Attempted symmetry affects dynamic gait stability in individuals with lower-limb amputation.

BACKGROUND: Gait in people with lower limb amputation (LLA) is typically asymmetrical. Reducing this asymmetry is often attempted to minimise the impact of secondary health issues. However, temporal-spatial asymmetry in gait of people with LLA has also been shown to underpin dynamic stability. RESEARCH QUESTION: The current study aimed to identify the effects of acute attempts to achieve temporal-spatial symmetry on the dynamic stability of people with unilateral transtibial amputation (UTA). The secondary aim of this study was to identify the corresponding biomechanical adaptations during attempted symmetrical gait. METHODS: Eleven people with UTA walked along a 15 m walkway in four different conditions: normal (NORM), attempted symmetrical step length and step frequency (SYMSL+SF) attempted symmetrical step length (SYMSL) and attempted symmetrical step frequency (SYMSF). Dynamic stability was measured using the backward (BW) and medio-lateral (ML) margins of stability (MoS). RESULTS: Results indicate that attempting SYMSF had a positive effect on gait stability in BW and ML directions, while attempting SYMSL had a potentially negative effect, although these results did not appear to be significant. The absence of clustering in principal component analysis, supported the lack of significant results, indicating no features differentiating between conditions of attempted symmetry. Conversely, there was clustering by limbs which were associated with differences in knee and ankle joint angles between the prosthetic and non-prosthetic limbs, and clustering by individuals highlighting the importance of patient-specific analysis. CONCLUSION: The data suggests that attempted symmetrical gait reduces asymmetry but also affects dynamic stability.

The Reliability and Validity of a Portable Three-Dimensional Scanning System to Measure Leg Volume.

(1) Background: The study examined the reliability (test-retest, intra- and inter-day) and validity of a portable 3D scanning method when quantifying human leg volume. (2) Methods: Fifteen males volunteered to participate (age, 24.6 ± 2.0 years; stature, 178.9 ± 4.5 cm; body mass, 77.4 ± 6.5 kg; mean ± standard deviation). The volume of the lower and upper legs was examined using a water displacement method (the criterion) and two consecutive 3D scans. Measurements were taken at baseline, 1 h post-baseline (intra-day) and 24 h post-baseline (inter-day). Reliability and validity of the 3D scanning method was assessed using Bland-Altman limits of agreement and Pearson's product moment correlations. (3) Results: With respect to the test-retest reliability, the 3D scanning method had smaller systematic bias and narrower limits of agreement (±1%, and 3-5%, respectively) compared to the water displacement method (1-2% and 4-7%, respectively), when measuring lower and upper leg volume in humans. The correlation coefficients for all reliability comparisons (test-retest, intra-day, inter-day) would all be regarded as 'very strong' (all 0.94 or greater). (4) Conclusions: The study's results suggest that a 3D scanning method is a reliable and valid method to quantify leg volume.

Non-Syndromic Sensorineural Hearing Loss in Children.

Pediatric hearing loss is common with significant consequences in terms of language, communication, social and emotional development, and academic advancement. Radiological imaging provides useful information regarding hearing loss etiology, prognosis, therapeutic options, and potential surgical pitfalls. This review provides an overview of temporal bone imaging protocols, an outline of the classification of inner ear anomalies associated with sensorineural hearing loss and illustrates some of the more frequently encountered and/or important causes of non-syndromic hearing loss.

Syndromic Hearing Loss in Children.

Pattern recognition of specific temporal bone radiological phenotypes, in association with abnormalities in other organ systems, is critical in the diagnosis and management of syndromic causes of hearing loss. Several recent publications have demonstrated the presence of specific radiological appearances, allowing precise genetic and/or syndromic diagnosis, in the right clinical context. This review article aims to provide an extensive but practical guide to the radiologist dealing with syndromic causes of hearing loss.

Reliability of Near-Infrared Spectroscopy with and without Compression Tights during Exercise and Recovery Activities.

