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To understand human learning and progress, it is crucial to understand curiosity. But how consistent is curiosity's conception and assessment across scientific research disciplines? We present the results of a large collaborative project assessing the correspondence between curiosity measures in personality psychology and cognitive science. A total of 820 participants completed 15 personality trait measures and 9 cognitive tasks that tested multiple aspects of information demand. We show that shared variance across the cognitive tasks was captured by a dimension reflecting directed (uncertainty-driven) versus random (stochasticity-driven) exploration and individual differences along this axis were significantly and consistently predicted by personality traits. However, the personality metrics that best predicted information demand were not the central curiosity traits of openness to experience, deprivation sensitivity, and joyous exploration, but instead included more peripheral curiosity traits (need for cognition, thrill seeking, and stress tolerance) and measures not traditionally associated with curiosity (extraversion and behavioral inhibition). The results suggest that the umbrella term "curiosity" reflects a constellation of cognitive and emotional processes, only some of which are shared between personality measures and cognitive tasks. The results reflect the distinct methods that are used in these fields, indicating a need for caution in comparing results across fields and for future interdisciplinary collaborations to strengthen our emerging understanding of curiosity. [ABSTRACT FROM AUTHOR]

Pyrazolo[3,4-b]pyridine scaffolds have been heavily exploited in the development of nitrogen-containing heterocycles with numerous therapeutic applications in the field of medicinal and pharmaceutical chemistry. The present work describes the synthesis of eighteen biaryl pyrazolo[3,4-b]pyridine ester (6a–i) and hydrazide (7a–i) derivatives via the Suzuki cross-coupling reaction. These derivatives were subsequently screened for their therapeutic potential to inhibit the diabetic α-amylase enzyme, which is a key facet of the development of anti-diabetic agents. Initially, the ethyl 4-(4-bromophenyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate 4 was synthesized through a modified Doebner method under solvent-free conditions, providing an intermediate for further derivatization with a 60% yield. This intermediate 4 was subjected to Suzuki cross-coupling, reacting with electronically diverse aryl boronic acids to obtain the corresponding pyrazolo[3,4-b]pyridine ester derivatives (6a–i). Following this, the biaryl ester derivatives (6a–i) were converted into hydrazide derivatives (7a–i) through a straightforward reaction with hydrazine monohydrate and were characterized using 1H-NMR, 13C-NMR, and LC-MS spectroscopic techniques. These derivatives were screened for their α-amylase inhibitory chemotherapeutic efficacy, and most of the biaryl ester and hydrazide derivatives demonstrated promising amylase inhibition. In the (6a–i) series, the compounds 6b, 6c, 6h, and 6g exhibited excellent inhibition, with almost similar IC50 values of 5.14, 5.15, 5.56, and 5.20 μM, respectively. Similarly, in the series (7a–i), the derivatives 7a, 7b, 7c, 7d, 7f, 7g, and 7h displayed excellent anti-diabetic activities of 5.21, 5.18, 5.17, 5.12, 5.10, 5.16, and 5.19 μM, respectively. These in vitro results were compared with the reference drug acarbose (IC50 = 200.1 ± 0.15 μM), demonstrating better anti-diabetic inhibitory activity in comparison to the reference drug. The in silico molecular docking study results were consistent with the experimental biological findings, thereby supporting the in vitro pharmaceutical efficacy of the synthesized derivatives. [ABSTRACT FROM AUTHOR]

Contemporary quality control methods are often insufficient in predicting clinical outcomes after revascularization in lower extremity arterial disease (LEAD) patients. This study evaluates the potential of near-infrared fluorescence imaging with indocyanine green to predict the clinical outcome following revascularization. Near-infrared fluorescence imaging was performed before and within 5 days following the revascularization procedure. Clinical improvement was defined as substantial improvement of pain free walking distance, reduction of rest- and/or nocturnal pain, or tendency toward wound healing. Time-intensity curves and 8 perfusion parameters were extracted from the dorsum of the treated foot. The quantified postinterventional perfusion improvement was compared within the clinical outcome groups. Successful near-infrared fluorescence imaging was performed in 72 patients (76 limbs, 52.6% claudication, 47.4% chronic limb-threatening ischemia) including 40 endovascular- and 36 surgical/hybrid revascularizations. Clinical improvement was observed in 61 patients. All perfusion parameters showed a significant postinterventional difference in the clinical improvement group (P -values <.001), while no significant differences were seen in the group without clinical improvement (P -values.168–.929). Four parameters demonstrated significant differences in percentage improvement comparing the outcome groups (P -values within.002–.006). Near-infrared fluorescence imaging has promising additional value besides clinical parameters for predicting the clinical outcome of revascularized LEAD patients. [ABSTRACT FROM AUTHOR]

Background: The distance traveled by the positron before annihilation with an electron, the so‐called positron range, negatively effects the positron emission tomography (PET) image quality for radionuclides emitting high‐energy positrons such as Gallium‐68 (68Ga). Purpose: In this study, the effect of a tissue‐independent positron range correction for Gallium‐68 (68Ga‐PRC) was investigated based on phantom measurements. The effect of the 68Ga‐PRC was also explored in four patients. Methods: The positron range distribution profile of 68Ga in water was generated via Monte Carlo simulation. That profile was mapped to a spatially invariant 3D convolution kernel which was incorporated in the OSEM and Q.Clear reconstruction algorithms to perform the 68Ga‐PRC. In addition, each reconstruction method included point spread function (PSF) modeling and time‐of‐flight information. For both Fluorine‐18 (18F) and 68Ga, the NEMA IQ phantom was filled with a sphere‐to‐background ratio of 10:1 and scanned with the GE Discovery MI 5R PET/CT system. Standard non‐positron range correction (PRC) reconstructions were performed for both radionuclides, while also PRC reconstructions were performed for 68Ga. Reconstructions parameters (OSEM: number of updates, Q.Clear: beta value) were adapted to achieve similar noise levels between the corresponding reconstructions. The effect of 68Ga‐PRC was assessed for both OSEM and Q.Clear reconstructions and compared to non‐PRC reconstructions for 68Ga and 18F in terms of image contrast, noise, recovery coefficient (RC), and spatial resolution. For the clinical validation, 68Ga‐labeled prostate‐specific membrane antigen (68Ga‐PSMA) and 68Ga‐DOTATOC PET scans were included of two patients each. For each PET scan, patients were injected with 1.5 MBq/kg of 68Ga‐PSMA or 68Ga‐DOTATOC and the contrast‐to‐noise ratio (CNR) was calculated and compared to the non‐PRC reconstructions. Results: For OSEM reconstructions, including the 68Ga‐PRC improved the RC by 9.4% (3.7%–19.3%) and spatial resolution by 21.7% (4.6 mm vs. 3.6 mm) for similar noise levels. For Q.Clear reconstructions, 68Ga‐PRC modeling improved the RC by 6.7% (2.8%–10.5%) and spatial resolution by 15.3% (5.9 mm vs. 5.0 mm) while obtaining similar noise levels. In the patient data, the use of 68Ga‐PRC enhanced the CNR by 13.2%. Conclusions: Including 68Ga‐PRC in the PET reconstruction enhanced the image quality of 68Ga PET data compared to the standard non‐PRC reconstructions for similar noise levels. Limited patient results also supported this improvement. [ABSTRACT FROM AUTHOR]

