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Background: Variant‐adapted COVID‐19 vaccines are recommended for patients with inflammatory bowel disease (IBD). However, many patients rely on pre‐existing immunity by original vaccines or prior infections. Aim: To assess whether such immunity sufficiently combats the highly immune‐evasive SARS‐CoV‐2 JN.1 variant. Methods: Utilising two longitudinal cohorts, we evaluated immunity against JN.1 induced by original vaccines (IBD: n = 98; healthy: n = 48), omicron breakthrough infection (IBD: n = 55; healthy: n = 57) or XBB.1.5‐adapted vaccines (IBD: n = 18). Neutralisation and anti‐receptor‐binding domain (RBD) IgG levels against wild‐type SARS‐CoV‐2 and JN.1 were assessed using multiplex immunoassays. Study outcomes were wild‐type and JN.1 neutralisation following three doses of original mRNA vaccines, stratified by immunosuppressive therapy (primary outcome), and JN.1 neutralisation following third‐dose breakthrough infection or a fourth dose of XBB.1.5‐adapted mRNA vaccines (secondary outcomes). Results: Following original vaccines, JN.1 neutralisation was lower than wild‐type neutralisation in all study groups (healthy, anti‐TNF and non‐anti‐TNF; each p < 0.001); most individuals lacked JN.1 neutralisation (healthy: 97.9%; anti‐TNF: 98.3% and non‐anti‐TNF: 92.3%). Confounder‐adjusted multivariable modelling strongly associated anti‐TNF therapy with low levels of anti‐JN.1‐RBD IgG (fold‐change 0.48 [95% CI 0.39–0.59]). JN.1 neutralisation was similar in patients with or without breakthrough infection (anti‐TNF, non‐anti‐TNF; each p > 0.05); neutralisation failure was 100% despite breakthrough infection. XBB.1.5‐adapted vaccines enhanced JN.1 neutralisation (p < 0.001) and reduced neutralisation failure rates in patients with IBD (94.4% pre‐vaccination vs. 44.4% post‐vaccination; p = 0.003). Conclusions: Only variant‐adapted vaccines protect against emerging SARS‐CoV‐2 variants. Patients with IBD and healthy individuals without recent vaccination may lack protection against the JN.1 subvariant KP.3 which causes current COVID‐19 surges. [ABSTRACT FROM AUTHOR]

Background: Regulators and oncology healthcare providers are increasingly interested in using observational studies of real‐world data (RWD) to complement clinical evidence from randomized controlled trials for informed decision‐making. To generate valid evidence, RWD studies must be carefully designed to avoid systematic biases. The clone‐censor‐weight (CCW) method has been proposed to address immortal time and other time‐related biases. Methods: The objective of this manuscript is to de‐mystify the CCW method for cancer researchers by describing and presenting its core components in an accessible and digestible format, using visualizations and examples from cancer‐relevant studies. The CCW method has been applied in diverse settings, including investigations of the effects of surgery within a certain time after cancer diagnosis, the continuation of annual screening mammography, and chemotherapy duration on survival. Results: The method handles complex data wherein the treatment group to which an individual belongs is unknown at the start of follow‐up. The three steps of the CCW method involve cloning or duplicating the patient population and assigning one clone to each treatment strategy, artificially censoring the clones when their observed data are inconsistent with the assigned strategy and weighting the cloned and censored population to address selection bias created by the artificial censoring. Conclusions: The CCW method is a powerful tool for designing RWD studies in cancer that are free from time‐related biases and successfully, to the extent possible, emulate features of a randomized clinical trial. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Vervets are non‐human primates that share high genetic homology with humans and develop amyloid beta (Aβ) pathology with aging. We expand current knowledge by examining Aβ pathology, aging, cognition, and biomarker proteomics. METHODS: Amyloid immunoreactivity in the frontal cortex and temporal cortex/hippocampal regions from archived vervet brain samples ranging from young adulthood to old age was quantified. We also obtained cognitive scores, plasma samples, and cerebrospinal fluid (CSF) samples in additional animals. Plasma and CSF proteins were quantified with platforms utilizing human antibodies. RESULTS: We found age‐related increases in Aβ deposition in both brain regions. Bioinformatic analyses assessed associations between biomarkers and age, sex, cognition, and CSF Aβ levels, revealing changes in proteins related to immune‐related inflammation, metabolism, and cellular processes. DISCUSSION: Vervets are an effective model of aging and early‐stage Alzheimer's disease, and we provide translational biomarker data that both align with previous results in humans and provide a basis for future investigations. Highlights: We found changes in immune and metabolic plasma biomarkers associated with age and cognition.Cerebrospinal fluid (CSF) biomarkers revealed changes in cell signaling indicative of adaptative processes.TNFRSF19 (TROY) and Artemin co‐localize with Alzheimer's disease pathology.Vervets are a relevant model for translational studies of early‐stage Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Although several adult rat models of medial temporal lobe epilepsy (mTLE) have been described in detail, our knowledge of mTLE epileptogenesis in infant rats is limited. Here, we present a novel infant rat model of mTLE (InfRPil‐mTLE) based on a repetitive, triphasic injection regimen consisting of low‐dose pilocarpine administrations (180 mg/kg. i.p.) on days 9, 11, and 15 post partum (pp). The model had a survival rate of >80% and exhibited characteristic spontaneous recurrent electrographic seizures (SRES) in both the hippocampus and cortex that persisted into adulthood. Using implantable video‐EEG radiotelemetry, we quantified a complex set of seizure parameters that demonstrated the induction of chronic electroencephalographic seizure activity in our InfRPil‐mTLE model, which predominated during the dark cycle. We further analyzed selected candidate genes potentially relevant to epileptogenesis using a RT‐qPCR approach. Several candidates, such as the low‐voltage‐activated Ca2+ channel Cav3.2 and the auxiliary subunits β1 and β2, which were previously reported to be upregulated in the hippocampus of the adult pilocarpine mTLE model, were found to be downregulated (together with Cav2.1, Cav2.3, M1, and M3) in the hippocampus and cortex of our InfRPil‐mTLE model. From a translational point of view, our model could serve as a blueprint for childhood epileptic disorders and further contribute to antiepileptic drug research and development in the future. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Tropomyosin related kinase B (TrkB) and C (TrkC) receptor signaling promotes synaptic plasticity and interacts with pathways affected by amyloid beta (Aβ) toxicity. Upregulating TrkB/C signaling could reduce Alzheimer's disease (AD)‐related degenerative signaling, memory loss, and synaptic dysfunction. METHODS: PTX‐BD10‐2 (BD10‐2), a small molecule TrkB/C receptor partial agonist, was orally administered to aged London/Swedish‐APP mutant mice (APPL/S) and wild‐type controls. Effects on memory and hippocampal long‐term potentiation (LTP) were assessed using electrophysiology, behavioral studies, immunoblotting, immunofluorescence staining, and RNA sequencing. RESULTS: In APPL/S mice, BD10‐2 treatment improved memory and LTP deficits. This was accompanied by normalized phosphorylation of protein kinase B (Akt), calcium‐calmodulin–dependent kinase II (CaMKII), and AMPA‐type glutamate receptors containing the subunit GluA1; enhanced activity‐dependent recruitment of synaptic proteins; and increased excitatory synapse number. BD10‐2 also had potentially favorable effects on LTP‐dependent complement pathway and synaptic gene transcription. DISCUSSION: BD10‐2 prevented APPL/S/Aβ‐associated memory and LTP deficits, reduced abnormalities in synapse‐related signaling and activity‐dependent transcription of synaptic genes, and bolstered transcriptional changes associated with microglial immune response. Highlights: Small molecule modulation of tropomyosin related kinase B (TrkB) and C (TrkC) restores long‐term potentiation (LTP) and behavior in an Alzheimer's disease (AD) model.Modulation of TrkB and TrkC regulates synaptic activity‐dependent transcription.TrkB and TrkC receptors are candidate targets for translational therapeutics.Electrophysiology combined with transcriptomics elucidates synaptic restoration.LTP identifies neuron and microglia AD‐relevant human‐mouse co‐expression modules. [ABSTRACT FROM AUTHOR]