Near-infrared spectroscopy (NIRS) is widely used in sports science research, despite the limited reliability of available data. The aim of the present study was to assess the reliability of NIRS with and without compression tights. Thirteen healthy active males, (age 21.5 ± 2.7 years, body mass 82.1 ± 11.2 kg, BMI 24.6 ± 3.2 kg·m-2) completed four trials (two control trials and two trials using compression tights) over a 28-day period. During each trial, participants completed 20 min each of laying supine, sitting, walking (4 km·h-1), jogging, and sitting following the jogging. An NIRS device was attached to the muscle belly of the vastus lateralis and gastrocnemius and recorded tissue saturation index (TSI), muscle oxygenation, and muscle deoxygenation. Systematic bias and 95% limits of agreement (LOA) and coefficient of variation (CV) were used to report reliability measures for each activity type. For TSI, systematic bias (LOA) at the gastrocnemius during the control and tights trial ranged from -0.4 to 1.7% (4.4 to 10.3%) and -1.9 to 3.5% (8.1 to 12.0%), respectively. For the vastus lateralis, the systematic bias (LOA) for the control trial ranged from -2.4 to 1.0% (5.1 to 6.9%) and for the tights trial was -0.8 to 0.6% (7.0 to 9.5%). For TSI, the CV during the control trial ranged from 1.7 to 4.0% for the gastrocnemius and 1.9 to 2.6% for the vastus lateralis. During the tights trials, the CV ranged from 3.0 to 4.5% for the gastrocnemius and 2.6 to 3.5% for the vastus lateralis. The CV for muscle oxygenation during the control and tights trials for the gastrocnemius was 2.7 to 6.2% and 1.0 to 8.8% and for the vastus lateralis was 0.6 to 4.0% and 4.0 to 4.5%, respectively. The relative reliability was poorer in the tights trials, but if the aim was to detect a 5% difference in TSI, NIRS would be sufficiently reliable. However, the reliability of muscle oxygenation and deoxygenation varies considerably with activity type, and this should be considered when determining whether to employ NIRS in research studies.

The spectrum of cochlear malformations in CHARGE syndrome and insights into the role of the CHD7 gene during embryogenesis of the inner ear.

PURPOSE: We reviewed the genotypes and the imaging appearances of cochleae in CHARGE patients from two large tertiary centres and analysed the observed cochlear anomalies, providing detailed anatomical description and a grading system. The goal was to gain insight into the spectrum of cochlear anomalies in CHARGE syndrome, and thus, in the role of the CHD7 gene in otic vesicle development. METHODS: We retrospectively reviewed CT and/or MR imaging of CHARGE patients referred to our institutions between 2005 and 2022. Cochlear morphology was analysed and, when abnormal, divided into 3 groups in order of progressive severity. Other radiological findings in the temporal bone were also recorded. Comparison with the existing classification system of cochlear malformation was also attempted. RESULTS: Cochlear morphology in our CHARGE cohort ranged from normal to extreme hypoplasia. The most common phenotype was cochlear hypoplasia in which the basal turn was relatively preserved, and the upper turns were underdeveloped. All patients in the cohort had absent or markedly hypoplastic semicircular canals and small, misshapen vestibules. Aside from a stenotic cochlear aperture (fossette) being associated with a hypoplastic or absent cochlear nerve, there was no consistent relationship between cochlear nerve status (normal, hypoplasia, or aplasia) and cochlear morphology. CONCLUSION: Cochlear morphology in CHARGE syndrome is variable. Whenever the cochlea was abnormal, it was almost invariably hypoplastic. This may shed light on the role of CHD7 in cochlear development. Accurate morphological description of the cochlea contributes to proper clinical diagnosis and is important for planning surgical treatment options.

The epigenetic reader PHF21B modulates murine social memory and synaptic plasticity-related genes.