Prediction errors have a prominent role in many forms of learning. For example, in reinforcement learning, agents learn by updating the association between states and outcomes as a function of the prediction error elicited by the event. One paradigm often used to study error-driven learning is blocking. In forward blocking, participants are first presented with stimulus A, followed by outcome X (A→X). In the second phase, A and B are presented together, followed by X (AB→X). Here, A→X blocks the formation of B→X, given that X is already fully predicted by A. In backward blocking, the order of phases is reversed. Here, the association between B and X that is formed during the first learning phase of AB→X is weakened when participants learn exclusively A→X in the second phase. The present study asked the question whether forward and backward blocking occur during visual statistical learning, i.e., the incidental learning of the statistical structure of the environment. In a series of studies, using both forward and backward blocking, we observed statistical learning of temporal associations among pairs of images. While we found no forward blocking, we observed backward blocking, thereby suggesting a retrospective revaluation process in statistical learning and supporting a functional similarity between statistical learning and reinforcement learning. [ABSTRACT FROM AUTHOR]

This article provides an overview of the field of bioorthogonal chemistry and its advancements at Radboud University. Bioorthogonal chemistry involves conducting chemical reactions within a biological environment with high selectivity and compatibility. Radboud University has made significant contributions to this field, including the development of strained alkynes and the synthesis of bioorthogonal tools such as BCN and TCO. These tools have been applied in various areas such as chemical biology and materials science. The article also highlights the interdisciplinary nature of research at Radboud University and the importance of synthetic availability in bioorthogonal reagents. The text specifically discusses the use of VBAs in bioorthogonal chemistry, particularly in the IEDDA reaction with tetrazines. The authors found that introducing boronic acid substituents on linear alkenes improved their reactivity in the IEDDA reaction. They also observed that the reactivity of VBAs varied depending on the coordinating substituent on the tetrazine. The authors explored the potential of VBAs in click-to-release chemistry, protein modification, and drug delivery applications. The article emphasizes the collaborative efforts and interdisciplinary approach necessary for advancing bioorthogonal chemistry. [Extracted from the article]

Background: The importance of CD11b/CD18 expression in neutrophil effector functions is well known. Beyond KINDLIN3 and TALIN1, which are involved in the induction of the high-affinity binding CD11b/CD18 conformation, the signaling pathways that orchestrate this response remain incompletely understood. Method: We performed an unbiased screening method for protein selection by biotin identification (BioID) and investigated the KINDLIN3 interactome. We used liquid chromatography with tandem mass spectrometry as a powerful analytical tool. Generation of NB4 CD18, KINDLIN3, or SKAP2 knockout neutrophils was achieved using CRISPR-Cas9 technology, and the cells were examined for their effector function using flow cytometry, live cell imaging, microscopy, adhesion, or antibody-dependent cellular cytotoxicity (ADCC). Results: Among the 325 proteins significantly enriched, we identified Src kinase-associated phosphoprotein 2 (SKAP2), a protein involved in actin polymerization and integrin-mediated outside-in signaling. CD18 immunoprecipitation in primary or NB4 neutrophils demonstrated the presence of SKAP2 in the CD11b/CD18 complex at a steady state. Under this condition, adhesion to plastic, ICAM-1, or fibronectin was observed in the absence of SKAP2, which could be abrogated by blocking the actin rearrangements with latrunculin B. Upon stimulation of NB4 SKAP2-deficient neutrophils, adhesion to fibronectin was enhanced whereas CD18 clustering was strongly reduced. This response corresponded with significantly impaired CD11b/CD18-dependent NADPH oxidase activity, phagocytosis, and cytotoxicity against tumor cells. Conclusion: Our results suggest that SKAP2 has a dual role. It may restrict CD11b/ CD18-mediated adhesion only under resting conditions, but its major contribution lies in the regulation of dynamic CD11b/CD18-mediated actin rearrangements and clustering as required for cellular effector functions of human neutrophils. [ABSTRACT FROM AUTHOR]

Cyclobutanes are attracting a growing interest in medicinal chemistry because of their unique structure and potentially advantageous pharmacological properties. Specifically, 1,3‐disubstituted cyclobutanes have been explored as conformationally restricted propyl isosteres in drug development. In this study, a concise two‐diversification‐point library of 3‐amino‐3‐[(arenesulfonyl)methyl]cyclobutanols was synthesized through a hyperbaric [2+2] cycloaddition reaction between sulfonyl allenes and benzyl vinyl ether as the key step. Three different sulfonyl allenes were used for synthesizing the core structures that were further derivatized by the addition of up to seven amines. The amino groups were incorporated in a moderate to excellent diastereoselectivity through conjugate addition to the four‐membered‐ring scaffolds. Overall, this synthesis process demonstrates the potential for further chemical expansion and fragment growth in drug development. [ABSTRACT FROM AUTHOR]

The treatment landscape for haemophilia is changing rapidly, creating opportunities for personalized treatment. As major morbidity is still caused by haemophilic arthropathy, understanding the factors affecting joint damage and joint damage progression might lead to more individualized treatment regimens. We investigated the association of HFE mutations or HMOX1 polymorphisms affecting iron/heme handling with radiographic joint damage in 252 haemophilia patients (severe and moderate). Although iron levels and transferrin saturation were significantly increased in the 95 patients with an HFE mutation, neither carrying this mutation nor the HMOX1 polymorphism was associated with radiographic joint damage, and the same was true after adjustment for well-known factors associated with arthropathy. In conclusion, this study does not support the hypothesis that HFE mutations or HMOX1 polymorphisms can be used to predict the development of haemophilic arthropathy. [ABSTRACT FROM AUTHOR]

Measuring glycosidase activity is important to monitor any aberrations in carbohydrate hydrolase activity, but also for the screening of potential glycosidase inhibitors. To this end, synthetic substrates are needed which provide an enzyme‐dependent read‐out upon hydrolysis by the glycosidase. Herein, we present two new routes for the synthesis of caged luminescent carbohydrates, which can be used for determining glycosidase activity with a luminescent reporter molecule. The substrates were validated with glycosidase and revealed a clear linear range and enzyme‐dependent signal upon the in situ generation of the luciferin moiety from the corresponding nitrile precursors. Besides, we showed that these compounds could directly be synthesized from unprotected glycosyl‐α‐fluorides in a two‐step procedure with yields up to 75 %. The intermediate methyl imidate appeared a key intermediate which also reacted with d‐cysteine to give the corresponding d‐luciferin substrate rendering this a highly attractive method for synthesizing glycosyl luciferins in good yields. [ABSTRACT FROM AUTHOR]

The desire to create biomolecules modified with functionalities that go beyond nature's toolbox has resulted in the development of biocompatible and selective methodologies and reagents, each with different scope and limitations. In this overview, we highlight recent advances in the field of bioconjugation from 2016 to 2023. First, (metal-mediated) protein functionalization by exploiting the specific reactivity of amino acids will be discussed, followed by novel bioorthogonal reagents for bioconjugation of modified biomolecules. [ABSTRACT FROM AUTHOR]