Glaucoma drainage devices are implanted in the eye to treat glaucoma, a disease that can cause vision loss and blindness. These devices are designed to reduce intraocular pressure (IOP), a major risk factor for the progression of glaucoma, by providing an alternative outflow path for the fluid produced by the eye, the aqueous humor. Here, a novel polymeric minimally invasive glaucoma implant designed to enhance aqueous humor outflow is demonstrated. The implant is made of a unique, potentially biodegradable thermoplastic material, polycarbonate bisamide (PC‐BA), and produced through replica molding using hot embossing and femtosecond laser‐machined glass molds. Post‐mortem experiments demonstrate successful device implantation into a rabbit's eye, with the implant remaining securely in place. Although the mass loss and changes in molecular weight observed in the in vitro degradation experiments are not significant within the tested times and degradation conditions, the PC‐BA is a slow‐degradation polymer that may take a few years to fully degrade. Thus, the implant will also slowly degrade and be absorbed by the body over time, leaving behind a natural outflow pathway. This potentially biodegradable glaucoma implant may represent a promising new approach for restoring outflow in a more natural way. [ABSTRACT FROM AUTHOR]

This article introduces a novel transnational family configuration (TNFC) approach to study the diversity of family forms across kinship and geographical boundaries. Integrating theoretical insights from family sociology and transnational family research, it examines contemporary families as personal networks that encompass both subjectively identified and potentially transnationally dispersed kin and non‐kin members. Drawing on original survey data and in‐depth interviews with adults aged 55+ living in Switzerland, it compares migrants' and non‐migrants' personal family networks. The results indicate that these networks are both diverse and transnational. Although there is a strong correlation between transnationality and migration background, other life‐course factors also contribute to the development of transnational family networks beyond the scope of migrant 'exceptionalism'. By advocating the adoption of a TNFC approach to the study of contemporary families, in diverse population groups and various cultural contexts, this study paves the way for future research in this area. [ABSTRACT FROM AUTHOR]

The endangered population of humpback whales (Megaptera novaeangliae) breeding and calving off the Cape Verde Islands (CVI) are known to migrate to feeding areas located along the eastern margin of the North Atlantic Ocean (Iceland, and Norway). Here, we report for the first time a confirmed migration of an individual humpback whale from CVI breeding ground to a western North Atlantic feeding ground of West Greenland. This individual humpback, which was photographed and identified off the coast of West Greenland in 2021, was previously documented in CVI 22 years before (1999). An annual subsistence hunt for humpbacks occurs in West Greenland and the resighting at this location with a humpback whale from CVI has strong implications for the conservation efforts of the small CVI population. [ABSTRACT FROM AUTHOR]

Background: Pregnant women with obesity are more likely to experience cesarean birth compared to women without obesity. Yet, little is known about the underlying mechanisms. The objective of this study was therefore to evaluate how mediators contribute to the association between obesity and prelabor/intrapartum cesarean birth. Methods: We retrospectively analyzed Swiss cohort data from 394,812 singleton, cephalic deliveries between 2005 and 2020. Obesity (BMI ≥ 30 kg/m2) was defined as the exposure and prelabor or intrapartum cesarean birth as the outcomes. Hypothesized mediators included gestational comorbidities, large‐for‐gestational‐age infant, pregnancy duration >410/7 weeks, slower labor progress, labor induction, and history of cesarean birth. We performed path analyses using generalized structural equation modeling and assessed mediation by a counterfactual approach. Results: Women with obesity had a cesarean birth rate of 39.36% vs. 24.12% in women without obesity. The path models mainly showed positive direct and indirect associations between obesity and cesarean birth. In the total sample, the mediation models explained up to 39.47% (95% CI 36.92–42.02) of the association between obesity and cesarean birth, and up to 57.13% (95% CI 54.10–60.16) when including history of cesarean birth as mediator in multiparous women. Slower labor progress and history of cesarean birth were found to be the most clinically significant mediators. Conclusions: This study provides empirical insights into how obesity may increase cesarean birth rates through mediating processes. Particularly allowing for a slower labor progress in women with obesity might reduce cesarean birth rates and prevent subsequent repeat cesarean births in multiparous women. [ABSTRACT FROM AUTHOR]

INTRODUCTION: In this study, we leverage proteomic techniques to identify communities of proteins underlying Alzheimer's disease (AD) risk among clinically unimpaired (CU) older adults. METHODS: We constructed a protein co‐expression network using 3869 cerebrospinal fluid (CSF) proteins quantified by SomaLogic, Inc., in a cohort of participants along the AD clinical spectrum. We then replicated this network in an independent cohort of CU older adults and related these modules to clinically‐relevant outcomes. RESULTS: We discovered modules enriched for phosphorylation and ubiquitination that were associated with abnormal amyloid status, as well as p‐tau181 (M4: β = 2.44, p < 0.001, M7: β = 2.57, p < 0.001) and executive function performance (M4: β = −2.00, p = 0.005, M7: β = −2.39, p < 0.001). DISCUSSION: In leveraging CSF proteomic data from individuals spanning the clinical spectrum of AD, we highlight the importance of post‐translational modifications for early cognitive and pathological changes. [ABSTRACT FROM AUTHOR]

The flash Joule heating (FJH) method converts many carbon feedstocks into graphene in milliseconds to seconds using an electrical pulse. This opens an opportunity for processing low or negative value resources, such as coal and plastic waste, into high value graphene. Here, a lab‐scale automation FJH system that allows the synthesis of 1.1 kg of turbostratic flash graphene from coal‐based metallurgical coke (MC) in 1.5 h is demonstrated. The process is based on the automated conversion of 5.7 g of MC per batch using an electrical pulse width modulation system to conduct the bottom‐up upcycle of MC into flash graphene. This study then compare this method to two other scalable graphene synthesis techniques by both a life cycle assessment and a technoeconomic assessment. [ABSTRACT FROM AUTHOR]