Synaptic dysfunction is a manifestation of several neurobehavioral and neurological disorders. A major therapeutic challenge lies in uncovering the upstream regulatory factors controlling synaptic processes. Plant homeodomain (PHD) finger proteins are epigenetic readers whose dysfunctions are implicated in neurological disorders. However, the molecular mechanisms linking PHD protein deficits to disease remain unclear. Here, we generated a PHD finger protein 21B-depleted (Phf21b-depleted) mutant CRISPR mouse model (hereafter called Phf21bΔ4/Δ4) to examine Phf21b's roles in the brain. Phf21bΔ4/Δ4 animals exhibited impaired social memory. In addition, reduced expression of synaptic proteins and impaired long-term potentiation were observed in the Phf21bΔ4/Δ4 hippocampi. Transcriptome profiling revealed differential expression of genes involved in synaptic plasticity processes. Furthermore, we characterized a potentially novel interaction of PHF21B with histone H3 trimethylated lysine 36 (H3K36me3), a histone modification associated with transcriptional activation, and the transcriptional factor CREB. These results establish PHF21B as an important upstream regulator of synaptic plasticity-related genes and a candidate therapeutic target for neurobehavioral dysfunction in mice, with potential applications in human neurological and psychiatric disorders.

Perceptions of In-home Monitoring Technology for Activities of Daily Living: Semistructured Interview Study With Community-Dwelling Older Adults.

BACKGROUND: Many older adults prefer to remain in their own homes for as long as possible. However, there are still questions surrounding how best to ensure that an individual can cope with autonomous living. Technological monitoring systems are an attractive solution; however, there is disagreement regarding activities of daily living (ADL) and the optimal technologies that should be used to monitor them. OBJECTIVE: This study aimed to understand older adults' perceptions of important ADL and the types of technologies they would be willing to use within their own homes. METHODS: Semistructured interviews were conducted on the web with 32 UK adults, divided equally into a younger group (aged 55-69 years) and an older group (≥70 years). RESULTS: Both groups agreed that ADL related to personal hygiene and feeding were the most important and highlighted the value of socializing. The older group considered several activities to be more important than their younger counterparts, including stair use and foot care. The older group had less existing knowledge of monitoring technology but was more willing to accept wearable sensors than the younger group. The younger group preferred sensors placed within the home but highlighted that they would not have them until they felt that daily life was becoming a struggle. CONCLUSIONS: Overall, technological monitoring systems were perceived as an acceptable method for monitoring ADL. However, developers and carers must be aware that individuals may express differences in their willingness to engage with certain types of technology depending on their age and circumstances.

Cardioprotection of Immature Heart by Simultaneous Activation of PKA and Epac: A Role for the Mitochondrial Permeability Transition Pore.

Metabolic and ionic changes during ischaemia predispose the heart to the damaging effects of reperfusion. Such changes and the resulting injury differ between immature and adult hearts. Therefore, cardioprotective strategies for adults must be tested in immature hearts. We have recently shown that the simultaneous activation of protein kinase A (PKA) and exchange protein activated by cAMP (Epac) confers marked cardioprotection in adult hearts. The aim of this study is to investigate the efficacy of this intervention in immature hearts and determine whether the mitochondrial permeability transition pore (MPTP) is involved. Isolated perfused Langendorff hearts from both adult and immature rats were exposed to global ischaemia and reperfusion injury (I/R) following control perfusion or perfusion after an equilibration period with activators of PKA and/or Epac. Functional outcome and reperfusion injury were measured and in parallel, mitochondria were isolated following 5 min of reperfusion to determine whether cardioprotective interventions involved changes in MPTP opening behaviour. Perfusion for 5 min preceding ischaemia of injury-matched adult and immature hearts with 5 µM 8-Br (8-Br-cAMP-AM), an activator of both PKA and Epac, led to significant reduction in post-reperfusion CK release and infarct size. Perfusion with this agent also led to a reduction in MPTP opening propensity in both adult and immature hearts. These data show that immature hearts are innately more resistant to I/R injury than adults, and that this is due to a reduced tendency of MPTP opening following reperfusion. Furthermore, simultaneous stimulation of PKA and Epac causes cardioprotection, which is additive to the innate resistance.

Bicyclic Heterocyclic Replacement of an Aryl Amide Leading to Potent and Kinase-Selective Adaptor Protein 2-Associated Kinase 1 Inhibitors.

