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Diabetes mellitus is a common condition that requires intensive treatment and markedly impacts the welfare of affected cats. The aim of this study was to identify diabetes mellitus-associated perturbations in the feline pancreatic islet microenvironment. The utility of "clear, unobstructed brain/body imaging cocktails and computational analysis" (CUBIC) for three-dimensional pancreatic analysis was investigated.Formalin-fixed paraffin-embedded tissues from cats with diabetes mellitus, or control cats without pancreatic pathology, were retrospectively identified. Immunohistochemistry for synaptophysin and ionised calcium binding adaptor molecule 1, and immunofluorescence for insulin and synaptophysin, were used to assess changes in islets. An image analysis pipeline was developed to analyse images acquired from two-dimensional immunofluorescence. CUBIC was used to optically clear selected pancreas samples before immunofluorescence and deep three-dimensional confocal microscopy.Diabetic cats have a significant reduction in synaptophysin-positive islet area. Whilst islets from diabetic patients have similar numbers of β cells to islets from control cats, significantly lower intensity of insulin expression can be observed in the former. CUBIC facilitates clear visualisation of pancreatic islets in three dimensions.The data presented support the theory that there is a decrease in function of β cells before their destruction, suggesting a potentially significant step in the pathogenesis of feline diabetes mellitus. In parallel, we demonstrate CUBIC as a valuable new tool to visualise the shape of feline pancreatic islets and to interrogate pathology occurring in the islets of diabetic pets.

Background: The “central vein sign” (CVS), a linear hypointensity on T2*-weighted imaging corresponding to a central vein/venule, is associated with multiple sclerosis (MS) lesions. The effect of lesion-size exclusion criteria on MS diagnostic accuracy has not been extensively studied. Objective: Investigate the optimal lesion-size exclusion criteria for CVS use in MS diagnosis. Methods: Cross-sectional study of 163 MS and 51 non-MS, and radiological/histopathological correlation of 5 MS and 1 control autopsy cases. The effects of lesion-size exclusion on MS diagnosis using the CVS, and intralesional vein detection on histopathology were evaluated. Results: CVS+ lesions were larger compared to CVS− lesions, with effect modification by MS diagnosis (mean difference +7.7 mm3, p = 0.004). CVS percentage-based criteria with no lesion-size exclusion showed the highest diagnostic accuracy in differentiating MS cases. However, a simple count of three or more CVS+ lesions greater than 3.5 mm is highly accurate and can be rapidly implemented (sensitivity 93%; specificity 88%). On magnetic resonance imaging (MRI)-histopathological correlation, the CVS had high specificity for identifying intralesional veins (0/7 false positives). Conclusion: Lesion-size measures add important information when using CVS+ lesion counts for MS diagnosis. The CVS is a specific biomarker corresponding to intralesional veins on histopathology.

Many individuals consider themselves a fan of something (e.g. music, sports) and discuss these interests with others. However, these interactions may be risky: a positive interaction could make someone feel socially connected and valued by others, whereas a negative interaction may prompt feelings of exclusion. Thus, these interactions could impact one’s basic psychological needs (e.g. belonging, self-esteem) depending upon the specific conversation dynamics. Three experiments provide data supporting these hypotheses. Specifically, individuals who recalled discussing their fan interest with either a fellow fan or a non-fan who positively reacted to their passions reported increased basic need satisfaction, whereas individuals who recalled a negative interaction with a non-fan reported lower basic need satisfaction. Participants recalled these interactions as having similar effects on their perceived relational value (i.e. how valuable, close or important others perceive them). Collectively, these studies connect fan studies research to the psychology of social inclusion and exclusion, providing directions for future research.

The fabrication and characterization of steep slope transistor devices based on low-dimensional materials requires precise electrostatic doping profiles with steep spatial gradients in order to maintain maximum control over the channel. In this proof-of-concept study we present a versatile graphene heterostructure platform with three buried individually addressable gate electrodes. The platform is based on a vertical stack of embedded titanium and graphene separated by an intermediate oxide to provide an almost planar surface. We demonstrate the functionality and advantages of the platform by exploring transfer and output characteristics at different temperatures of carbon nanotube field-effect transistors with different electrostatic doping configurations. Furthermore, we back up the concept with finite element simulations to investigate the surface potential. The presented heterostructure is an ideal platform for analysis of electrostatic doping of low-dimensional materials for novel low-power transistor devices.

