major chassis for synthetic biology, as it generates concern that novel applications of the system are still encumbered by licensing requirements of the very basic strains. In the spirit of open science and freedom to operate for what is a key component of biotechnology, we set out to resolve this by using genome sequencing of type strains, reverse engineering where necessary, and comparative protein expression and strain characterisation studies. We find that the industrial strains derive from theK. phaffiitype strain lineage deposited as 54-11.239 in the UC Davis Phaff Yeast Strain collection by Herman Phaff in 1954. This type strain has valid equivalent deposits that are replicated/derived from it in other yeast strain collections, incl. in ARS-NRRL NRRL YB-4290 (deposit also made by Herman Phaff) and NRRL Y-7556, CBS 2612 and NCYC 2543. We furthermore discovered that NRRL Y-11430 and its derivatives carry an ORF-truncating mutation in theHOC1cell wall synthesis gene, and that reverse engineering of a similar mutation in the NCYC 2543 type strain imparts the high transformability that is characteristic of the industrial strains. Uniquely, the NCYC 2543 type strain, which we propose to call ‘OPENPichia’ henceforth, is freely available from the NCYC culture collection, incl. resale and commercial production licenses at nominal annual licensing fees1. Furthermore, our not-for-profit research institute VIB has also acquired a resale/distribution license from NCYC, which we presently use to openly provide to end-users our genome-sequenced OPENPichia subclone strain and its derivatives, i.e., currently the highly transformablehoc1trand thehis4auxotrophic mutants. To complement the OPENPichia platform, a fully synthetic modular gene expression vector building toolkit was developed, which is also openly distributed, for any purpose. We invite other researchers to contribute to our open science resource-building effort to establish a new unencumbered standard chassis forPichiasynthetic biology.

Poor sleep quality and sleep disorders, including obstructive sleep apnea and insomnia disorder, are considered important potential risk factors for cognitive decline and dementia, including Alzheimer's disease (AD). Potential reasons include sleep fragmentation, intermittent hypoxia, and immune dysfunction, which may precede lower Amyloid β (Aβ) clearance from the brain and increased Aβ and tau depositions (Emamian et al., 2016; Bucks et al., 2017; Xu et al., 2020). Sleep deprivation also affects the molecular signaling pathways in the hippocampus that are required for synaptic consolidation during memory formation (Havekes et al., 2017). Recently, the association between insufficient or excessive sleep duration (≤4 or ≥10 hours per night) and cognitive decline has been demonstrated in a large-scale study (Ma et al., 2020), suggesting that cognitive performance should be carefully monitored in individuals with short or long sleep duration. Similarly, another study assessing the link between sleep and cognitive performance in ∼500,000 older adults from the UK-Biobank revealed that abnormal sleep duration is linked to cognitive impairment (Kyle et al., 2017). In addition, the previous behavioral studies on the link between sleep and cognition have been mostly limited to the subjective assessment of sleep and are usually restricted to a population from a single country. Moreover, the neurobiological underpinnings of their association are still poorly understood. On the other hand, several studies have highlighted the key role of apolipoprotein E (APOE) ε4 on brain network connectivity, memory performance, and rate of cognitive decline in patients with minimal cognitive impairment (MCI), AD and cognitively unimpaired individuals. Thus, understanding the potential pathogenic link between sleep, APOE ε4, brain, and cognitive function might enable us to provide a model for earlier identification of people at increased risk of cognitive decline and dementia (Liu et al., 2013) that could be tested in future studies. Thus, the predictive role of objectively measured poor sleep quality on the cognitive performance of healthy adults, as well as the genetic and neurobiological mechanism of the interplay between sleep quality and cognitive functions, is still far from clear. To address these key questions on the road towards clinical translation, we propose a study to comprehensively assess the relationship between sleep, brain structure, APOE genotype, and cognitive functions in a large-scale worldwide population-based cohort throughout the ENIGMA-Sleep consortium (Tahmasian et al., 2021).