Aim: Subclinical bleeding and inflammation play a role in progression of haemophilic arthropathy. Synovial proliferation is predictive of joint bleeding and its early detection may guide treatment changes and prevent arthropathy progression. This study evaluated the prevalence of active and inactive subclinical synovial proliferation and investigated potential biochemical blood/urine markers to identify patients with active subclinical synovial proliferation. Methods: This cross‐sectional study included patients with severe haemophilia A born 1970–2006 who were evaluated during routine clinic visits. Patients with (a history of) inhibitors or recent joint bleeding were excluded. Elbows, knees and ankles were examined for subclinical synovial proliferation by ultrasound and physical examination. Active synovial proliferation was distinguished from inactive synovial proliferation using predefined criteria. Blood/urine biochemical markers (serum osteopontin, sVCAM‐1, Coll2‐1, COMP, CS846, TIMP, and urinary CTX‐II) were compared individually and as combined indexes between patients with and without active synovial proliferation. Results: This cohort consisted of 79 patients with a median age of 31 years (range 16.5–50.8 years) with 62/79 (78%) of the patients using continuous prophylaxis. The annualized joint bleeding rate over the last 5 years was.6 (.2–1.1). Active (17/79, 22%) and inactive subclinical synovial proliferation (17/79, 22%) were both prevalent in this cohort. Biochemical markers were not correlated with active subclinical synovial proliferation. Conclusion: Subclinical synovial proliferation, both active and inactive, was prevalent in patients with severe haemophilia A with access to prophylaxis and would be overlooked without routinely performed ultrasounds. Biochemical markers were unable to identify patients with active subclinical synovial proliferation. [ABSTRACT FROM AUTHOR]

The group of Costa Figueiredo reported Cu-based catalysts for the electrosynthesis of ammonia from nitrate, and X-ray photoelectron spectroscopy demonstrated that Cu(0) is the active phase during catalysis. The Hamlin and Bickelhaupt group performed high level quantum chemical analysis, showing that C(spn)-halogen bonds are easier to activate by a palladium catalyst when the halogen is larger, due to a difference in activation strain and a more favorable electrostatic attraction between the palladium catalyst and the substrate. The importance of catalysis has been recognized a long time ago and the first industrial application stems from the early nineteenth century. We develop new catalytic processes based on 1) rational ligand design in transition metal catalysis 2) Supramolecular catalysis 3) Bio-inspired catalysis. [Extracted from the article]

Non‐hydrogenative Para‐Hydrogen Induced Hyperpolarization (nhPHIP) is a Nuclear Magnetic Resonance (NMR) hyperpolarization technique which has experimentally been used to analyze complex biological samples containing amino acids using the Ir‐IMes hyperpolarization transfer catalyst. A computational study based on Density Function Theory (DFT) was performed on all relevant stereoisomers of [Ir(H)2(IMes)(AA)(Py)] (with AA=glycine, alanine, valine; Py=pyridine), for which R/S chirality and orientation of the amino acid chelation (C/A) were considered. A total of 30 structures were calculated comprising of 6 stereoisomers for achiral glycine, and 12 stereoisomers for each of the chiral amino acids. The abundances derived from the DFT energies confirmed the trends observed in thermal (non‐hyperpolarized) NMR experiments. Additionally, theoretical calculations of electronic (Wiberg bond indices, Natural Bond Orders, Frontier Orbital Analysis), bond dissociation energies, transition states, and activation energies related to interconversion between binding modes, and steric factors (Solid angle) were performed to provide detailed explanations for NMR experimental observations. [ABSTRACT FROM AUTHOR]

Background: Indocyanine green near-infrared fluorescence bowel perfusion assessment has shown its potential benefit in preventing anastomotic leakage. However, the surgeon's subjective visual interpretation of the fluorescence signal limits the validity and reproducibility of the technique. Therefore, this study aimed to identify objective quantified bowel perfusion patterns in patients undergoing colorectal surgery using a standardized imaging protocol. Method: A standardized fluorescence video was recorded. Postoperatively, the fluorescence videos were quantified by drawing contiguous region of interests (ROIs) on the bowel. For each ROI, a time-intensity curve was plotted from which perfusion parameters (n = 10) were derived and analyzed. Furthermore, the inter-observer agreement of the surgeon's subjective interpretation of the fluorescence signal was assessed. Results: Twenty patients who underwent colorectal surgery were included in the study. Based on the quantified time-intensity curves, three different perfusion patterns were identified. Similar for both the ileum and colon, perfusion pattern 1 had a steep inflow that reached its peak fluorescence intensity rapidly, followed by a steep outflow. Perfusion pattern 2 had a relatively flat outflow slope immediately followed by its plateau phase. Perfusion pattern 3 only reached its peak fluorescence intensity after 3 min with a slow inflow gradient preceding it. The inter-observer agreement was poor-moderate (Intraclass Correlation Coefficient (ICC): 0.378, 95% CI 0.210–0.579). Conclusion: This study showed that quantification of bowel perfusion is a feasible method to differentiate between different perfusion patterns. In addition, the poor-moderate inter-observer agreement of the subjective interpretation of the fluorescence signal between surgeons emphasizes the need for objective quantification. [ABSTRACT FROM AUTHOR]

Primary Sjögren's syndrome (pSS) is an autoimmune disease characterised by B cell hyperactivity. CXCR5+ follicular helper T cells (Tfh), CXCR5-PD-1hi peripheral helper T cells (Tph) and CCR9+ Tfh-like cells have been implicated in driving B cell hyperactivity in pSS; however, their potential overlap has not been evaluated. Our aim was to study the overlap between the two CXCR5- cell subsets and to study their PD-1/ICOS expression compared to "true" CXCR5/PD-1/ICOS-expressing Tfh cells. CXCR5- Tph and CCR9+ Tfh-like cell populations from peripheral blood mononuclear cells of pSS patients and healthy controls (HC) were compared using flow cytometry. PD-1/ICOS expression from these cell subsets was compared to each other and to CXCR5+ Tfh cells, taking into account their differentiation status. CXCR5- Tph cells and CCR9+ Tfh-like cells, both in pSS patients and HC, showed limited overlap. PD-1/ICOS expression was higher in memory cells expressing CXCR5 or CCR9. However, the highest expression was found in CXCR5/CCR9 co-expressing T cells, which are enriched in the circulation of pSS patients. CXCR5- Tph and CCR9+ Tfh-like cells are two distinct cell populations that both are enriched in pSS patients and can drive B cell hyperactivity in pSS. The known upregulated expression of CCL25 and CXCL13, ligands of CCR9 and CXCR5, at pSS inflammatory sites suggests concerted action to facilitate the migration of CXCR5+CCR9+ T cells, which are characterised by the highest frequencies of PD-1/ICOS-positive cells. Hence, these co-expressing effector T cells may significantly contribute to the ongoing immune responses in pSS. [ABSTRACT FROM AUTHOR]

Objective: To gain better understanding of osteoarthritis (OA) heterogeneity and its predictors for distinguishing OA phenotypes. This could provide the opportunity to tailor prevention and treatment strategies and thus improve care. Design: Ten year follow-up data from CHECK (1002 early-OA subjects with first general practitioner visit for complaints ≤6 months before inclusion) was used. Data were collected on WOMAC (pain, function, stiffness), quantitative radiographic tibiofemoral (TF) OA characteristics, and semi-quantitative radiographic patellofemoral (PF) OA characteristics. Using functional data analysis, distinctive sets of trajectories were identified for WOMAC, TF and PF characteristics, based on model fit and clinical interpretation. The probabilities of knee membership to each trajectory were used in hierarchical cluster analyses to derive knee OA phenotypes. The number and composition of potential phenotypes was selected again based on model fit (silhouette score) and clinical interpretation. Results: Five trajectories representing different constant levels or changing WOMAC scores were identified. For TF and PF OA, eight and six trajectories respectively were identified based on (changes in) joint space narrowing, osteophytes and sclerosis. Combining the probabilities of knees belonging to these different trajectories resulted in six clusters ('phenotypes') of knees with different degrees of functional (WOMAC) and radiographic (PF) parameters; TF parameters were found not to significantly contribute to clustering. Including baseline characteristics as well resulted in eight clusters of knees, dominated by sex, menopausal status and WOMAC scores, with only limited contribution of PF features. Conclusions: Several stable and progressive trajectories of OA symptoms and radiographic features were identified, resulting in phenotypes with relatively independent symptomatic and radiographic features. Sex and menopausal status may be especially important when phenotyping knee OA patients, while radiographic features contributed less. Possible phenotypes were identified that, after validation, could aid personalized treatments and patients selection. [ABSTRACT FROM AUTHOR]