Adaptor protein 2-associated kinase 1 (AAK1) is a serine/threonine kinase that was identified as a therapeutic target for the potential treatment of neuropathic pain. Inhibition of AAK1 in the central nervous system, particularly within the spinal cord, was found to be the relevant site for achieving an antinociceptive effect. We previously reported that compound 7 is a brain-penetrant, AAK1 inhibitor that showed efficacy in animal models for neuropathic pain. One approach we took to improve upon the potency of 7 involved tying the amide back into the neighboring phenyl ring to form a bicyclic heterocycle. Investigation of the structure-activity relationships (SARs) of substituents on the resultant quinazoline and quinoline ring systems led to the identification of (S)-31, a brain-penetrant, AAK1-selective inhibitor with improved enzyme and cellular potency compared to 7. The synthesis, SAR, and in vivo evaluation of a series of quinazoline and quinoline-based AAK1 inhibitors are described herein.

Filtration-Histogram Based Magnetic Resonance Texture Analysis (MRTA) for the Distinction of Primary Central Nervous System Lymphoma and Glioblastoma.

Primary central nervous system lymphoma (PCNSL) has variable imaging appearances, which overlap with those of glioblastoma (GBM), thereby necessitating invasive tissue diagnosis. We aimed to investigate whether a rapid filtration histogram analysis of clinical MRI data supports the distinction of PCNSL from GBM. Ninety tumours (PCNSL n = 48, GBM n = 42) were analysed using pre-treatment MRI sequences (T1-weighted contrast-enhanced (T1CE), T2-weighted (T2), and apparent diffusion coefficient maps (ADC)). The segmentations were completed with proprietary texture analysis software (TexRAD version 3.3). Filtered (five filter sizes SSF = 2-6 mm) and unfiltered (SSF = 0) histogram parameters were compared using Mann-Whitney U non-parametric testing, with receiver operating characteristic (ROC) derived area under the curve (AUC) analysis for significant results. Across all (n = 90) tumours, the optimal algorithm performance was achieved using an unfiltered ADC mean and the mean of positive pixels (MPP), with a sensitivity of 83.8%, specificity of 8.9%, and AUC of 0.88. For subgroup analysis with >1/3 necrosis masses, ADC permitted the identification of PCNSL with a sensitivity of 96.9% and specificity of 100%. For T1CE-derived regions, the distinction was less accurate, with a sensitivity of 71.4%, specificity of 77.1%, and AUC of 0.779. A role may exist for cross-sectional texture analysis without complex machine learning models to differentiate PCNSL from GBM. ADC appears the most suitable sequence, especially for necrotic lesion distinction.

Inhibition of Cardiac RIP3 Mitigates Early Reperfusion Injury and Calcium-Induced Mitochondrial Swelling without Altering Necroptotic Signalling.

Receptor-interacting protein kinase 3 (RIP3) is a convergence point of multiple signalling pathways, including necroptosis, inflammation and oxidative stress; however, it is completely unknown whether it underlies acute myocardial ischemia/reperfusion (I/R) injury. Langendorff-perfused rat hearts subjected to 30 min ischemia followed by 10 min reperfusion exhibited compromised cardiac function which was not abrogated by pharmacological intervention of RIP3 inhibition. An immunoblotting analysis revealed that the detrimental effects of I/R were unlikely mediated by necroptotic cell death, since neither the canonical RIP3-MLKL pathway (mixed lineage kinase-like pseudokinase) nor the proposed non-canonical molecular axes involving CaMKIIδ-mPTP (calcium/calmodulin-dependent protein kinase IIδ-mitochondrial permeability transition pore), PGAM5-Drp1 (phosphoglycerate mutase 5-dynamin-related protein 1) and JNK-BNIP3 (c-Jun N-terminal kinase-BCL2-interacting protein 3) were activated. Similarly, we found no evidence of the involvement of NLRP3 inflammasome signalling (NOD-, LRR- and pyrin domain-containing protein 3) in such injury. RIP3 inhibition prevented the plasma membrane rupture and delayed mPTP opening which was associated with the modulation of xanthin oxidase (XO) and manganese superoxide dismutase (MnSOD). Taken together, this is the first study indicating that RIP3 regulates early reperfusion injury via oxidative stress- and mitochondrial activity-related effects, rather than cell loss due to necroptosis.