Background: Adult asthma is complex and incompletely understood. Plasma proteomics is an evolving technique that can both generate biomarkers and provide insights into disease mechanisms. We aimed to identify plasma proteomic signatures of adult asthma. Methods: Protein abundance in plasma was measured in individuals from the Agricultural Lung Health Study (ALHS) (761 asthma, 1095 non‐case) and the Atherosclerosis Risk in Communities study (470 asthma, 10,669 non‐case) using the SOMAScan 5K array. Associations with asthma were estimated using covariate adjusted logistic regression and meta‐analyzed using inverse‐variance weighting. Additionally, in ALHS, we examined phenotypes based on both asthma and seroatopy (asthma with atopy (n = 207), asthma without atopy (n = 554), atopy without asthma (n = 147), compared to neither (n = 948)). Results: Meta‐analysis of 4860 proteins identified 115 significantly (FDR<0.05) associated with asthma. Multiple signaling pathways related to airway inflammation and pulmonary injury were enriched (FDR<0.05) among these proteins. A proteomic score generated using machine learning provided predictive value for asthma (AUC = 0.77, 95% CI = 0.75–0.79 in training set; AUC = 0.72, 95% CI = 0.69–0.75 in validation set). Twenty proteins are targeted by approved or investigational drugs for asthma or other conditions, suggesting potential drug repurposing. The combined asthma‐atopy phenotype showed significant associations with 20 proteins, including five not identified in the overall asthma analysis. Conclusion: This first large‐scale proteomics study identified over 100 plasma proteins associated with current asthma in adults. In addition to validating previous associations, we identified many novel proteins that could inform development of diagnostic biomarkers and therapeutic targets in asthma management. [ABSTRACT FROM AUTHOR]

Objectives: A feasibility proof‐of‐concept study was conducted to assess the effects of acute tibial nerve stimulation (TNS) on the central nervous system in healthy volunteers using functional magnetic resonance imaging (fMRI). Materials and Methods: Fourteen healthy volunteers were included in a prospective, single‐site study conducted on a clinical 3T MRI scanner. Four scans of functional MRI, each lasting 6 min, were acquired: two resting‐state fMRI scans (prior and following the TNS intervention) and in‐between two fMRI scans, both consisting of alternating rest periods and noninvasive acute transcutaneous TNS (TTNS). Whole brain seed‐based functional connectivity (FC) correlation analysis was performed comparing TTNS stimulation with rest periods. Cluster‐level familywise error (FWE) corrected p and a minimal cluster size of 200 voxels were used to explore FC patterns. Results: Increased FC is reported between inferior frontal gyrus, posterior cingulate gyrus, and middle temporal gyrus with the precuneus as central receiving node. In addition, decreased FC in the cerebellum, hippocampus, and parahippocampal areas was observed. Conclusions: Altered FC is reported in areas which have been described to be also involved in lower urinary tract control. Although conducted with healthy controls, the assumption that the underlying therapeutic effect of TNS involves the central nervous system is supported and has to be further examined in patients with incomplete spinal cord injury. [ABSTRACT FROM AUTHOR]

Ensiling forage from species‐rich mountain grasslands is challenging. Low concentrations of fermentable carbohydrates and the coarse morphological structure of the forage promote the activity of butyric acid forming bacteria. This is associated with the formation of ammonia from protein degradation, resulting in an insufficient pH decline. On the other hand, forage from species‐rich swards may contain tanniferous plant species which contain varying contents of condensed tannins (CT). Therefore, the silage quality of forage prepared from species‐rich mountain grasslands and the role CT may play in silage fermentation was studied. A set‐up of two long‐term mineral fertilization field experiments, located in the Jura mountains and the Alps in Switzerland were used to obtain forage with contrasting species and chemical composition. Collection was done during both the generative and vegetative growth stage from three differently fertilized swards: unfertilised ("0"), fertilized with phosphorus and potassium ("PK") or fertilized with PK and nitrogen ("NPK"). The forage was wilted to approximately 37% dry matter (DM), chopped to 2 cm lengths and ensiled for at least 65 days as laboratory‐scale silages. The wilted forage was characterized by concentrations of crude protein between 117 and 130 g/kg DM and water‐soluble carbohydrates varying from 84 to 148 g/kg DM. Concentrations of CT ranged from 6 g to 14 g/kg DM and those of soluble CT from 1.8 to 7.6 g/kg DM. All silages contained butyric acid, irrespective of the type of fertilization or harvest stage (range: 1.5 g to 16 g/kg DM). Concentrations of acetic and lactic acid ranged from 2.1 g to 15.0 g/kg DM and from 21.0 to 44.0 g/kg DM, respectively. Concentrations of unfermented sugar remained high and pH levels were above those expected. Formation of non‐protein‐N (NPN) increased in the range of 130 to 264 g/kg N from wilted to ensiled forage. The negative correlations of CT or soluble CT contents with ammonia‐N or NPN in silage were found in both forage from the generative and vegetative harvests indicating a possible relationship with protein degradation during ensiling. [ABSTRACT FROM AUTHOR]

Background: Vascular dysfunction, blood‐brain barrier (BBB) dysregulation, and neuroinflammation are thought to participate in Alzheimer's disease (AD) pathogenesis, though the mechanism is poorly understood. Among pathways of interest, AD pathology appears to affect vascular endothelial growth factor‐A (VEGFA) signaling in a bidirectional manner. Higher VEGF levels are thought to have a protective role and slow cognitive decline. Neuronal intracellular adhesion molecules (ICAMs) may also be a marker of BBB permeability. ICAMs participate in the immune‐nervous system interactions, synaptic plasticity, and cognition. Method: We used the SomaLogic platform for cerebrospinal fluid (CSF) proteome profiling to investigate the levels of ICAM 1, 2, 3, 5 and VEGFA as markers of vascular dysfunction and neuroinflammation in 83 participants from the Stanford Alzheimer Disease Research Center cohort (54 cognitively unimpaired healthy controls (HC) and 29 with mild cognitive impairment or dementia due to AD). All samples were blinded for analysis. Montreal Cognitive Assessment (MoCA) was used as a measure of global cognition. ANOVA compared the levels of biomarkers in diagnostic groups. Linear regression and interaction terms of group (AD vs HC) by biomarker levels were used to investigate the effect on global cognition. Result: ICAM5 and VEGFA were significantly associated with cognition in our cohort. Both ICAM5 and VEGFA levels were lower in AD compared to HC (Figure 1). Interaction terms of diagnosis by ICAM5 were significant on MoCA (b = ‐59.29, p‐value <.0001), and of diagnosis by VEGFA were also significant on MoCA (b = ‐134.8, p:0.00027), indicating a divergent role for these biomarkers in AD vs. HC (Figure 2). Other ICAMs were not significantly associated with cognition in our cohort. Conclusion: VEGFA and ICAM5 may play an important and dynamic role in AD. More research is needed to understand the interplay between ICAM5 and VEGF and their relationship with AD. References: Tao QQ et al. Aging Dis. 2022; Tubi MA et al. Neurobiol Aging. 2021; Petrelis AM et al. Aging (Albany NY). 2022; Yuan L et al. Aging Dis. 2017; Hino H et al. Brain Res. 1997; Yang H. Comp Funct Genomics. 2012; Birkner K et al. Front Neurol. 2019 [ABSTRACT FROM AUTHOR]

