Deep learning-assisted radiomics facilitates multimodal prognostication for personalized treatment strategies in low-grade glioma.

Determining the optimal course of treatment for low grade glioma (LGG) patients is challenging and frequently reliant on subjective judgment and limited scientific evidence. Our objective was to develop a comprehensive deep learning assisted radiomics model for assessing not only overall survival in LGG, but also the likelihood of future malignancy and glioma growth velocity. Thus, we retrospectively included 349 LGG patients to develop a prediction model using clinical, anatomical, and preoperative MRI data. Before performing radiomics analysis, a U2-model for glioma segmentation was utilized to prevent bias, yielding a mean whole tumor Dice score of 0.837. Overall survival and time to malignancy were estimated using Cox proportional hazard models. In a postoperative model, we derived a C-index of 0.82 (CI 0.79-0.86) for the training cohort over 10 years and 0.74 (Cl 0.64-0.84) for the test cohort. Preoperative models showed a C-index of 0.77 (Cl 0.73-0.82) for training and 0.67 (Cl 0.57-0.80) test sets. Our findings suggest that we can reliably predict the survival of a heterogeneous population of glioma patients in both preoperative and postoperative scenarios. Further, we demonstrate the utility of radiomics in predicting biological tumor activity, such as the time to malignancy and the LGG growth rate.

Isolated effects of footwear structure and cushioning on running mechanics in habitual mid/forefoot runners.

The true differences between barefoot and shod running are difficult to directly compare because of the concomitant change to a mid/forefoot footfall pattern that typically occurs during barefoot running. The purpose of this study was to compare isolated effects of footwear structure and cushioning on running mechanics in habitual mid/forefoot runners running shod (SHOD), barefoot (BF), and barefoot on a foam surface (BF+FOAM). Ten habitually shod mid/forefoot runners were recruited (male = 8, female = 2). Repeated measures ANOVA (α = 0.05) revealed differences between conditions for only vertical peak active force, contact time, negative and total ankle joint work, and peak dorsiflexion angle. Post hoc tests revealed that BF+FOAM resulted in smaller vertical active peak magnitude and instantaneous vertical loading rate than SHOD. SHOD resulted in lower total ankle joint work than BF and BF+FOAM. BF+FOAM resulted in lower negative ankle joint work than either BF or SHOD. Contact time was shorter with BF than BF+FOAM or SHOD. Peak dorsiflexion angle was smaller in SHOD than BF. No other differences in sagittal joint kinematics, kinetics, or ground reaction forces were observed. These overall similarities in running mechanics between SHOD and BF+FOAM question the effects of footwear structure on habituated mid/forefoot running described previously.

Chronic gut inflammation impairs contextual control of fear.

Chronic inflammatory diseases are highly comorbid with anxiety in humans. The extent to which chronic inflammation is responsible for this relationship remains to be determined. We therefore tested the hypothesis that prolonged, but not brief, gut inflammation is sufficient to evoke anxiety-related behaviours in mice. We used the discriminative fear to context conditioning paradigm to assess fear generalization, which is a prominent feature of anxiety disorders. Gut inflammation was induced by exposure to dextran sodium sulfate (DSS) in the drinking water, a well-established rodent model of ulcerative colitis evoking prolonged inflammation. Neither acute (1 × 5 day cycle) nor chronic (3 × 5 day cycles) exposure to DSS affected fear responses when tested shortly after conditioning. Mice in all groups generated more fear responses (freezing) in a chamber previously paired with mild shock, as compared to a chamber with no pairing. This suggests DSS exposure had no effect on acquisition or expression of conditioned fear. Acute and control animals showed this same contextual control of freezing when tested 9 days later. In contrast, at this remote time point, the chronically treated animals exhibited increased freezing in the unpaired chamber such that freezing was equivalent in both contexts. These animals, however, showed intact preference for the unpaired chamber when allowed to freely move between chambers. These data suggest that some mnemonic process engaged after training, such as memory consolidation, is affected by past chronic inflammation so as to generalize negative associations and engage fearful responding in inappropriate contexts, despite intact knowledge that the chambers have different affective associations sufficient for place preference.

Tropical Peatland Hydrology Simulated With a Global Land Surface Model.