Introduction: Identifying patient-reported outcomes of the nurse-patient relationship is a priority in inpatient mental healthcare to guide clinical decision-making and quality improvement initiatives. Moreover, demonstrating nurse-sensitive patient outcomes can be a strategy to avoid further erosion of the specialism of psychiatric and/or mental health nursing. Aim/question: To measure nurse-sensitive patient outcomes of the nurse-patient relationship. Method: In a multicentred cross-sectional study, 296 inpatients admitted to five psychiatric hospitals completed the recently developed and validated Mental Health Nurse-Sensitive Patient Outcome-Scale (MH-NURSE-POS). The MH-NURSE-POS consists of 21 items (six-point Likert-scale) in four domains: 'growth', 'expression', 'control', and 'motivation'. Results: Participants displayed moderate to good average scores for the MH-NURSE-POS total (4.42) and domain scores (≥4.09). Especially outcomes related to 'motivation' to follow and stay committed to the treatment received high average scores (≥4.60). Discussion: The results demonstrate that patients perceive the nurse-patient relationship and the care given by psychiatric and/or mental health nurses as contributing to their treatment. Implications for practices: Patient-reported outcomes can guide nurses and managers to provide and organize nursing care and to build a nurse-patient relationship that has a positive impact on these outcomes. Additionally, outcomes can create nursing visibility as a profession in- and outside mental healthcare.

ispartof: pages:229-237 ispartof: 2022 Sixth IEEE International Conference on Robotic Computing (IRC) pages:229-237 ispartof: 2022 Sixth IEEE International Conference on Robotic Computing (IRC) location:Italy date:5 Dec - 7 Dec 2022 status: published

Sleep loss negatively affects brain function with repercussion not only on objective measures of performance but also on many subjective dimensions, including effort perceived for the completion of cognitive processes. This may be particularly important in aging, which is accompanied by important changes in sleep and wakefulness regulation. We aimed to determine whether subjectively perceived effort covaried with cognitive performance in healthy late-middle-aged individuals.We assessed effort and performance to cognitive tasks in 99 healthy adults (66 women; 50-70 years) during a 20-hr wake extension protocol, following 7 days of regular sleep and wake times and a baseline night of sleep in the laboratory. We further explored links with cortical excitability using transcranial magnetic stimulation coupled to electroencephalography.Perceived effort increased during wake extension and was highly correlated to subjective metrics of sleepiness, fatigue, and motivation, but not to variations in cortical excitability. Moreover, effort increase was associated with decreased performance to some cognitive tasks (psychomotor vigilance and two-back working memory task). Importantly, effort variations during wakefulness extension decreased from age 50 to 70 years, while more effort is associated with worse performance in older individuals.In healthy late-middle-aged individuals, more effort is perceived to perform cognitive tasks, but it is not sufficient to overcome the performance decline brought by lack of sleep. Entry in the seventh decade may stand as a turning point in the daily variations of perceived effort and its link with cognition. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Ocrelizumab demonstrated significant clinical benefit for the treatment of relapsing (RMS) and primary progressive (PPMS) multiple sclerosis (MS), an incurable disease characterized by disability progression. This study evaluated the clinical and economic impact of ocrelizumab relative to current clinical practice, including other disease-modifying therapies (DMT), available in Portugal.Markov models for MS were adapted to estimate the impact of ocrelizumab across three patient populations: treatment-naïve RMS, previously treated RMS, and PPMS. Health states were defined according to the Expanded Disability Status Scale. For RMS, the model further captured the occurrence of relapses and progression to secondary progressive multiple sclerosis (SPMS). A lifetime time-horizon and Portuguese societal perspective were adopted.For RMS patients, ocrelizumab was estimated to maximize the expected time (years) without progression to SPMS (10.50) relative to natalizumab (10.10), dimethyl fumarate (8.64), teriflunomide (8.39), fingolimod (8.38), interferon β-1a (8.33) and glatiramer acetate (8.18). As the most effective option, with quality-adjusted life year (QALY) gains between 0.3 and 1.2, ocrelizumab was found to be cost-saving relative to natalizumab and fingolimod, and presented incremental cost-effectiveness ratios (ICER) below €16,720/QALY relative to the remaining DMT. For PPMS patients, the ICER of ocrelizumab versus best supportive care was estimated at €78,858/QALY.Ocrelizumab provides important health benefits for RMS and PPMS patients, comparing favourably with other widely used therapies. In RMS, ocrelizumab was revealed to be either cost-saving or have costs-per-QALY likely below commonly accepted cost-effectiveness thresholds. In PPMS, ocrelizumab fills a clear clinical gap in the current clinical practice. Overall, ocrelizumab is expected to provide good value for money in addressing the need of MS patients.