Non‐coplanar radiotherapy treatment techniques on C‐arm linear accelerators have the potential to reduce dose to organs‐at‐risk in comparison with coplanar treatment techniques. Accurately predicting possible collisions between gantry, table and patient during treatment planning is needed to ensure patient safety. We offer a freely available collision prediction tool using Blender, a free and open‐source 3D computer graphics software toolset. A geometric model of a C‐arm linear accelerator including a library of patient models is created inside Blender. Based on the model, collision predictions can be used both to calculate collision‐free zones and to check treatment plans for collisions. The tool is validated for two setups, once with and once without a full body phantom with the same table position. For this, each gantry‐table angle combination with a 2° resolution is manually checked for collision interlocks at a TrueBeam system and compared to simulated collision predictions. For the collision check of a treatment plan, the tool outputs the minimal distance between the gantry, table and patient model and a video of the movement of the gantry and table, which is demonstrated for one use case. A graphical user interface allows user‐friendly input of the table and patient specification for the collision prediction tool. The validation resulted in a true positive rate of 100%, which is the rate between the number of correctly predicted collision gantry‐table combinations and the number of all measured collision gantry‐table combinations, and a true negative rate of 89%, which is the ratio between the number of correctly predicted collision‐free combinations and the number of all measured collision‐free combinations. A collision prediction tool is successfully created and able to produce maps of collision‐free zones and to test treatment plans for collisions including visualisation of the gantry and table movement. [ABSTRACT FROM AUTHOR]

Summary: Background: Vaccine‐elicited immune responses are impaired in patients with inflammatory bowel disease (IBD) treated with anti‐TNF biologics. Aims: To assess vaccination efficacy against the novel omicron sublineages BQ.1.1 and XBB.1.5 in immunosuppressed patients with IBD. Methods: This prospective multicentre case–control study included 98 biologic‐treated patients with IBD and 48 healthy controls. Anti‐spike IgG concentrations and surrogate neutralisation against SARS‐CoV‐2 wild‐type, BA.1, BA.5, BQ.1.1, and XBB.1.5 were measured at two different time points (2–16 weeks and 22–40 weeks) following third dose vaccination. Surrogate neutralisation was based on antibody‐mediated blockage of ACE2‐spike protein–protein interaction. Primary outcome was surrogate neutralisation against tested SARS‐CoV‐2 sublineages. Secondary outcomes were proportions of participants with insufficient surrogate neutralisation, impact of breakthrough infection, and correlation of surrogate neutralisation with anti‐spike IgG concentration. Results: Surrogate neutralisation against all tested sublineages was reduced in patients with IBD who were treated with anti‐TNF biologics compared to patients treated with non‐anti‐TNF biologics and healthy controls (each p ≤ 0.001) at visit 1. Anti‐TNF therapy (odds ratio 0.29 [95% CI 0.19–0.46]) and time since vaccination (0.85 [0.72–1.00]) were associated with low, and mRNA‐1273 vaccination (1.86 [1.12–3.08]) with high wild‐type surrogate neutralisation in a β‐regression model. Accordingly, higher proportions of patients treated with anti‐TNF biologics had insufficient surrogate neutralisation against omicron sublineages at visit 1 compared to patients treated with non‐anti‐TNF biologics and healthy controls (each p ≤ 0.015). Surrogate neutralisation against all tested sublineages decreased over time but was increased by breakthrough infection. Anti‐spike IgG concentrations correlated with surrogate neutralisation. Conclusions: Patients with IBD who are treated with anti‐TNF biologics show impaired neutralisation against novel omicron sublineages BQ.1.1 and XBB.1.5 and may benefit from prioritisation for future variant‐adapted vaccines. [ABSTRACT FROM AUTHOR]

In this paper, we determine the motivic class -- in particular, the weight polynomial and conjecturally the Poincaré polynomial -- of the open de Rham space, defined and studied by Boalch, of certain moduli spaces of irregular meromorphic connections on the trivial rank n bundle on ℙ¹. The computation is by motivic Fourier transform. We show that the result satisfies the purity conjecture, that is, it agrees with the pure part of the conjectured mixed Hodge polynomial of the corresponding wild character variety. We also identify the open de Rham spaces with quiver varieties with multiplicities of Yamakawa and Geiss-Leclerc-Schröer. We finish with constructing natural complete hyperkähler metrics on them, which in the four-dimensional cases are expected to be of type ALF. [ABSTRACT FROM AUTHOR]

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Natural language processing (NLP) tools turn free‐text notes (FTNs) from electronic health records (EHRs) into data features that can supplement confounding adjustment in pharmacoepidemiologic studies. However, current applications are difficult to scale. We used unsupervised NLP to generate high‐dimensional feature spaces from FTNs to improve prediction of drug exposure and outcomes compared with claims‐based analyses. We linked Medicare claims with EHR data to generate three cohort studies comparing different classes of medications on the risk of various clinical outcomes. We used "bag‐of‐words" to generate features for the top 20,000 most prevalent terms from FTNs. We compared machine learning (ML) prediction algorithms using different sets of candidate predictors: Set1 (39 researcher‐specified variables), Set2 (Set1 + ML‐selected claims codes), and Set3 (Set1 + ML‐selected NLP‐generated features), vs. Set4 (Set1 + 2 + 3). When modeling treatment choice, we observed a consistent pattern across the examples: ML models utilizing Set4 performed best followed by Set2, Set3, then Set1. When modeling the outcome risk, there was little to no improvement beyond models based on Set1. Supplementing claims data with NLP‐generated features from free text notes improved prediction of prescribing choices but had little or no improvement on clinical risk prediction. These findings have implications for strategies to improve confounding using EHR data in pharmacoepidemiologic studies. [ABSTRACT FROM AUTHOR]