Objective: Longitudinal weight-bearing radiographic joint space width (JSW) and non-weight-bearing MRI-based cartilage thickness changes often show weak correlations. The current objective was to investigate these correlations, and to explore the influence of different factors that could contribute to longitudinal differences between the two methods. Methods: The current study included 178 participants with medial osteoarthritis (OA) out of the 297 knee OA participants enrolled in the IMI-APPROACH cohort. Changes over 2 years in medial JSW (ΔJSWmed), minimum JSW (ΔJSWmin), and medial femorotibial cartilage thickness (ΔMFTC) were assessed using linear regression, using measurements from radiographs and MRI acquired at baseline, 6 months, and 1 and 2 years. Pearson R correlations were calculated. The influence of cartilage quality (T2 mapping), meniscal extrusion (MOAKS scoring), potential pain-induced unloading (difference in knee-specific pain scores), and increased loading (BMI) on the correlations was analyzed by dividing participants in groups based on each factor separately, and comparing correlations (slope and strength) between groups using linear regression models. Result: Correlations between ΔMFTC and ΔJSWmed and ΔJSWmin were statistically significant (p < 0.004) but weak (R < 0.35). Correlations were significantly different between groups based on cartilage quality and on meniscal extrusion: only patients with the lowest T2 values and with meniscal extrusion showed significant moderate correlations. Pain-induced unloading or BMI-induced loading did not influence correlations. Conclusions: While the amount of loading does not seem to make a difference, weight-bearing radiographic JSW changes are a better reflection of non-weight-bearing MRI cartilage thickness changes in knees with higher quality cartilage and with meniscal extrusion. [ABSTRACT FROM AUTHOR]

Perceivers can use past experiences to make sense of ambiguous sensory signals. However, this may be inappropriate when the world changes and past experiences no longer predict what the future holds. Optimal learning models propose that observers decide whether to stick with or update their predictions by tracking the uncertainty or "precision" of their expectations. However, contrasting theories of prediction have argued that we are prone to misestimate uncertainty—leading to stubborn predictions that are difficult to dislodge. To compare these possibilities, we had participants learn novel perceptual predictions before using fMRI to record visual brain activity when predictive contingencies were disrupted—meaning that previously "expected" events became objectively improbable. Multivariate pattern analyses revealed that expected events continued to be decoded with greater fidelity from primary visual cortex, despite marked changes in the statistical structure of the environment, which rendered these expectations no longer valid. These results suggest that our perceptual systems do indeed form stubborn predictions even from short periods of learning—and more generally suggest that top–down expectations have the potential to help or hinder perceptual inference in bounded minds like ours. [ABSTRACT FROM AUTHOR]

Vascular endothelial cells (ECs) form a dynamic interface between blood and tissue and play a crucial role in the progression of vascular inflammation. Here, we aim to dissect the system-wide molecular mechanisms of inflammatory endothelial-cytokine responses. Applying an unbiased cytokine library, we determined that TNFα and IFNγ induced the largest EC response resulting in distinct proteomic inflammatory signatures. Notably, combined TNFα + IFNγ stimulation induced an additional synergetic inflammatory signature. We employed a multi-omics approach to dissect these inflammatory states, combining (phospho-) proteome, transcriptome and secretome and found, depending on the stimulus, a wide-array of altered immune-modulating processes, including complement proteins, MHC complexes and distinct secretory cytokines. Synergy resulted in cooperative activation of transcript induction. This resource describes the intricate molecular mechanisms that are at the basis of endothelial inflammation and supports the adaptive immunomodulatory role of the endothelium in host defense and vascular inflammation. Combined TNFα + IFNγ stimulation induces a synergetic inflammatory signature, which is the basis of endothelial inflammation, emphasizing the role of endothelial cell-cytokine interactions in inflammatory pathogenesis and role of endothelial cells in inflammation. [ABSTRACT FROM AUTHOR]

Piperidine alkaloids are members of the alkaloid family that is characterized by the presence of a six‐membered nitrogen‐containing heterocycle. Piperidine alkaloids are found mainly in plants and often exhibit interesting biological and pharmacological activities. Despite the accumulation of these natural products in plants, relatively low quantities of alkaloids are produced in absolute terms and thus synthesis of alkaloids and derivatives thereof remains relevant to identify targets for drug discovery. Throughout the years, researchers have come up with a myriad of methods to synthesize piperidine derivatives. This review describes methods that employ stereoselective Mannich reactions to create the core of piperidine alkaloids. Asymmetric induction in the Mannich reaction has been achieved by a range of methods that have been divided into three conceptual approaches: (1) chiral pool‐based (internal asymmetric induction), (2) chiral auxiliary‐based (relayed asymmetric induction) and (3) asymmetric catalysis‐based (external asymmetric induction). Of each approach, we describe the reaction mechanism and rationalize the stereochemical outcome of the Mannich products. [ABSTRACT FROM AUTHOR]

Vascular endothelial cells (ECs) form a dynamic interface between blood and tissue and play a crucial role in the progression of vascular inflammation. Here, we aim to dissect the system-wide molecular mechanisms of inflammatory endothelial-cytokine responses. Applying an unbiased cytokine library, we determined that TNFα and IFNγ induced the largest EC response resulting in distinct proteomic inflammatory signatures. Notably, combined TNFα + IFNγ stimulation induced an additional synergetic inflammatory signature. We employed a multi-omics approach to dissect these inflammatory states, combining (phospho-) proteome, transcriptome and secretome and found, depending on the stimulus, a wide-array of altered immune-modulating processes, including complement proteins, MHC complexes and distinct secretory cytokines. Synergy resulted in cooperative activation of transcript induction. This resource describes the intricate molecular mechanisms that are at the basis of endothelial inflammation and supports the adaptive immunomodulatory role of the endothelium in host defense and vascular inflammation. Combined TNFα + IFNγ stimulation induces a synergetic inflammatory signature, which is the basis of endothelial inflammation, emphasizing the role of endothelial cell-cytokine interactions in inflammatory pathogenesis and role of endothelial cells in inflammation. [ABSTRACT FROM AUTHOR]