Background: Cortical multiple sclerosis lesions are clinically relevant but inconspicuous at conventional clinical MRI. Double inversion recovery (DIR) and phase-sensitive inversion recovery (PSIR) are more sensitive but often unavailable. In the past 2 years, artificial intelligence (AI) was used to generate DIR and PSIR from standard clinical sequences (eg, T1-weighted, T2-weighted, and fluid-attenuated inversion-recovery sequences), but multicenter validation is crucial for further implementation. Purpose: To evaluate cortical and juxtacortical multiple sclerosis lesion detection for diagnostic and disease monitoring purposes on AI-generated DIR and PSIR images compared with MRI-acquired DIR and PSIR images in a multicenter setting. Materials and Methods: Generative adversarial networks were used to generate AI-based DIR (n = 50) and PSIR (n = 43) images. The number of detected lesions between AI-generated images and MRI-acquired (reference) images was compared by randomized blinded scoring by seven readers (all with >10 years of experience in lesion assessment). Reliability was expressed as the intraclass correlation coefficient (ICC). Differences in lesion subtype were determined using Wilcoxon signed-rank tests. Results: MRI scans of 202 patients with multiple sclerosis (mean age, 46 years ± 11 [SD]; 127 women) were retrospectively collected from seven centers (February 2020 to January 2021). In total, 1154 lesions were detected on AI-generated DIR images versus 855 on MRI-acquired DIR images (mean difference per reader, 35.0% ± 22.8; P < .001). On AI-generated PSIR images, 803 lesions were detected versus 814 on MRI-acquired PSIR images (98.9% ± 19.4; P = .87). Reliability was good for both DIR (ICC, 0.81) and PSIR (ICC, 0.75) across centers. Regionally, more juxtacortical lesions were detected on AI-generated DIR images than on MRI-acquired DIR images (495 [42.9%] vs 338 [39.5%]; P < .001). On AI-generated PSIR images, fewer juxtacortical lesions were detected than on MRI-acquired PSIR images (232 [28.9%] vs 282 [34.6%]; P = .02). Conclusion: Artificial intelligence–generated double inversion-recovery and phase-sensitive inversion-recovery images performed well compared with their MRI-acquired counterparts and can be considered reliable in a multicenter setting, with good between-reader and between-center interpretative agreement.

ObjectivesPerivascular spaces have been involved in neuroinflammatory and neurodegenerative diseases. Upon a certain size, these spaces can become visible on magnetic resonance imaging (MRI), referred to as enlarged perivascular spaces (EPVS) or MRI-visible perivascular spaces (MVPVS). However, the lack of systematic evidence on etiology and temporal dynamics of MVPVS hampers their diagnostic utility as MRI biomarker. Thus, the goal of this systematic review was to summarize potential etiologies and evolution of MVPVS.MethodsIn a comprehensive literature search, out of 1,488 unique publications, 140 records assessing etiopathogenesis and dynamics of MVPVS were eligible for a qualitative summary. 6 records were included in a meta-analysis to assess the association between MVPVS and brain atrophy.ResultsFour overarching and partly overlapping etiologies of MVPVS have been proposed: (1) Impairment of interstitial fluid circulation, (2) Spiral elongation of arteries, (3) Brain atrophy and/or perivascular myelin loss, and (4) Immune cell accumulation in the perivascular space. The meta-analysis in patients with neuroinflammatory diseases did not support an association between MVPVS and brain volume measures [R: −0.15 (95%-CI −0.40–0.11)]. Based on few and mostly small studies in tumefactive MVPVS and in vascular and neuroinflammatory diseases, temporal evolution of MVPVS is slow.ConclusionCollectively, this study provides high-grade evidence for MVPVS etiopathogenesis and temporal dynamics. Although several potential etiologies for MVPVS emergence have been proposed, they are only partially supported by data. Advanced MRI methods should be employed to further dissect etiopathogenesis and evolution of MVPVS. This can benefit their implementation as an imaging biomarker.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=346564, identifier CRD42022346564.