The vasculature is a key regulator of leukocyte trafficking into the central nervous system (CNS) during inflammatory diseases including multiple sclerosis (MS). However, the impact of endothelial‐derived factors on CNS immune responses remains unknown. Bioactive lipids, in particular oxysterols downstream of Cholesterol‐25‐hydroxylase (Ch25h), promote neuroinflammation but their functions in the CNS are not well‐understood. Using floxed‐reporter Ch25h knock‐in mice, we trace Ch25h expression to CNS endothelial cells (ECs) and myeloid cells and demonstrate that Ch25h ablation specifically from ECs attenuates experimental autoimmune encephalomyelitis (EAE). Mechanistically, inflamed Ch25h‐deficient CNS ECs display altered lipid metabolism favoring polymorphonuclear myeloid‐derived suppressor cell (PMN‐MDSC) expansion, which suppresses encephalitogenic T lymphocyte proliferation. Additionally, endothelial Ch25h‐deficiency combined with immature neutrophil mobilization into the blood circulation nearly completely protects mice from EAE. Our findings reveal a central role for CNS endothelial Ch25h in promoting neuroinflammation by inhibiting the expansion of immunosuppressive myeloid cell populations. Synopsis: Cholesterol 25‐hydroxylase (Ch25h) expression increases in central nervous system‐endothelial cells (ECs) during inflammation and regulates lipid secretion. Partial loss of Ch25h in ECs promotes polymorphonuclear myeloid‐derived suppressor cell (PMN‐MDSC) expansion and reduces experimental autoimmune encephalomyelitis (EAE) severity. Ch25h expression and related 25‐hydroxycholesterol (25‐OHC) are increased in ECs during neuroinflammation.Ch25h‐specific ablation from the microvascular endothelium alters fatty acid desaturase 2 (FADS2) expression, which promotes the production of anti‐inflammatory lipids, in particular Prostaglandin E2 (PGE2).25‐OHC and PGE2 control PMN‐MDSC expansion.Partial loss of Ch25h promotes PMN‐MDSC accumulation within the central nervous system (CNS) and attenuates EAE. [ABSTRACT FROM AUTHOR]

Introduction: Numerous studies have indicated that intra-articular steroid injections to the hip are beneficial for short-term pain relief. However, recent studies have drawn concerns of rapidly progressive osteoarthritis of the hip (RPOH) following intra-articular steroid injections. The prevalence of RPOH following intra-articular steroid injections varies widely in the literature.Objective: To identify the prevalence of RPOH following intra-articular steroid injections, and to compare baseline characteristics between patients with and without RPOH.Design: Case series.Setting: Tertiary academic hospital.Patients: A total of 924 patients (median [interquartile range; IQR] age: 59 [45-70] years; 579 female) who received an intra-articular hip steroid/anesthetic injection from January 2016 to March 2018 and had available pre- and post-injection imaging (prior to surgical intervention) were included in the study.Interventions: Baseline and injection-related data-including demographics, age, body mass index, medical history, laterality, and steroid type-were collected from electronic medical records.Main Outcome Measures: Post-injection RPOH was determined via imaging review by a physiatry fellow, followed by an attending physiatrist and a musculoskeletal radiologist to confirm findings.Results: The majority of patients received unilateral injections into the hip, and the most common steroids used were triamcinolone and methylprednisolone. Review of pre- and post-injection imaging revealed 26 cases of RPOH, for an overall prevalence of 2.8% (95% confidence interval [CI] 1.9%-4.1%). Compared to those without RPOH, patients with RPOH were significantly older (median age [IQR]: 64 [60-73] vs. 59 [44-70] years, p = .003) and had a shorter duration of symptoms prior to their injections (median [IQR]: 3 vs. 12 [6-36] months, p < .001). Adjusted regression analyses showed that age was associated with greater odds of RPOH (odds ratio [OR], 95% CI: 1.04, 1.01 to 1.07; p = .003).Conclusions: The prevalence of RPOH following intra-articular steroid injections into the hip was lower than previously reported but still clinically relevant. This should be considered when counseling patients prior to intra-articular hip steroid injections. [ABSTRACT FROM AUTHOR]

Diffusion kurtosis imaging (DKI) is applied to gain insights into the microstructural organization of brain tissues. However, the reproducibility of DKI outside brain white matter, particularly in combination with advanced estimation to remedy its noise sensitivity, remains poorly characterized. Therefore, in this study, we investigated the variability and reliability of DKI metrics while correcting implausible values with a fit method called mean kurtosis (MK)‐Curve. A total of 10 volunteers (four women; age: 41.4 ± 9.6 years) were included and underwent two MRI examinations of the brain. The images were acquired on a clinical 3‐T scanner and included a T1‐weighted image and a diffusion sequence with multiple diffusion weightings suitable for DKI. Region of interest analysis of common kurtosis and tensor metrics derived with the MK‐Curve DKI fit was performed, including intraclass correlation (ICC) and Bland–Altman (BA) plot statistics. A p value of less than 0.05 was considered statistically significant. The analyses showed good to excellent agreement of both kurtosis tensor‐ and diffusion tensor‐derived MK‐Curve–corrected metrics (ICC values: 0.77–0.98 and 0.87–0.98, respectively), with the exception of two DKI‐derived metrics (axial kurtosis in the cortex: ICC = 0.68, and radial kurtosis in deep gray matter: ICC = 0.544). Non‐MK‐Curve–corrected kurtosis tensor‐derived metrics ranged from 0.01 to 0.52 and diffusion tensor‐derived metrics from 0.06 to 0.66, indicating poor to moderate reliability. No structural bias was observed in the BA plots for any of the diffusion metrics. In conclusion, MK‐Curve–corrected DKI metrics of the human brain can be reliably acquired in white and gray matter at 3 T and DKI metrics have good to excellent agreement in a test–retest setting. [ABSTRACT FROM AUTHOR]

The effect of three types of nanofillers on the physical, mechanical, and thermal properties of flexible polyurethane foams (FPUF) was studied. FPUF with nanofillers are of interest to the automotive industry due to their potential for enhancing compression properties and enabling sustainable foams. Holey and wrinkled flash graphene, and untreated and silane coated boron nitride were tested as fillers up to 0.1 wt% loading level. Flash graphene filled FPUF showed significant improvement in compressive properties, especially at the 0.025 wt% loading level, showing a 22% increase in compressive force deflection at 25% strain and a 17% increase at 50% strain compared to the unfilled control foam sample. Boron nitride nanoparticles, treated and untreated, were shown to be an effective means of reducing wet compression set properties, addressing a key area of concern for sustainable polyols. Wet compression set was reduced by 20%–30% for most boron nitride foams compared to their unfilled control samples. Boron nitride may enable implementation of more sustainable polyols in automotive FPUF. Nanofillers did not significantly improve thermal stability of FPUF. [ABSTRACT FROM AUTHOR]