A crucial ability of the human brain is to learn and exploit probabilistic associations between stimuli to facilitate perception and behavior by predicting future events. Although studies have shown how perceptual relationships are used to predict sensory inputs, relational knowledge is often between concepts rather than percepts (e.g., we learned to associate cats with dogs, rather than specific images of cats and dogs). Here, we asked if and how sensory responses to visual input may be modulated by predictions derived from conceptual associations. To this end we exposed participants of both sexes to arbitrary word-word pairs (e.g., car-dog) repeatedly, creating an expectation of the second word, conditional on the occurrence of the first. In a subsequent session, we exposed participants to novel word-picture pairs, while measuring fMRI BOLD responses. All word-picture pairs were equally likely, but half of the pairs conformed to the previously formed conceptual (word-word) associations, whereas the other half violated this association. Results showed suppressed sensory responses throughout the ventral visual stream, including early visual cortex, to pictures that corresponded to the previously expected words compared with unexpected words. This suggests that the learned conceptual associations were used to generate sensory predictions that modulated processing of the picture stimuli. Moreover, these modulations were tuning specific, selectively suppressing neural populations tuned toward the expected input. Combined, our results suggest that recently acquired conceptual priors are generalized across domains and used by the sensory brain to generate category-specific predictions, facilitating processing of expected visual input. [ABSTRACT FROM AUTHOR]

Introduction: Ankle joint distraction (AJD) is a promising treatment for patients with severe haemophilic ankle arthropathy (HAA). However, some patients showed no clinical improvement after AJD and these differences may be related to structural differences. Aim: Primarily to quantify the structural changes after AJD in patients with HAA by the use of 3D joint space width (JSW) measurements and biochemical markers and secondarily to correlate these findings with clinical pain/function. Methods: Patients with haemophilia A/B who underwent AJD were included for this study. Bone contours on MRI (performed before and 12 and 36 months after AJD) were drawn manually and percentage change in JSW was calculated. Blood/urine (before and 6, 12, 24 and 36 months after AJD) was collected for biomarker measurement (COMP, CS846, C10C, CALC2, PRO‐C2, CTX‐II) and combined indexes of markers were calculated. Mixed effects models were used for analyses on group level. Structural changes were compared with clinical parameters. Results: Eight patients were evaluated. On group level, percentage changes in JSW showed a slight decrease after 12 months followed by a non‐statistically significant increase in JSW after 36 months compared to baseline. Biochemical marker collagen/cartilage formation also showed an initial decrease, followed by a trend towards net formation 12, 24 and 36 months after AJD. On individual patient level, no clear correlations between structural changes and clinical parameters were observed. Conclusion: Cartilage restoration activity on group level in patients with HAA after AJD was in concordance with clinical improvements. Correlating structural modifications with clinical parameters in the individual patient remains difficult. [ABSTRACT FROM AUTHOR]

Aim: Minimally invasive colorectal surgery reduces surgical trauma with better preservation of abdominal wall integrity, but the extraction site is still at risk of incisional hernia (IH). The aim of this study was to determine pooled incidence of IH for each type of extraction site and to compare rates of IH after midline, nonmidline and Pfannenstiel extraction. Method: A systematic review and meta‐analysis was conducted using the PRISMA guidelines. Single‐armed and multiple‐armed cohort studies and randomized controlled trials regarding minimally invasive colorectal surgery were searched from five databases. Outcomes were pooled and compared with random‐effects, inverse‐variance models. Risk of bias within the studies was assessed using the Cochrane ROBINS‐I and RoB 2 tool. Results: Thirty six studies were included, with a total 11,788 patients. The pooled extraction site IH rate was 16.0% for midline (n = 4081), 9.3% for umbilical (n = 2425), 5.2% for transverse (n = 3213), 9.4% for paramedian (n = 134) and 2.1% for Pfannenstiel (n = 1449). Nonmidline extraction (transverse and paramedian) showed significantly lower odds ratios (ORs) for IH when compared with midline extraction (including umbilical). Pfannenstiel extraction resulted in a significantly lower OR for IH compared with midline [OR 0.12 (0.50–0.30)], transverse [OR 0.25 (0.13–0.50)] and umbilical (OR 0.072 [0.033–0.16]) extraction sites. The risks of surgical site infection, seroma/haematoma or wound dehiscence were not significantly different in any of the analyses. Conclusion: Pfannenstiel extraction is the preferred method in minimally invasive colorectal surgery. In cases where Pfannenstiel extraction is not possible, surgeons should avoid specimen extraction in the midline. [ABSTRACT FROM AUTHOR]

The blood coagulation cascade is a complex physiological process involving the action of multiple coupled enzymes, cofactors, and substrates, ultimately leading to clot formation. Serine proteases have a crucial role, and aberrations in their activity can lead to life‐threatening bleeding disorders and thrombosis. This review summarizes the essential proteases involved in blood coagulation and fibrinolysis, the endogenous peptide sequences they recognize and hydrolyze, and synthetic peptide probes based on these sequences to measure their activity. The information in this review can contribute to developing novel anticoagulant therapies and specific substrates for point‐of‐care diagnosis of coagulation pathologies. [ABSTRACT FROM AUTHOR]

Background: Biomonitoring may provide important insights into the impact of a whole blood donation for individual blood donors. Study Design and Methods: Here, we used unbiased mass spectrometry (MS)‐based proteomics to assess longitudinal changes in the global plasma proteome, after a single blood donation for new and regular donors. Subsequently, we compared plasma proteomes of 76 male and female whole blood donors, that were grouped based on their ferritin and hemoglobin (Hb) levels. Results: The longitudinal analysis showed limited changes in the plasma proteomes of new and regular donors after a whole blood donation during a 180‐day follow‐up period, apart from a significant short‐term decrease in fibronectin. No differences were observed in the plasma proteomes of donors with high versus low Hb and/or ferritin levels. Plasma proteins with the highest variation between and within donors included pregnancy zone protein, which was associated with sex, Alfa 1‐antitrypsin which was associated with the allelic variation, and Immunoglobulin D. Coexpression analysis revealed clustering of proteins that are associated with platelet, red cell, and neutrophil signatures as well as with the complement system and immune responses, including a prominent correlating cluster of immunoglobulin M (IgM), immunoglobulin J chain (JCHAIN), and CD5 antigen‐like (CD5L). Discussion: Overall, our proteomic approach shows that whole blood donation has a limited impact on the plasma proteins measured. Our findings suggest that plasma profiling can be successfully employed to consistently detect proteins and protein complexes that reflect the functionality and integrity of platelets, red blood cells, and immune cells in blood donors and thus highlights its potential use for donor health monitoring. [ABSTRACT FROM AUTHOR]

The relationship between conscious experience and brain activity has intrigued scientists and philosophers for centuries. In the last decades, several theories have suggested different accounts for these relationships. These theories have developed in parallel, with little to no cross-talk among them. To advance research on consciousness, we established an adversarial collaboration between proponents of two of the major theories in the field, Global Neuronal Workspace and Integrated Information Theory. Together, we devised and preregistered two experiments that test contrasting predictions of these theories concerning the location and timing of correlates of visual consciousness, which have been endorsed by the theories' proponents. Predicted outcomes should either support, refute, or challenge these theories. Six theory-impartial laboratories will follow the study protocol specified here, using three complementary methods: Functional Magnetic Resonance Imaging (fMRI), Magneto-Electroencephalography (M-EEG), and intracranial electroencephalography (iEEG). The study protocol will include built-in replications, both between labs and within datasets. Through this ambitious undertaking, we hope to provide decisive evidence in favor or against the two theories and clarify the footprints of conscious visual perception in the human brain, while also providing an innovative model of large-scale, collaborative, and open science practice. [ABSTRACT FROM AUTHOR]