Tropical peatlands are among the most carbon-dense ecosystems on Earth, and their water storage dynamics strongly control these carbon stocks. The hydrological functioning of tropical peatlands differs from that of northern peatlands, which has not yet been accounted for in global land surface models (LSMs). Here, we integrated tropical peat-specific hydrology modules into a global LSM for the first time, by utilizing the peatland-specific model structure adaptation (PEATCLSM) of the NASA Catchment Land Surface Model (CLSM). We developed literature-based parameter sets for natural (PEATCLSMTrop,Nat) and drained (PEATCLSMTrop,Drain) tropical peatlands. Simulations with PEATCLSMTrop,Nat were compared against those with the default CLSM version and the northern version of PEATCLSM (PEATCLSMNorth,Nat) with tropical vegetation input. All simulations were forced with global meteorological reanalysis input data for the major tropical peatland regions in Central and South America, the Congo Basin, and Southeast Asia. The evaluation against a unique and extensive data set of in situ water level and eddy covariance-derived evapotranspiration showed an overall improvement in bias and correlation compared to the default CLSM version. Over Southeast Asia, an additional simulation with PEATCLSMTrop,Drain was run to address the large fraction of drained tropical peatlands in this region. PEATCLSMTrop,Drain outperformed CLSM, PEATCLSMNorth,Nat, and PEATCLSMTrop,Nat over drained sites. Despite the overall improvements of PEATCLSMTrop,Nat over CLSM, there are strong differences in performance between the three study regions. We attribute these performance differences to regional differences in accuracy of meteorological forcing data, and differences in peatland hydrologic response that are not yet captured by our model.

Neuroinflammatory remodeling of the anterior cingulate cortex as a key driver of mood disorders in gastrointestinal disease and disorders.

Most gastrointestinal diseases and disorders (GIDD) are associated with depression, anxiety, and cognitive dysfunction. This suggests that shared features of GIDD, particularly chronic pain and inflammation, affect specific neural targets. The critical review of clinical and animal research presented here reveals that anterior cingulate cortex (ACC) is a primary target. It is particularly sensitive to neuroinflammation, and its function accounts for altered mental function emergent in GIDD. We propose that peripherally-triggered neuroinflammation normally signals injury/illness to ACC, which increases threat assessment and pain sensitivity to cope with increased vulnerability. Chronic peripheral inflammation over-drives this process, leading to long-term ACC structural remodeling, and excessive threat signaling. This evokes anxiodepressive phenotypes even without direct evidence of threats because ACC utilizes schemas to infer affective outcomes (e.g. pain) based on complex contextual information. This activates the autonomic nervous system, exacerbates immune dysfunction, and promotes further gut pathology. This theory provides a mechanistic account of bidirectional interactions among gastrointestinal, immunological, and neural systems in GIDD, and is likely applicable to other chronic inflammatory conditions.

Chronic unpredictable stress shifts rat behavior from exploration to exploitation.

Chronic stress evokes wide-ranging behavioral alterations, including risk avoidance, increased motoric output, and reduced consummatory behaviors. These are often interpreted as dysfunctions, but they may subserve adaptations for coping with existential threats. We tested this in a cohort of rats previously exposed to mild unpredictable stress for 5 weeks. Previously stressed rats exhibited the typically increased avoidance of open field and altered responses to predator odor, suggesting enhanced sensitivity to threatening contexts and cues. Interestingly, these animals collected rewards at a higher rate than controls, because they locomoted faster, spent less time in off-task (exploratory) behavior, and committed fewer licks at feeders. Further, they were not impaired in flexibly shifting choice as reward probabilities changed among feeders, suggesting that behavioral adaptations are not simply of transference to behavioral control to neural systems insensitive to reward (e.g. habits). These data add to a small but growing body of evidence indicating that stress shifts responses away from exploration and toward exploitation of resources, possibly to reduce threat exposure.HighlightsRats with a history of stress collected reward at a higher rate than controls on an operant task, owing to increase locomotion speed, reduced off-task behavior, and reduced time licking at feeders.Previously stressed rats exhibited increased win-stay responses than controls, suggesting the involvement of neural circuits related to goal-directed responding.Previously stressed rats performed equally to controls on a task requiring a shift of preferences based on reward probability, suggesting that they are not simply relying more on habit-based neural systems.

Development of Coagulation Factor XII Antibodies for Inhibiting Vascular Device-Related Thrombosis.