Discovery, Structure-Activity Relationships, and In Vivo Evaluation of Novel Aryl Amides as Brain Penetrant Adaptor Protein 2-Associated Kinase 1 (AAK1) Inhibitors for the Treatment of Neuropathic Pain.

Effective treatment of chronic pain, in particular neuropathic pain, without the side effects that often accompany currently available treatment options is an area of significant unmet medical need. A phenotypic screen of mouse gene knockouts led to the discovery that adaptor protein 2-associated kinase 1 (AAK1) is a potential therapeutic target for neuropathic pain. The synthesis and optimization of structure-activity relationships of a series of aryl amide-based AAK1 inhibitors led to the identification of 59, a brain penetrant, AAK1-selective inhibitor that proved to be a valuable tool compound. Compound 59 was evaluated in mice for the inhibition of µ2 phosphorylation. Studies conducted with 59 in pain models demonstrated that this compound was efficacious in the phase II formalin model for persistent pain and the chronic-constriction-injury-induced model for neuropathic pain in rats. These results suggest that AAK1 inhibition is a promising approach for the treatment of neuropathic pain.

The BMP antagonist gremlin 1 contributes to the development of cortical excitatory neurons, motor balance and fear responses.

Bone morphogenetic protein (BMP) signaling is required for early forebrain development and cortical formation. How the endogenous modulators of BMP signaling regulate the structural and functional maturation of the developing brain remains unclear. Here, we show that expression of the BMP antagonist Grem1 marks committed layer V and VI glutamatergic neurons in the embryonic mouse brain. Lineage tracing of Grem1-expressing cells in the embryonic brain was examined by administration of tamoxifen to pregnant Grem1creERT; Rosa26LSLTdtomato mice at 13.5 days post coitum (dpc), followed by collection of embryos later in gestation. In addition, at 14.5 dpc, bulk mRNA-seq analysis of differentially expressed transcripts between FACS-sorted Grem1-positive and -negative cells was performed. We also generated Emx1-cre-mediated Grem1 conditional knockout mice (Emx1-Cre;Grem1flox/flox) in which the Grem1 gene was deleted specifically in the dorsal telencephalon. Grem1Emx1cKO animals had reduced cortical thickness, especially layers V and VI, and impaired motor balance and fear sensitivity compared with littermate controls. This study has revealed new roles for Grem1 in the structural and functional maturation of the developing cortex.

The Calculation, Thresholds and Reporting of Inter-Limb Strength Asymmetry: A Systematic Review.

The prevalence of inter-limb strength differences is well documented in the literature however, there are inconsistencies related to measurement and reporting, and the normative values and effects associated with inter-limb asymmetry. Therefore, the aims of this systematic review were to: 1) assess the appropriateness of existing indices for the calculation of asymmetry, 2) interrogate the evidence basis for literature reported thresholds used to define asymmetry and 3) summarise normative levels of inter-limb strength asymmetry and their effects on injury and performance. To conduct this systematic review, scientific databases (PubMed, Scopus, SPORTDiscus and Web of Science) were searched and a total of 3,594 articles were retrieved and assessed for eligibility and article quality. The robustness of each identified asymmetry index was assessed, and the evidence-basis of the identified asymmetry thresholds was appraised retrospectively using the references provided. Fifty-three articles were included in this review. Only four of the twelve identified indices were unaffected by the limitations associated with selecting a reference limb. Eighteen articles applied a threshold to original research to identify "abnormal" asymmetry, fifteen of which utilised a threshold between 10-15%, yet this threshold was not always supported by appropriate evidence. Asymmetry scores ranged between and within populations from approximate symmetry to asymmetries larger than 15%. When reporting the effects of strength asymmetries, increased injury risk and detriments to performance were often associated with larger asymmetry, however the evidence was inconsistent. Limitations of asymmetry indices should be recognised, particularly those that require selection of a reference limb. Failure to reference the origin of the evidence for an asymmetry threshold reinforces doubt over the use of arbitrary thresholds, such as 10-15%. Therefore, an individual approach to defining asymmetry may be necessary to refine robust calculation methods and to establish appropriate thresholds across various samples and methodologies that enable appropriate conclusions to be drawn.