The click reaction between a functionalized trans‐cyclooctene (TCO) and a tetrazine (Tz) is a compelling method for bioorthogonal conjugation in combination with payload releasing capabilities. However, the synthesis of difunctionalized TCOs remains challenging. As a result, these compounds are poorly accessible, which impedes the development of novel applications. In this work, the scalable and accessible synthesis of a new bioorthogonal difunctionalized TCO is reported in only four single selective high yielding steps starting from commercially available compounds. The TCO‐Tz click reaction was assessed and revealed excellent kinetic rates and subsequently payload release was shown with various functionalized derivatives. Tetrazine triggered release of carbonate and carbamate payloads was demonstrated up to 100 % release efficiency and local drug release was shown in a cellular toxicity study which revealed a >20‐fold increase in cytotoxicity. [ABSTRACT FROM AUTHOR]

Sounds enhance the detection of visual stimuli while concurrently biasing an observer's decisions. To investigate the neural mechanisms that underlie such multisensory interactions, we decoded time-resolved Signal Detection Theory sensitivity and criterion parameters from magneto-encephalographic recordings of participants that performed a visual detection task. We found that sounds improved visual detection sensitivity by enhancing the accumulation and maintenance of perceptual evidence over time. Meanwhile, criterion decoding analyses revealed that sounds induced brain activity patterns that resembled the patterns evoked by an actual visual stimulus. These two complementary mechanisms of audiovisual interplay differed in terms of their automaticity: Whereas the sound-induced enhancement in visual sensitivity depended on participants being actively engaged in a detection task, we found that sounds activated the visual cortex irrespective of task demands, potentially inducing visual illusory percepts. These results challenge the classical assumption that sound-induced increases in false alarms exclusively correspond to decision-level biases. Magnetoencephalography recordings from participants in a visual detection task reveals that sounds improved visual detection sensitivity by enhancing the accumulation and maintenance of perceptual evidence over time. [ABSTRACT FROM AUTHOR]

Objectives The IMI-APPROACH knee osteoarthritis study used machine learning (ML) to predict structural and/or pain progression, expressed by a structural (S) and pain (P) predicted-progression score, to select patients from existing cohorts. This study evaluates the actual 2-year progression within the IMI-APPROACH, in relation to the predicted-progression scores. Methods Actual structural progression was measured using minimum joint space width (minJSW). Actual pain (progression) was evaluated using the Knee injury and Osteoarthritis Outcomes Score (KOOS) pain questionnaire. Progression was presented as actual change (Δ) after 2 years, and as progression over 2 years based on a per patient fitted regression line using 0, 0.5, 1 and 2-year values. Differences in predicted-progression scores between actual progressors and non-progressors were evaluated. Receiver operating characteristic (ROC) curves were constructed and corresponding area under the curve (AUC) reported. Using Youden's index, optimal cut-offs were chosen to enable evaluation of both predicted-progression scores to identify actual progressors. Results Actual structural progressors were initially assigned higher S predicted-progression scores compared with structural non-progressors. Likewise, actual pain progressors were assigned higher P predicted-progression scores compared with pain non-progressors. The AUC-ROC for the S predicted-progression score to identify actual structural progressors was poor (0.612 and 0.599 for Δ and regression minJSW, respectively). The AUC-ROC for the P predicted-progression score to identify actual pain progressors were good (0.817 and 0.830 for Δ and regression KOOS pain, respectively). Conclusion The S and P predicted-progression scores as provided by the ML models developed and used for the selection of IMI-APPROACH patients were to some degree able to distinguish between actual progressors and non-progressors. Trial registration ClinicalTrials.gov, https://clinicaltrials.gov , NCT03883568. [ABSTRACT FROM AUTHOR]

The brain has the extraordinary capacity to construct predictive models of the environment by internalizing statistical regularities in the sensory inputs. The resulting sensory expectations shape how we perceive and react to the world; at the neural level, this relates to decreased neural responses to expected than unexpected stimuli ("expectation suppression"). Crucially, expectations may need revision as context changes. However, existing research has often neglected this issue. Further, it is unclear whether contextual revisions apply selectively to expectations relevant to the task at hand, hence serving adaptive behavior. The present fMRI study examined how contextual visual expectations spread throughout the cortical hierarchy as we update our beliefs. We created a volatile environment: two alternating contexts contained different sequences of object images, thereby producing context-dependent expectations that needed revision when the context changed. Human participants of both sexes attended a training session before scanning to learn the contextual sequences. The fMRI experiment then tested for the emergence of contextual expectation suppression in two separate tasks, respectively, with task-relevant and task-irrelevant expectations. Effects of contextual expectation emerged progressively across the cortical hierarchy as participants attuned themselves to the context: expectation suppression appeared first in the insula, inferior frontal gyrus, and posterior parietal cortex, followed by the ventral visual stream, up to early visual cortex. This applied selectively to task-relevant expectations. Together, the present results suggest that an insular and frontoparietal executive control network may guide the flexible deployment of contextual sensory expectations for adaptive behavior in our complex and dynamic world. [ABSTRACT FROM AUTHOR]

Background: The IMI-APPROACH cohort is an exploratory, 5-centre, 2-year prospective follow-up study of knee osteoarthritis (OA). Aim was to describe baseline multi-tissue semiquantitative MRI evaluation of index knees and to describe change for different MRI features based on number of subregion-approaches and change in maximum grades over a 24-month period.Methods: MRIs were acquired using 1.5 T or 3 T MRI systems and assessed using the semi-quantitative MRI OA Knee Scoring (MOAKS) system. MRIs were read at baseline and 24-months for cartilage damage, bone marrow lesions (BML), osteophytes, meniscal damage and extrusion, and Hoffa- and effusion-synovitis. In descriptive fashion, the frequencies of MRI features at baseline and change in these imaging biomarkers over time are presented for the entire sample in a subregional and maximum score approach for most features. Differences between knees without and with structural radiographic (R) OA are analyzed in addition.Results: Two hundred eighty-nine participants had readable baseline MRI examinations. Mean age was 66.6 ± 7.1 years and participants had a mean BMI of 28.1 ± 5.3 kg/m2. The majority (55.3%) of included knees had radiographic OA. Any change in total cartilage MOAKS score was observed in 53.1% considering full-grade changes only, and in 73.9% including full-grade and within-grade changes. Any medial cartilage progression was seen in 23.9% and any lateral progression on 22.1%. While for the medial and lateral compartments numbers of subregions with improvement and worsening of BMLs were very similar, for the PFJ more improvement was observed compared to worsening (15.5% vs. 9.0%). Including within grade changes, the number of knees showing BML worsening increased from 42.2% to 55.6%. While for some features 24-months change was rare, frequency of change was much more common in knees with vs. without ROA (e.g. worsening of total MOAKS score cartilage in 68.4% of ROA knees vs. 36.7% of no-ROA knees, and 60.7% vs. 21.8% for an increase in maximum BML score per knee).Conclusions: A wide range of MRI-detected structural pathologies was present in the IMI-APPROACH cohort. Baseline prevalence and change of features was substantially more common in the ROA subgroup compared to the knees without ROA.Trial Registration: Clinicaltrials.gov identification: NCT03883568. [ABSTRACT FROM AUTHOR]