INTRODUCTION: Vascular devices such as stents, hemodialyzers, and membrane oxygenators can activate blood coagulation and often require the use of systemic anticoagulants to selectively prevent intravascular thrombotic/embolic events or extracorporeal device failure. Coagulation factor (F)XII of the contact activation system has been shown to play an important role in initiating vascular device surface-initiated thrombus formation. As FXII is dispensable for hemostasis, targeting the contact activation system holds promise as a significantly safer strategy than traditional antithrombotics for preventing vascular device-associated thrombosis. OBJECTIVE: Generate and characterize anti-FXII monoclonal antibodies that inhibit FXII activation or activity. METHODS: Monoclonal antibodies against FXII were generated in FXII-deficient mice and evaluated for their binding and anticoagulant properties in purified and plasma systems, in whole blood flow-based assays, and in an in vivo non-human primate model of vascular device-initiated thrombus formation. RESULTS: A FXII antibody screen identified over 400 candidates, which were evaluated in binding studies and clotting assays. One non-inhibitor and six inhibitor antibodies were selected for characterization in functional assays. The most potent inhibitory antibody, 1B2, was found to prolong clotting times, inhibit fibrin generation on collagen under shear, and inhibit platelet deposition and fibrin formation in an extracorporeal membrane oxygenator deployed in a non-human primate. CONCLUSION: Selective contact activation inhibitors hold potential as useful tools for research applications as well as safe and effective inhibitors of vascular device-related thrombosis.

Image-guided lymph node core-needle biopsy predicts survival in mycosis fungoides and Sézary syndrome.

BACKGROUND: The prognosis of Sézary syndrome (SS) and mycosis fungoides (MF) depends on lymph node (LN) involvement. The usefulness of LN image-guided core-needle biopsies (CNBs), instead of surgical sampling, has been poorly evaluated. OBJECTIVES: To determine the prognostic value of LN CNB in MF/SS. METHODS: A retrospective search was conducted to identify all LN biopsy specimens of MF/SS between 2008 and 2019. Biopsies were staged according to the International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer (ISCL/EORTC) criteria. We performed immunolabelling and determined the tumour clone frequency (TCF) by high-throughput sequencing of the T-cell receptor beta locus. RESULTS: We included 119 consecutive biopsies from 100 patients, 45 with MF and 55 with SS. N1, N2 and N3 stages were diagnosed in 34 (29%), 26 (22%) and 59 (49%) cases, respectively. The TCF, Ki67 index, and percentage of cells positive for thymocyte selection-associated high mobility group box protein (TOX), programmed cell death protein 1 (PD1), killer cell immunoglobulin-like receptor 3DL2 (KIR3DL2) and cluster of differentiation (CD)30 were all positively correlated with the N stage. Median overall survival (OS) for N1/N2 vs. N3 patients was 42 months (range 26-not reached) vs. 14 months (range 5-30), respectively (P < 0·001). In univariate analyses, an age > 75 years, LN short-axis diameter > 15 mm, N3 stage, presence of large-cell transformation, TOX > 60%, PD1 > 25%, Ki67 > 30%, KIR3DL2 > 15%, CD30 > 10% and TCF > 25% were identified as adverse prognostic factors. In multivariate analyses, only an age > 75 years and Ki67 index > 30% were associated with reduced OS. We developed a new prognostic index associating the N stage and the Ki67 index, which better discriminates N3 patients with poor prognosis. CONCLUSIONS: CNB allows an objective assessment of the LN involvement in MF/SS, relevant for staging and prognosis.

The Family of Chloride Channel Regulator, Calcium-activated Proteins in the Feline Respiratory Tract: A Comparative Perspective on Airway Diseases in Man and Animal Models.

Members of the chloride channel regulator, calcium-activated (CLCA) family are considered to be modifiers in inflammatory, mucus-based respiratory conditions such as asthma and cystic fibrosis. Previous work has shown substantial differences between human and murine CLCA orthologues that limit the value of mouse models. As an alternative, the cat is an unfamiliar but powerful model of human asthma. We therefore characterized the expression profiles of CLCA proteins in the feline respiratory tract. Identical to other species, the feline CLCA1 protein was immunohistochemically localized to virtually all goblet cells and found to be secreted into the mucus. However, it was not detected in submucosal glands where it is expressed in other species. In contrast to all other species studied to date, feline CLCA2 was not found in submucosal glands or any other airway cells. Similar to mice, but in contrast to man and pigs, the feline respiratory tract was devoid of CLCA4 expression. In the airways of asthmatic cats, CLCA1 was strongly overexpressed, similar to human patients. Therefore, despite some similarities in CLCA1 protein expression and secretion, substantial differences were identified between several feline CLCA family members and their respective orthologues in man, mice and pigs, which must be considered in comparative medicine.