Caviomorph rodents have been diverse and abundant components of South American mammal communities since the late Eocene. We describe herein the octodontoids of Pampa Castillo, a Lower Miocene site in southern Chile (Aysén Region). Six genera and seven species of octodontoids are present, two of which are new: Dudumus berggreni sp. nov. and Caviocricetus guenekko sp. nov. The octodontoids from Pampa Castillo support assignment of this fauna to the Santacrucian South American Land Mammal Age (SALMA), which is consistent with previous studies. We conducted similarity analyses on 11 Early–Middle Miocene Patagonian rodent faunas using hierarchical clustering. Faunas generally fell into the three SALMAs to which they were traditionally assigned: Colhuehuapian, Santacrucian and 'post‐Santacrucian'. The 'Pinturan' is a proposed biochronological interval between the Colhuehuapian and Santacrucian. At the genus level, Pampa Castillo clustered with 'Pinturan' faunas, while at the species level it clustered with the 'typical' faunas on which the Santacrucian SALMA is based (from outcrops of the Santa Cruz Formation along the Atlantic coast and Río Santa Cruz). The Pampa Castillo rodent fauna resembles both 'Pinturan' and 'typical' Santacrucian faunas in taxon distributions, reflecting complex temporal and palaeoenvironmental influences. Geochronological data indicate that some 'Pinturan' sites overlap temporally with Pampa Castillo and the upper Pinturas Formation, which both clustered with 'typical' Santacrucian faunas. These results indicate that the 'Pinturan' does not represent a distinct biochronological interval, but that the differences between it and 'typical' Santacrucian faunas are attributable to geographic or palaeoenvironmental differences. [ABSTRACT FROM AUTHOR]

Summary: Background: Immunosuppressed patients with inflammatory bowel disease (IBD) experience increased risk of vaccine‐preventable diseases such as COVID‐19. Aims: To assess humoral and cellular immune responses following SARS‐CoV‐2 booster vaccination in immunosuppressed IBD patients and healthy controls. Methods: In this prospective, multicentre, case–control study, 139 IBD patients treated with biologics and 110 healthy controls were recruited. Serum anti‐SARS‐CoV‐2 spike IgG concentrations were measured 2–16 weeks after receiving a third mRNA vaccine dose. The primary outcome was to determine if humoral immune responses towards booster vaccines differ in IBD patients under anti‐TNF versus non‐anti‐TNF therapy and healthy controls. Secondary outcomes were antibody decline, impact of previous infection and SARS‐CoV‐2‐targeted T cell responses. Results: Anti‐TNF‐treated IBD patients showed reduced anti‐spike IgG concentrations (geometric mean 2357.4 BAU/ml [geometric SD 3.3]) when compared to non‐anti‐TNF‐treated patients (5935.7 BAU/ml [3.9]; p < 0.0001) and healthy controls (5481.7 BAU/ml [2.4]; p < 0.0001), respectively. In multivariable modelling, prior infection (geometric mean ratio 2.00 [95% CI 1.34–2.90]) and vaccination with mRNA‐1273 (1.53 [1.01–2.27]) increased antibody concentrations, while anti‐TNF treatment (0.39 [0.28–0.54]) and prolonged time between vaccination and antibody measurement (0.72 [0.58–0.90]) decreased anti‐SARS‐CoV‐2 spike antibodies. Antibody decline was comparable in IBD patients independent of anti‐TNF treatment and antibody concentrations could not predict breakthrough infections. Cellular and humoral immune responses were uncoupled, and more anti‐TNF‐treated patients than healthy controls developed inadequate T cell responses (15/73 [20.5%] vs 2/100 [2.0%]; p = 0.00031). Conclusions: Anti‐TNF‐treated IBD patients have impaired humoral and cellular immunogenicity following SARS‐CoV‐2 booster vaccination. Fourth dose administration may be beneficial for these patients. [ABSTRACT FROM AUTHOR]

2022 marks the centenary of the discovery of vitamin E by Evans and Bishop, an important milestone in vitamin research. An enormous amount of scientific data related to the importance of its activity has been published on this micronutrient. Globally, researchers from industry and academia have contributed to improve and implement highly efficient and commercially viable production processes for vitamin E. All processes share a common final step, but differ in the generation of their key building blocks. Today, Vitamin E, accounts for a worldwide production of >75.000 t/a. Vitamin E is applied predominantly as feed supplement for various animal species and in addition is used in a variety of human applications. Moreover, its impressive antioxidative behavior enables frequent use as stabilizing ingredient in many product forms and final consumer applications. This review will provide the current state of science, with clear focus on highlighting the different routes for industrial syntheses of vitamin E. Furthermore, approaches directed towards successful product form development including suitable auxiliary substances combined with appropriate formulation technologies, as well as a broad variety of applications in animal and human nutrition and health will be discussed. Insights on isolation approaches, biosynthesis, and future trends complete the status of Vitamin E research. [ABSTRACT FROM AUTHOR]

Purpose: Supplementing investigator‐specified variables with large numbers of empirically identified features that collectively serve as 'proxies' for unspecified or unmeasured factors can often improve confounding control in studies utilizing administrative healthcare databases. Consequently, there has been a recent focus on the development of data‐driven methods for high‐dimensional proxy confounder adjustment in pharmacoepidemiologic research. In this paper, we survey current approaches and recent advancements for high‐dimensional proxy confounder adjustment in healthcare database studies. Methods: We discuss considerations underpinning three areas for high‐dimensional proxy confounder adjustment: (1) feature generation—transforming raw data into covariates (or features) to be used for proxy adjustment; (2) covariate prioritization, selection, and adjustment; and (3) diagnostic assessment. We discuss challenges and avenues of future development within each area. Results: There is a large literature on methods for high‐dimensional confounder prioritization/selection, but relatively little has been written on best practices for feature generation and diagnostic assessment. Consequently, these areas have particular limitations and challenges. Conclusions: There is a growing body of evidence showing that machine‐learning algorithms for high‐dimensional proxy‐confounder adjustment can supplement investigator‐specified variables to improve confounding control compared to adjustment based on investigator‐specified variables alone. However, more research is needed on best practices for feature generation and diagnostic assessment when applying methods for high‐dimensional proxy confounder adjustment in pharmacoepidemiologic studies. [ABSTRACT FROM AUTHOR]

Group‐2 innate lymphoid cells (ILC2s), which are involved in type 2 inflammatory diseases such as allergy, can exhibit immunological memory, but the basis of this ILC2 "trained immunity" has remained unclear. Here, we found that stimulation with IL‐33/IL‐25 or exposure to the allergen papain induces the expression of the transcription factor c‐Maf in mouse ILC2s. Chronic papain exposure results in high production of IL‐5 and IL‐13 cytokines and lung eosinophil recruitment, effects that are blocked by c‐Maf deletion in ILCs. Transcriptomic analysis revealed that knockdown of c‐Maf in ILC2s suppresses expression of type 2 cytokine genes, as well as of genes linked to a memory‐like phenotype. Consistently, c‐Maf was found highly expressed in human adult ILC2s but absent in cord blood and required for cytokine production in isolated human ILC2s. Furthermore, c‐Maf‐deficient mouse or human ILC2s failed to exhibit strengthened ("trained") responses upon repeated challenge. Thus, the expression of c‐Maf is indispensable for optimal type 2 cytokine production and proper memory‐like responses in group‐2 innate lymphoid cells. Synopsis: Group‐2 innate lymphoid cells (ILC2s) exhibit "trained immunity". Here, allergen exposure is found to induce the transcription factor c‐Maf for mounting of an optimal type‐2 inflammatory signaling and memory‐like responses in human and mice.Mouse ILC2s lack c‐Maf at steady‐state, but upregulate upon IL‐33/IL‐25 or allergen exposure.Human cord‐blood ILC2s lack c‐Maf, while c‐Maf levels are high in ILC2s in adult blood.Expression of c‐Maf results in a stronger type‐2 cytokine production and supports memory‐like responses.Knock‐down of c‐Maf in mouse ILC2s protects from lung inflammation induced by the allergen papain. [ABSTRACT FROM AUTHOR]