Introduction: Haemophilic ankle arthropathy (HAA) causes major morbidity. When conservative treatment fails, major surgical interventions are indicated. An alternative treatment to maintain joint mobility and postpone these interventions is desired. Aim: To gather prospective data on clinical/structural changes after ankle joint distraction (AJD) in HAA. Methods: This study includes patients with severe HAA insufficiently responding to conservative treatment. AJD was performed during 8–10 weeks by use of an external frame. Questionnaires, physical examination and radiology were used to evaluate pain, function and structural changes before and 6, 12, 24 and 36 months after distraction. Mixed effect models were used for analysis. Results: This study includes eight cases (21–53 years). The fixed effects estimates of the visual analogue score (0–10) improved from 7.5 at baseline to 3.4 (p =.023) 3 years after distraction. The Haemophilia Activities List (HAL, 0–100) for basic/complex lower extremities functions improved from respectively 29.6 and 31.5 to 54.3 (p =.015) and 50.7 (p =.031). Joint mobility was maintained. Magnetic resonance imaging (MRI) showed thickened cartilage and reduced bone marrow oedema and subchondral cysts. Pin tract infections (n = 6) were effectively treated and no adverse bleeding events occurred. At 3‐year follow‐up, in none of the patients the originally indicated arthrodesis was performed. Conclusion: This first prospective study showed that AJD in HAA results in decreased pain, improved function and decreased arthropathy‐related MRI findings in the majority of patients for prolonged time. Although the study population is small and follow‐up is relatively short, AJD may be promising to postpone invalidating interventions and might be a breakthrough treatment. [ABSTRACT FROM AUTHOR]

Hyperprolinemia type II (HPII) is an inborn error of metabolism due to genetic variants in ALDH4A1, leading to a deficiency in Δ-1-pyrroline-5-carboxylate (P5C) dehydrogenase. This leads to an accumulation of toxic levels of P5C, an intermediate in proline catabolism. The accumulating P5C spontaneously reacts with, and inactivates, pyridoxal 5'-phosphate, a crucial cofactor for many enzymatic processes, which is thought to be the pathophysiological mechanism for HPII. Here, we describe the use of a combination of LC-QTOF untargeted metabolomics, NMR spectroscopy and infrared ion spectroscopy (IRIS) to identify and characterize biomarkers for HPII that result of the spontaneous reaction of P5C with malonic acid and acetoacetic acid. We show that these biomarkers can differentiate between HPI, caused by a deficiency of proline oxidase activity, and HPII. The elucidation of their molecular structures yields insights into the disease pathophysiology of HPII. Combined metabolomics, NMR, and, IRIS identify biomarkers of hyperprolinemia type II (HPII) distinct from HPI and similar metabolic signatures as in patients with pyridoxine-dependent epilepsy. [ABSTRACT FROM AUTHOR]

Purpose: To improve the quantitative accuracy and diagnostic confidence of PET images reconstructed without time-of-flight (ToF) using deep learning models trained for ToF image enhancement (DL-ToF). Methods: A total of 273 [18F]-FDG PET scans were used, including data from 6 centres equipped with GE Discovery MI ToF scanners. PET data were reconstructed using the block-sequential-regularised-expectation–maximisation (BSREM) algorithm with and without ToF. The images were then split into training (n = 208), validation (n = 15), and testing (n = 50) sets. Three DL-ToF models were trained to transform non-ToF BSREM images to their target ToF images with different levels of DL-ToF strength (low, medium, high). The models were objectively evaluated using the testing set based on standardised uptake value (SUV) in 139 identified lesions, and in normal regions of liver and lungs. Three radiologists subjectively rated the models using testing sets based on lesion detectability, diagnostic confidence, and image noise/quality. Results: The non-ToF, DL-ToF low, medium, and high methods resulted in − 28 ± 18, − 28 ± 19, − 8 ± 22, and 1.7 ± 24% differences (mean; SD) in the SUVmax for the lesions in testing set, compared to ToF-BSREM image. In background lung VOIs, the SUVmean differences were 7 ± 15, 0.6 ± 12, 1 ± 13, and 1 ± 11% respectively. In normal liver, SUVmean differences were 4 ± 5, 0.7 ± 4, 0.8 ± 4, and 0.1 ± 4%. Visual inspection showed that our DL-ToF improved feature sharpness and convergence towards ToF reconstruction. Blinded clinical readings of testing sets for diagnostic confidence (scale 0–5) showed that non-ToF, DL-ToF low, medium, and high, and ToF images scored 3.0, 3.0, 4.1, 3.8, and 3.5 respectively. For this set of images, DL-ToF medium therefore scored highest for diagnostic confidence. Conclusion: Deep learning–based image enhancement models may provide converged ToF-equivalent image quality without ToF reconstruction. In clinical scoring DL-ToF-enhanced non-ToF images (medium and high) on average scored as high as, or higher than, ToF images. The model is generalisable and hence, could be applied to non-ToF images from BGO-based PET/CT scanners. [ABSTRACT FROM AUTHOR]

Objective: To develop and validate a composite rheumatoid arthritis (RA) disease activity index using optical spectral transmission (OST) scores obtained with the HandScan, replacing tender and swollen joint counts. Methods: RA patients from a single center routinely undergoing HandScan measurements with at least 1 concurrent OST score and Disease Activity Score in 28 joints (DAS28) were included. Data were extracted from medical records. Linear regression analyses with the DAS28 as the outcome were performed to create a disease activity index (DAS‐OST). OST score, erythrocyte sedimentation rate (ESR), and patient global assessment (PtGA) visual analog scale (VAS), sex, age, disease duration, and rheumatoid factor status were evaluated as independent variables. Final models were derived based on the statistical significance of coefficients and model fit. Of the data, two‐thirds were used for development and one‐third for validation; external validation was performed in a cohort from another center. Agreement between DAS‐OST and DAS28 was assessed using the Bland‐Altman plot method and intraclass correlation coefficient (ICC). Diagnostic value of the DAS‐OST was determined for established definitions of remission, low disease activity (LDA), and high disease activity (HDA). Results: Data of 3,358 observations from 1,505 unique RA patients were extracted. DAS‐OST was defined as: –0.44 + OST × 0.03 + male × –0.11 + LN(ESR) × 0.77 + PtGA VAS × 0.03. The ICCs between DAS‐OST and DAS28 were 0.88 (95% confidence interval [95% CI] 0.87–0.90) and 0.82 (95% CI 0.75–0.86) and measurement errors were 0.58 and 0.87 in internal and external validation, respectively. Sensitivity for remission, LDA, and HDA was 79%, 91%, and 43%, respectively, and specificity was 92%, 80%, and 96% in external validation. Conclusion: Using the HandScan, RA disease activity can be accurately estimated if combined with ESR, PtGA VAS, and sex into a disease activity index (DAS‐OST). [ABSTRACT FROM AUTHOR]

Treatment-resistant glioma stem cells are thought to propagate and drive growth of malignant gliomas, but their markers and our ability to target them specifically are not well understood. We demonstrate that podoplanin (PDPN) expression is an independent prognostic marker in gliomas across multiple independent patient cohorts comprising both high- and low-grade gliomas. Knockdown of PDPN radiosensitized glioma cell lines and glioma-stem-like cells (GSCs). Clonogenic assays and xenograft experiments revealed that PDPN expression was associated with radiotherapy resistance and tumor aggressiveness. We further demonstrate that knockdown of PDPN in GSCs in vivo is sufficient to improve overall survival in an intracranial xenograft mouse model. PDPN therefore identifies a subset of aggressive, treatment-resistant glioma cells responsible for radiation resistance and may serve as a novel therapeutic target. [ABSTRACT FROM AUTHOR]