Purpose: To evaluate the image quality of low voltage chest computed tomography with enhancement (CECT) using low-concentration-iodine contrast media (LCCM). Method: From 9 December to 19 December 2019, three different protocols were used for 263 patients undergoing chest CECT. Chest CECT was done using routine (300 mgI/ml contrast media with 100 kVp) protocol (group 1), LCCM (240 mgI/ml contrast media)–100 kVp protocol (group 2) and LCCM–80 kVp protocol (group 3) in 91, 97 and 75 patients, respectively. The overall diagnostic acceptability, anatomical depiction, noise and contrast-related artifacts were assessed. Additionally, the mean attenuation, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR) and figure of merit (FOM) in the aorta and the main pulmonary trunk were measured. Results: The overall diagnostic acceptability scores were not significantly different between groups 1 and 2 ( P = .261); group 3 demonstrated significantly lower overall diagnostic acceptability score compared with group 1 ( P = .011) or group 2 ( P < .001). However, in CECT with iterative reconstruction (IR), the overall diagnostic acceptability scores did not show significant difference among 3 groups. Group 3 showed significantly lower effective radiation dose compared with group 1 (2.33 vs 1.22 mSv, P < .001) or group 2 (2.28 vs .22 mSv, P < .001). Conclusions: In 100 kVp chest CECT, the image quality of using 240 mg/mL iodinated contrast media is comparable to that using 300 mg/mL iodine contrast media, regardless of application of IR; with IR, chest CECT using 80 kVp and 240 mg/mL iodinated contrast media results in acceptable image quality and lower radiation dose.

Objective COVID-19 and associated measures to control the spread of the COVID-19 has significantly impacted clinical research. This study aimed to determine the impact COVID-19 has had on psychiatric clinical trials and to assess whether certain trial areas or trial types were differentially affected. Methods We used information from ClinicalTrials.gov, the largest online database of clinical trial information, to examine changes in psychiatric clinical trials from January 2010–December 2020. Results Clinical trial initiation decreased in 2020, with a year-on-year percent change in trial initiation of −5.4% versus an expected percent change based on forecasting observed trends from 2010 to 2019 of 8.6%. When broken down by disease area, the distribution of trials observed in 2020 was significantly different from the predicted distribution (p

Peer reviewed: True, Funder: King’s College London, Funder: National Institute for Health Research (NIHR), Organoids are 3D cultures that to some extent reproduce the structure, composition and function of the mammalian tissues from which they derive, thereby creating in vitro systems with more in vivo-like characteristics than 2D monocultures. Here, the ability of human organoids derived from normal gastric, pancreas, liver, colon and kidney tissues to metabolise the environmental carcinogen benzo[a]pyrene (BaP) was investigated. While organoids from the different tissues showed varied cytotoxic responses to BaP, with gastric and colon organoids being the most susceptible, the xenobiotic-metabolising enzyme (XME) genes, CYP1A1 and NQO1, were highly upregulated in all organoid types, with kidney organoids having the highest levels. Furthermore, the presence of two key metabolites, BaP-t-7,8-dihydrodiol and BaP-tetrol-l-1, was detected in all organoid types, confirming their ability to metabolise BaP. BaP bioactivation was confirmed both by the activation of the DNA damage response pathway (induction of p-p53, pCHK2, p21 and γ-H2AX) and by DNA adduct formation. Overall, pancreatic and undifferentiated liver organoids formed the highest levels of DNA adducts. Colon organoids had the lowest responses in DNA adduct and metabolite formation, as well as XME expression. Additionally, high-throughput RT-qPCR explored differences in gene expression between organoid types after BaP treatment. The results demonstrate the potential usefulness of organoids for studying environmental carcinogenesis and genetic toxicology.

Unloading knee braces represent a conservative treatment option for non-pharmalogical management of unicompartmental osteoarthritis of the knee. Though there is consensus on the clinical effectiveness of unloading, the effect mechanism of bracing remains part of a debate. Our study was designed to assess the effect of unloader bracing on damaged cartilage via MRI cartilage mappings.Fourteen patients (7 female, 7 male, mean age 43.1 ± 9.4 years) with unicompartmental cartilage wear in knees with varus or valgus malalignment were enrolled. Clinical scores, radiographs and MR-graphic properties (T2/T2* mapping, T1 Delayed Gadolinium Enhanced MRI of the cartilage (dGEMRIC) mapping, high-resolution PDw sequences) of knee cartilage were recorded before and three months after brace use.Bracing the knees for a mean of 14.4 ± 2.0 weeks (range 11 to 18 weeks) resulted in significant pain reduction (VAS changed from 5.9 ± 2.0 to 2.0 ± 1.3, p 0.001) and improvement in knee function (KOOS increased from 42.1 ± 22.7 to 64.8 ± 18.7, p 0.001). In the affected cartilage regions T2 relaxation times significantly decreased from 56.1 ± 11.4 ms to 46.5 ± 11.2 ms (p 0.05). No changes in T1-dGEMRIC and T2* relaxation times, thickness or the extent of the damaged cartilage area could be detected.Our results suggest, that unloader bracing improves the biochemical properties of the damaged cartilage by increasing collagen and proteoglycan concentration as well as decreasing the cartilage edema.