Ceratium furcoides (Dinophyta) have gained international attention as invasive aquatic species, especially in South America, due to its fast proliferation into various aquatic systems and the subsequent adverse impacts on water quality and native biota. The present study reports the detection of dense populations of C. furcoides in the Paracambi Small Hydropower Plant (SHP) located in the Guandu River basin. Sampling was conducted at five sites during two sampling events in 2019 and 2020 during different seasons (spring and summer), respectively. We used two different standardized sampling methods, including surface collections (SS) (100‐ml) traditionally used for quantitative analysis of inland water phytoplankton, as well as filtration of 20‐L sub‐surface water (FS) through a zooplankton net. The cell densities were higher in SS (599 individuals/ml) than in FS (0.068 individuals/ml), possibly indicating a patchy distribution of Ceratium in the surface water layers. The total cell length exhibited high values (mean length of 249‐μm; mean width of 67‐μm), possibly accounting for water treatment impairment, an inability of zooplankton to consume them and/or fish gill clogging. This new observation within an extensively investigated area, and a source of water for nine million people, in the present study advocates for integrated samplings that also consider a search for cysts accumulated in the bottom sediments, as well as more detailed spatial and temporal investigations considering the salient features of C. furcoides' populations. [ABSTRACT FROM AUTHOR]

Univentricular heart malformations are rarely described in the veterinary literature. This case report describes a single‐inlet univentricular heart with persistent truncus arteriosus as a cause of death of a captive‐bred, 2‐day‐old, female Sumatran orangutan (Pongo abelii), a critically endangered species. [ABSTRACT FROM AUTHOR]

The glutamate and γ‐aminobutyric acid neuroreceptor subtypes mGluR5 and GABAA are hypothesized to be involved in the development of a variety of psychiatric diseases. However, detailed information relating to their in vivo distribution is generally unavailable. Maps of such distributions could potentially aid clinical studies by providing a reference for the normal distribution of neuroreceptors and may also be useful as covariates in advanced functional magnetic resonance imaging (MR) studies. In this study, we propose a comprehensive processing pipeline for the construction of standard space, in vivo distributions of non‐displaceable binding potential (BPND), and total distribution volume (VT) based on simultaneously acquired bolus‐infusion positron emission tomography (PET) and MR data. The pipeline was applied to [11C]ABP688‐PET/MR (13 healthy male non‐smokers, 26.6 ± 7.0 years) and [11C]Flumazenil‐PET/MR (10 healthy males, 25.8 ± 3.0 years) data. Activity concentration templates, as well as VT and BPND atlases of mGluR5 and GABAA, were generated from these data. The maps were validated by assessing the percent error δ from warped space to native space in a selection of brain regions. We verified that the average δABP = 3.0 ± 1.0% and δFMZ = 3.8 ± 1.4% were lower than the expected variabilities σ of the tracers (σABP = 4.0%–16.0%, σFMZ = 3.9%–9.5%). An evaluation of PET‐to‐PET registrations based on the new maps showed higher registration accuracy compared to registrations based on the commonly used [15O]H2O‐template distributed with SPM12. Thus, we conclude that the resulting maps can be used for further research and the proposed pipeline is a viable tool for the construction of standardized PET data distributions. [ABSTRACT FROM AUTHOR]

The ongoing COVID‐19 pandemic represents an unprecedented global health crisis. Here, we report the identification of a synthetic nanobody (sybody) pair, Sb#15 and Sb#68, that can bind simultaneously to the SARS‐CoV‐2 spike RBD and efficiently neutralize pseudotyped and live viruses by interfering with ACE2 interaction. Cryo‐EM confirms that Sb#15 and Sb#68 engage two spatially discrete epitopes, influencing rational design of bispecific and tri‐bispecific fusion constructs that exhibit up to 100‐ and 1,000‐fold increase in neutralization potency, respectively. Cryo‐EM of the sybody‐spike complex additionally reveals a novel up‐out RBD conformation. While resistant viruses emerge rapidly in the presence of single binders, no escape variants are observed in the presence of the bispecific sybody. The multivalent bispecific constructs further increase the neutralization potency against globally circulating SARS‐CoV‐2 variants of concern. Our study illustrates the power of multivalency and biparatopic nanobody fusions for the potential development of therapeutic strategies that mitigate the emergence of new SARS‐CoV‐2 escape mutants. Synopsis: Sybodies Sb#15 and Sb#68 inhibit SARS‐CoV‐2 infectivity by targeting non‐overlapping epitopes on the spike glycoprotein. Covalent sybody fusion and valency engineering enhances neutralization potency against variants and impedes emergence of escape mutants. Two synthetic nanobodies were in vitro selected against the SARS‐CoV‐2 receptor‐binding domain (RBD).Sb#15 and Sb#68 neutralize viral infection by blocking ACE2 association with the SARS‐CoV‐2 spike protein.Sb#15 and Sb#68 bind to distinct epitopes and promote a unique up/out conformation of the RBD.Sybody fusions increase neutralization potency and attenuate the emergence of novel escape mutants. [ABSTRACT FROM AUTHOR]

Purpose The high‐dimensional propensity score (HDPS) is a semi‐automated procedure for confounder identification, prioritisation and adjustment in large healthcare databases that requires investigators to specify data dimensions, prioritisation strategy and tuning parameters. In practice, reporting of these decisions is inconsistent and this can undermine the transparency, and reproducibility of results obtained. We illustrate reporting tools, graphical displays and sensitivity analyses to increase transparency and facilitate evaluation of the robustness of analyses involving HDPS. Methods: Using a study from the UK Clinical Practice Research Datalink that implemented HDPS we demonstrate the application of the proposed recommendations. Results: We identify seven considerations surrounding the implementation of HDPS, such as the identification of data dimensions, method for code prioritisation and number of variables selected. Graphical diagnostic tools include assessing the balance of key confounders before and after adjusting for empirically selected HDPS covariates and the identification of potentially influential covariates. Sensitivity analyses include varying the number of covariates selected and assessing the impact of covariates behaving empirically as instrumental variables. In our example, results were robust to both the number of covariates selected and the inclusion of potentially influential covariates. Furthermore, our HDPS models achieved good balance in key confounders. Conclusions: The data‐adaptive approach of HDPS and the resulting benefits have led to its popularity as a method for confounder adjustment in pharmacoepidemiological studies. Reporting of HDPS analyses in practice may be improved by the considerations and tools proposed here to increase the transparency and reproducibility of study results. [ABSTRACT FROM AUTHOR]