Understanding spoken language requires transforming ambiguous acoustic streams into a hierarchy of representations, from phonemes to meaning. It has been suggested that the brain uses prediction to guide the interpretation of incoming input. However, the role of prediction in language processing remains disputed, with disagreement about both the ubiquity and representational nature of predictions. Here, we address both issues by analyzing brain recordings of participants listening to audiobooks, and using a deep neural network (GPT-2) to precisely quantify contextual predictions. First, we establish that brain responses to words are modulated by ubiquitous predictions. Next, we disentangle model-based predictions into distinct dimensions, revealing dissociable neural signatures of predictions about syntactic category (parts of speech), phonemes, and semantics. Finally, we show that high-level (word) predictions inform low-level (phoneme) predictions, supporting hierarchical predictive processing. Together, these results underscore the ubiquity of prediction in language processing, showing that the brain spontaneously predicts upcoming language at multiple levels of abstraction. [ABSTRACT FROM AUTHOR]

Background: Optimal care for Parkinson’s disease (PD) requires coordination and collaboration between providers within a complex care network. Individual patients have personalised networks of their own providers, creating a unique informal network of providers who treat (‘share’) the same patient. These ‘patient-sharing networks’ differ in density, ie, the number of identical patients they share. Denser patient-sharing networks might reflect better care provision, since providers who share many patients might have made efforts to improve their mutual care delivery. We evaluated whether the density of these patient-sharing networks affects patient outcomes and costs. Methods: We analysed medical claims data from all PD patients in the Netherlands between 2012 and 2016. We focused on seven professional disciplines that are commonly involved in Parkinson care. We calculated for each patient the density score: the average number of patients that each patient’s providers shared. Density scores could range from 1.00 (which might reflect poor collaboration) to 83.00 (which might reflect better collaboration). This score was also calculated at the hospital level by averaging the scores for all patients belonging to a specific hospital. Using logistic and linear regression analyses we estimated the relationship between density scores and health outcomes, healthcare utilization, and healthcare costs. Results: The average density score varied considerably (average 6.7, SD 8.2). Adjusted for confounders, higher density scores were associated with a lower risk of PD-related complications (odds ratio [OR]: 0.901; P<.001) and with lower healthcare costs (coefficients: -0.018, P=.005). Higher density scores were associated with more frequent involvement of neurologists (coefficient 0.068), physiotherapists (coefficient 0.052) and occupational therapists (coefficient 0.048) (P values all <.001). Conclusion: Patient sharing networks showed large variations in density, which appears unwanted as denser networks are associated with better outcomes and lower costs. [ABSTRACT FROM AUTHOR]

Introduction: Increased CCL5 expression and CD8 T cells have been shown to be pivotal regulators of immunopathology in primary Sjögren's syndrome (pSS) and pSS-like disease. Increased CCL5 expression by CCR9+ CD4 T cells has previously been implicated as a contributor to immunopathology in pSS. The role of CD8 T cells and in particular CCR9+ CD8 T cells and their potential to secrete CCL5 has not previously been studied in pSS. In this study we investigated both CCR9 and CCL5 expression by CD8 T cells in pSS patients compared to healthy controls (HC). Methods: CCR9 expression on CD8 T cells from peripheral blood was compared between patients with pSS and HC by flow cytometry. Intracellular CCL5 expression by naive, memory and effector CCR9- and CCR9+ CD8 T cells was assessed. In addition, the capacity and pace of CCL5 release upon T cell activation was determined for all subsets and compared with CD4 T cells. Results: The frequency of circulating CCR9+ CD8 T cells in pSS patients is increased compared to HC. Antigen-experienced CD8 T cells, especially CCR9+ effector CD8 T cells, express the highest CCL5 levels, and release the highest levels of CCL5 upon activation. Memory and effector CD8 T cells of pSS patients express significantly less CCL5 and subsequently release less CCL5 upon stimulation compared to HC. CCR9+ CD8 T cells rapidly release CCL5 and significantly more than CCR9+ CD4 T cells. Conclusion: CCR9+ CD8 T cells express more CCL5 than CCR9- CD8 T cells. CCL5 is rapidly released upon activation, resulting in reduced intracellular expression. Reduced CCL5 expression by an elevated number of antigen-experienced CCR9-expressing CD8 T cells in pSS patients points towards increased release in vivo. This suggests that CCL5 release by CCR9+ CD8 T cells contributes to immunopathology in pSS. [ABSTRACT FROM AUTHOR]

Objective: To compare the effects of preventing radiographic progression (in its 3 components) of tocilizumab (TCZ) monotherapy with those of TCZ and methotrexate (MTX) in combination therapy (TCZ + MTX), and to evaluate possible effect modifiers in this model. Methods: Randomized trials that compared TCZ monotherapy to TCZ + MTX combination therapy for differences in radiographic progression were analyzed on an individual patient data level using mixed‐effects models, and data were collected from 820 subjects with either early rheumatoid arthritis (RA) or established RA. Outcomes were classified as the absence of radiographic progression after 2 years (i.e., preventing radiographic progression) as measured by total Sharp/van der Heijde score (SHS), erosion score, and joint space narrowing (JSN) score. Effect modification by baseline joint damage, disease duration, and Disease Activity Score in 28 joints (DAS28) was studied. Results: Overall, TCZ + MTX combination therapy was more effective in preventing radiographic progression compared to TCZ monotherapy, which was measured by total SHS score. However, in patients with early RA who had more joint damage compared to those with less joint damage at baseline (relative risk [RR] 1.02 versus RR 0.91, respectively) or in patients with a lower DAS28 score compared to those with a higher DAS28 score (RR 1.04 versus RR 0.92, respectively) at baseline, this advantage disappeared. In patients with established RA, the advantage of TCZ + MTX versus TCZ alone in the prevention of radiographic progression disappeared with a longer disease duration at baseline (RR 1.04 versus 0.83). Results of erosion scores as an outcome were in line with these findings, though findings for JSN scores were less clear. Conclusion: Combination therapy with TCZ + MTX is more effective in preventing radiographic progression compared to TCZ monotherapy, but the effectiveness of TCZ monotherapy may approximate the effectiveness of TCZ + MTX in patients with early RA who have more joint damage and/or a lower DAS28 at baseline and in patients with established RA who have longer disease duration. [ABSTRACT FROM AUTHOR]

Being able to anticipate events before they happen facilitates stimulus processing. The anticipation of the contents of events is thought to be implemented by the elicitation of prestimulus templates in sensory cortex. In contrast, the anticipation of the timing of events is typically associated with entrainment of neural oscillations. It is so far unknown whether and in which conditions temporal expectations interact with feature‐based expectations, and, consequently, whether entrainment modulates the generation of content‐specific sensory templates. In this study, we investigated the role of temporal expectations in a sensory discrimination task. We presented participants with rhythmically interleaved visual and auditory streams of relevant and irrelevant stimuli while measuring neural activity using magnetoencephalography. We found no evidence that rhythmic stimulation induced prestimulus feature templates. However, we did observe clear anticipatory rhythmic preactivation of the relevant sensory cortices. This oscillatory activity peaked at behaviourally relevant, in‐phase, intervals. Our results suggest that temporal expectations about stimulus features do not behave similarly to explicitly cued, nonrhythmic, expectations, yet elicit a distinct form of modality‐specific preactivation. [ABSTRACT FROM AUTHOR]