Technology Used to Recognize Activities of Daily Living in Community-Dwelling Older Adults.

The use of technology has been suggested as a means of allowing continued autonomous living for older adults, while reducing the burden on caregivers and aiding decision-making relating to healthcare. However, more clarity is needed relating to the Activities of Daily Living (ADL) recognised, and the types of technology included within current monitoring approaches. This review aims to identify these differences and highlight the current gaps in these systems. A scoping review was conducted in accordance with PRISMA-ScR, drawing on PubMed, Scopus, and Google Scholar. Articles and commercially available systems were selected if they focused on ADL recognition of older adults within their home environment. Thirty-nine ADL recognition systems were identified, nine of which were commercially available. One system incorporated environmental and wearable technology, two used only wearable technology, and 34 used only environmental technologies. Overall, 14 ADL were identified but there was variation in the specific ADL recognised by each system. Although the use of technology to monitor ADL of older adults is becoming more prevalent, there is a large variation in the ADL recognised, how ADL are defined, and the types of technology used within monitoring systems. Key stakeholders, such as older adults and healthcare workers, should be consulted in future work to ensure that future developments are functional and useable.

Diagnostic accuracy of dynamic contrast-enhanced perfusion MRI in stratifying gliomas: A systematic review and meta-analysis.

BACKGROUND: T1-weighted dynamic contrast-enhanced (DCE) perfusion magnetic resonance imaging (MRI) has been broadly utilized in the evaluation of brain tumors. We aimed at assessing the diagnostic accuracy of DCE-MRI in discriminating between low-grade gliomas (LGGs) and high-grade gliomas (HGGs), between tumor recurrence and treatment-related changes, and between primary central nervous system lymphomas (PCNSLs) and HGGs. METHODS: We performed this study based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis of Diagnostic Test Accuracy Studies criteria. We systematically surveyed studies evaluating the diagnostic accuracy of DCE-MRI for the aforementioned entities. Meta-analysis was conducted with the use of a random effects model. RESULTS: Twenty-seven studies were included after screening of 2945 possible entries. We categorized the eligible studies into three groups: those utilizing DCE-MRI to differentiate between HGGs and LGGs (14 studies, 546 patients), between recurrence and treatment-related changes (9 studies, 298 patients) and between PCNSLs and HGGs (5 studies, 224 patients). The pooled sensitivity, specificity, and area under the curve for differentiating HGGs from LGGs were 0.93, 0.90, and 0.96, for differentiating tumor relapse from treatment-related changes were 0.88, 0.86, and 0.89, and for differentiating PCNSLs from HGGs were 0.78, 0.81, and 0.86, respectively. CONCLUSIONS: Dynamic contrast-enhanced-Magnetic resonance imaging is a promising noninvasive imaging method that has moderate or high accuracy in stratifying gliomas. DCE-MRI shows high diagnostic accuracy in discriminating between HGGs and their low-grade counterparts, and moderate diagnostic accuracy in discriminating recurrent lesions and treatment-related changes as well as PCNSLs and HGGs.

Chronic stress induces hypersensitivity of murine gastric vagal afferents.