Although dry eye is highly prevalent, many challenges exist in diagnosing the symptom and related diseases. For this reason, anionic hydrogel-coated gold nanoshells (AuNSs) were used in the development of a label-free biosensor for detection of high isoelectric point tear biomarkers associated with dry eye. A custom, aldehyde-functionalized oligo(ethylene glycol)acrylate (Al-OEGA) was included in the hydrogel coating to enhance protein recognition through the formation of dynamic covalent (DC) imine bonds with solvent-accessible lysine residues present on the surface of select tear proteins. Our results demonstrated that hydrogel-coated AuNSs, composed of monomers that form ionic and DC bonds with select tear proteins, greatly enhance protein recognition due to changes in the maximum localized surface plasmon resonance wavelength exhibited by AuNSs in noncompetitive and competitive environments. Validation of the developed biosensor in commercially available pooled human tears revealed the potential for clinical translation to establish a method for dry eye diagnosis.

BackgroundWe aimed to develop a single step method for the production of human platelet lysate (hPL). The method must result in high hPL yields, be closed system and avoid heparin use. Study Design and MethodsThe method aimed at using glass beads and calcium. An optimal concentration of calcium and glass beads was determined by serial dilution. This was translated to a novel method and compared to known methods: freeze-thawing and high calcium. Quality outcome measures were transmittance, fibrinogen and growth factor content, and cell doubling time. ResultsAn optimal concentration of 5 mM Ca2+ and 0.2 g/ml glass beads resulted in hPL with yields of 92% +/- 1% (n = 50) independent of source material (apheresis or buffy coat-derived). The transmittance was highest (56% +/- 9%) compared to known methods (

While evidence shows that dental erosion (DE) is often caused by gastroesophageal reflux disease (GERD), the relationship of DE severity to a patient's symptoms and receipt of appropriate medical treatment for GERD is not clearly understood. The purpose of this study was to evaluate the association between DE and GERD. Eighty participants underwent a Basic Erosive Wear Examination for DE and completed the Patient-Reported Outcomes Measurement Information System (PROMIS) survey on symptoms of gastrointestinal reflux (PROMIS Scale v1.0, Gastrointestinal Gastroesophageal Reflux 13a) in English. Patients with observed erosive patterns were referred for gastroenterologic evaluation. The association between DE and GERD was assessed using multiple regression. The results showed that the extent of DE was positively associated with GERD symptoms (B = 0.585; 95% CI, 0.21-0.96), as measured by the PROMIS survey, in participants without a current diagnosis of GERD. Of the 80 patients in the study, 28 with more severe DE were evaluated in the gastroenterology department. A diagnosis of GERD was established for 27 of the 28, 9 of whom denied a past history of the disease. Twenty patients with GERD underwent upper endoscopy, and esophageal lesions were found in 6 patients (erosive esophagitis in 5 and Barrett esophagus in 1). Patients with clinically identified DE may benefit from medical evaluation and, if necessary, management of GERD. For a subset of patients, DE may be the only clinical indication of untreated or undertreated GERD, which could lead to serious esophageal changes. Dentists should consider referring patients with DE to primary care providers or gastrointestinal specialists to ensure that systemic conditions are identified and managed appropriately.