This paper engages with the violent conditions deriving from neoliberal trends in European migration and asylum governance. We explore how continuous precarity, in conjunction with an integration imperative, affects the lives of recently arrived Afghan refugees in Germany and Switzerland. Drawing on critical engagements with the politics of integration and theories of violence, we argue that, in both European countries, Afghans are increasingly forced to earn their right to remain on the basis of labour‐market performance instead of obtaining humanitarian protection. Based on qualitative interview data, we show that persons with a precarious legal status are urged to fulfil neoliberal integration requirements to avoid being deported to their country of citizenship. Employing the "continuum of violence" as an analytical entry point, we specify how the interplay and consequences of structural and cultural violence manifest in the way those affected navigate precarious living conditions and uncertain futures in receiving countries. [ABSTRACT FROM AUTHOR]

Polysilicon recombination junctions whose n‐type bottom layers double as a passivating contact to the silicon surface are investigated. Such recombination junctions are a key element in the interconnection of tandem devices with a silicon bottom cell, and they could be used to simplify the processing sequence of single‐junction cells with interdigitated back contacts (IBCs). Polysilicon tunneling junctions require high processing temperatures to crystallize the layers; however, this also facilitates interdiffusion of dopants, whereas tunnelling relies on degenerate doping concentrations in the constituent layers and sharp interfaces between them. Using secondary‐ion mass spectrometry (SIMS) in dynamic mode, it is found that dopants diffuse readily across the interface, thus compromising the junction. The undesired diffusion is suppressed by modifying the interface with C, O, or a combination of these. Moreover, it is found that the modification does not interfere with diffusion of H, an essential element to passivate defects at the surface of the silicon wafer. Thus, implied open‐circuit voltages (iVoc) of up to 740 mV are demonstrated for contact resistivities less than 40 mΩ cm2. [ABSTRACT FROM AUTHOR]

Background and Purpose: Single nucleotide polymorphism rs9557195 within the gene of the G protein‐coupled receptor Epstein‐Barr virus‐induced gene 2 (EBI2/GPR183) has been associated with increased risk for inflammatory bowel diseases (IBD). GPR183 mediates the migration of intestinal immune cells and promotes colitis in animal models. Here, we study GPR183 surface expression of immune cells and associations of rs9557195 with GPR183 expression and IBD disease course. Experimental Approach We recruited 27 IBD patients (15 with ulcerative colitis [UC] and 12 with Crohn's disease [CD]) and eight healthy volunteers (HV). GPR183 expression was measured by FACS in subtypes of peripheral blood mononuclear cells. We analysed IBD disease course in 2301 patients (1335 with CD and 966 with UC) of the Swiss IBD cohort study. Key Results: We found increased GPR183 expression in lymphocytes expressing chemokine receptors CCR6 or CCR9, implicated in IBD and on Th17 memory T cells. The GPR183 ligand 7α,25‐dihydroxycholesterol and the CCR6 ligand CCL20 stimulated migration of memory T cells in an additive manner. Further, IBD patients with the CC allele of rs9557195 had higher GPR183 surface expression compared to individuals with the TT allele. Swiss IBD cohort study patients carrying the rs9557195‐CC allele had higher psoriasis rates compared to individuals with the TT allele. Conclusion and Implications: We demonstrate increased GPR183 surface expression on T cells with a potential role in gut inflammation. An SNP of the GPR183 locus was associated with GPR183 surface expression and psoriasis rates in IBD patients. Our data suggest a pro‐inflammatory role of GPR183 in IBD. LINKED ARTICLES: This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc [ABSTRACT FROM AUTHOR]

Immune cell trafficking is an important mechanism for the pathogenesis of inflammatory bowel disease (IBD). The oxysterol receptor GPR183 and its ligands, dihydroxylated oxysterols, can mediate positioning of immune cells including innate lymphoid cells. GPR183 has been mapped to an IBD risk locus, however another gene, Ubac2 is encoded on the reverse strand and associated with Behçet's disease, therefore the role of GPR183 as a genetic risk factor requires validation. GPR183 and production of its oxysterol ligands are up-regulated in human IBD and murine colitis. Gpr183 inactivation reduced severity of colitis in group 3 innate lymphoid cells-dependent colitis and in IL-10 colitis but not in dextran sodium sulphate colitis. Irrespectively, Gpr183 knockout strongly reduced accumulation of intestinal lymphoid tissue in health and all colitis models. In conclusion, genetic, translational and experimental studies implicate GPR183 in IBD pathogenesis and GPR183-dependent cell migration might be a therapeutic drug target for IBD. LINKED ARTICLES: This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc. [ABSTRACT FROM AUTHOR]

Background and purpose: A peripheral spontaneous nystagmus (SN) is typically enhanced or revealed by removing fixation. Conversely, failure of fixation suppression of SN is usually a sign of a central disorder. Based on Luebke and Robinson (Vision Res 1988, vol. 28 (8), pp. 941–946), who suggested that the normal fixation mechanism is disengaged during pursuit, it is hypothesized that vertical tracking in the light would bring out or enhance a horizontal SN. Methods: Eighteen patients with acute vestibular neuritis were studied. Eye movements were recorded using video‐oculography at straight‐ahead gaze with and without visual fixation, and during smooth pursuit. The slow‐phase velocity and the fixation suppression indices of nystagmus (relative to SN in darkness) were compared in each condition. Results: During vertical tracking, the slow‐phase velocity of horizontal SN with eyes near straight‐ahead gaze was significantly higher (median 2.7°/s) than under static visual fixation (median 1.2°/s). Likewise, the fixation index was significantly higher (worse suppression) during pursuit (median 48%) than during fixation (median 26%). A release of SN was also suggested during horizontal pursuit, if one assumes superposition of SN on a normal and symmetrical pursuit capability. [ABSTRACT FROM AUTHOR]

Ablative fractionated carbon dioxide (fCO2) laser may be a useful tool to improve noticeable scars after skin cancer surgery. Therefore we evaluated 40 patients who have been treated with fCO2 laser for facial scars after skin cancer surgery. This retrospective study is based on blinded evaluation of pre‐ and postoperative photographs. Patients (n = 40), laypersons (n = 5) and experts (n = 5) evaluated the esthetics and the Vancouver scar scale as primary endpoints. Secondary endpoints included patient satisfaction and treatment safety. Patients, laypersons and experts consistently assessed a significant improvement of scar quality and appearance after fCO2 laser treatment, which was paralleled by high patient satisfaction. In conclusion, ablative fCO2 laser is effective in improving noticeable postsurgical scars. Patients are highly satisfied with post‐laser results. [ABSTRACT FROM AUTHOR]