BACKGROUND: Stress exposure is known to trigger and exacerbate functional dyspepsia (FD) symptoms. Increased gastric sensitivity to food-related stimuli is widely observed in FD patients and is associated with stress and psychological disorders. The mechanisms underlying the hypersensitivity are not clear. Gastric vagal afferents (GVAs) play an important role in sensing meal-related mechanical stimulation to modulate gastrointestinal function and food intake. This study aimed to determine whether GVAs display hypersensitivity after chronic stress, and whether its interaction with leptin was altered by stress. METHODS: Eight-week-old male C57BL/6 mice were exposed to unpredictable chronic mild stress or no stress (control) for 8 weeks. The metabolic rate, gastric emptying rate, and anxiety- and depression-like behaviors were determined. GVA mechanosensitivity, and its modulation by leptin, was determined using an in vitro single fiber recording technique. QRT-PCR was used to establish the levels of leptin and leptin receptor mRNA in the stomach and nodose ganglion, respectively. KEY RESULTS: The stressed mice had lower body weight and food intake, and increased anxiety-like behavior compared to the control mice. The mechanosensitivity of mucosal and tension-sensitive GVAs was higher in the stressed mice. Leptin potentiated mucosal GVA mechanosensitivity in control but not stressed mice. The expression of leptin mRNA in the gastric mucosa was lower in the stressed mice. CONCLUSIONS AND INFERENCES: In conclusion, chronic stress enhances GVA mechanosensitivity, which may contribute to the gastric hypersensitivity in FD. In addition, the modulatory effect of leptin on GVA signaling is lost after chronic stress exposure.

Filtration-histogram based magnetic resonance texture analysis (MRTA) for glioma IDH and 1p19q genotyping.

BACKGROUND: To determine if filtration-histogram based texture analysis (MRTA) of clinical MR imaging can non-invasively identify molecular subtypes of untreated gliomas. METHODS: Post Gadolinium T1-weighted (T1+Gad) images, T2-weighted (T2) images and apparent diffusion coefficient (ADC) maps of 97 gliomas (54 = WHO II, 20 = WHO III, 23 = WHO IV) between 2010 and 2016 were studied. Whole-tumor segmentations were performed on a proprietary texture analysis research platform (TexRAD, Cambridge, UK) using the software's freehand drawing tool. MRTA commences with a filtration step, followed by quantification of texture using histogram texture parameters. Results were correlated using non-parametric statistics with a logistic regression model generated. RESULTS: T1+Gad performed best for IDH typing of glioblastoma (sensitivity 91.9%, specificity 100%, AUC 0.945) and ADC for non-Gadolinium-enhancing gliomas (sensitivity 85.7%, specificity 78.4%, AUC 0.877). T2 was moderately precise (sensitivity 83.1%, specificity 78.9%, AUC 0.821). Excellent results for IDH typing were achieved from a combination of the three sequences (sensitivity 90.5%, specificity 94.5%, AUC = 0.98). For discriminating 1p19q genotypes, ADC produced the best results using unfiltered textures (sensitivity 80.6%, specificity 89.3%, AUC 0.811). CONCLUSION: Preoperative glioma genotyping with MRTA appears valuable with potential for clinical translation. The optimal choice of texture parameters is influenced by sequence choice, tumour morphology and segmentation method.

Mice lacking Casp1, Ifngr and Nos2 genes exhibit altered depressive- and anxiety-like behaviour, and gut microbiome composition.

Converging evidence supports the involvement of pro-inflammatory pathways and the gut microbiome in major depressive disorder (MDD). Pre-clinical and clinical studies suggest that decreasing pro-inflammatory signaling may provide clinical benefit in MDD. In this study, we used the chronic unpredictable stress (CUS) paradigm to assess whether mice lacking the pro-inflammatory caspase 1, interferon gamma-receptor, and nitric oxide synthase (Casp1, Ifngr, Nos2)-/- present altered depressive- and anxiety-like behaviour at baseline and in response to CUS. In comparison to wild-type (wt) mice, (Casp1, Ifngr, Nos2)-/- mice displayed decreased depressive- and anxiety-like behaviour, and increased hedonic-like behaviour and locomotor activity at baseline, and resistance to developing anhedonic-like behaviour and a heightened emotional state following stress. Plasma levels of ACTH and CORT did not differ between the triple knockout and wt mice following stress. The faecal microbiome of (Casp1, Ifngr, Nos2)-/- mice differed from that of wt mice at baseline and displayed reduced changes in response to chronic stress. Our results demonstrate that simultaneous deficit in multiple pro-inflammatory pathways has antidepressant-like effects at baseline, and confers resilience to stress-induced anhedonic-like behaviour. Moreover, accompanying changes in the gut microbiome composition suggest that CASP1, IFNGR and NOS2 play a role in maintaining microbiome homeostasis.