Tumour, but not Age-associated, Increase of Senescence Markers γH2AX and p21 in the Canine Eye.

Senescent cells display an irreversible cell cycle arrest with resistance to apoptosis. They are known to accumulate with age in mice, monkeys and man, and are suspected to drive the development and progression of neoplasia. Eyes develop age-associated changes, most commonly in the retina, cornea and lens. The aim of this study was to test whether senescent cells increase with age in the canine eye in general and in the microenvironment of ocular tumours in particular. The senescence markers γH2AX and p21 were tested in young (n = 10, age ≤2 years) versus old (n = 9, age range 9.5-12.4 years) canine eyes, as well as in the microenvironment of intraocular tumours, namely uveal melanocytomas (n = 13) and ciliary body adenomas (n = 9). To consider a potential association of senescence with biological behaviour, we compared the expression of both markers in tumour cells of benign uveal melanocytomas (n = 13) versus malignant conjunctival melanomas (n = 7). Canine eyes showed no age-dependent changes in senescent cells. However, a significant increase of the percentage of γH2AX- or p21-labelled cells was found in the retina, uvea and lens of tumour-bearing eyes. Tumour cells in conjunctival melanomas had a significantly increased percentage of p21-expressing cells compared with uveal melanocytomas. We conclude, that senescent cells do not accumulate with age in otherwise normal canine eyes and that a senescent microenvironment of intraocular tumours is unlikely to be age driven. In addition, as in man, the percentage of p21-positive cells was increased in melanomas, supporting the theory that malignant tumours may override the senescence-associated cell cycle arrest.

Soft X-ray microscopy for probing of topical tacrolimus delivery via micelles.

The penetration of topically applied tacrolimus formulated in micelles into murine skin is reported, measured by X-ray microscopy. Tacrolimus and micelles are probed for the first time by this high spatial resolution technique by element-selective excitation in the C 1s- and O 1s-regimes. This method allows selective detection of the distribution and penetration depth of drugs and carrier molecules into biologic tissues. It is observed that small, but distinct quantities of the drug and micelles, acting as a drug carrier, penetrate the stratum corneum. A comparison is made with the paraffin-based commercial tacrolimus ointment Protopic®, where local drug concentrations show to be low. A slight increase in local drug concentration in the stratum corneum is observed, if tacrolimus is formulated in micelles, as compared to Protopic®. This underscores the importance of the drug formulations for effective drug delivery. Time-resolved penetration shows presence of drug in the stratum corneum 100 min after formulation application, with penetration to deeper skin layers at 1000 min. High resolution micrographs give indications for a penetration pathway along the lipid membranes between corneocytes, but also suggest that the compound may penetrate corneocytes.

[Patients in the IDEAL cohort: A snapshot of severe asthma in France]. / Les patients de la cohorte IDEAL : une photographie de l'asthme sévère en France.

INTRODUCTION: This paper reports the French data from a post-hoc analysis of the international IDEAL study, which aimed to describe a recent cohort of patients with severe asthma, the impact of the disease on quality of life, as well as the population of patients eligible for treatment with omalizumab, mepolizumab and reslizumab. METHODS: Eligible patients were≥12 years of age, with severe asthma (GINA steps 4 and 5). RESULTS: A total of 129 patients were included in this post-hoc analysis. Their mean age was 53 years, the majority were overweight, they were mainly women (64%) and had at least one medical comorbidity (85%). More than half had suffered from asthma for more than 25 years and were non-smokers. Lung function was moderately impaired. Blood eosinophil count was≥150 cells/µL in 66% of patients,≥300 cells/µL in 34% of patients, and≥500 cells/µL in 12% of patients. One out of three patients was currently treated with omalizumab and 24% had maintenance oral corticosteroids. Asthma was poorly controlled with a negative impact on quality of life (ACQ≥1.5) in 67% of patients. In this population 40% of patients were eligible for omalizumab, 27% for mepolizumab and 2% for reslizumab. CONCLUSIONS: These findings show that a considerable proportion of patients with severe asthma remain uncontrolled and are not eligible for any of the available biological treatments. This underlines the need for therapeutic innovations in this disease.

Establishment of a Mucin Secreting Cell Line Cx-03 from an Uterine Carcino Sarcoma.

PURPOSE: The identification of novel cell lines which combine the most important properties of mucosal membranes in terms of drug absorption, transmembrane transport and mucus secretion can help to establish improved and meaningful test systems for pharmacological and infectiological studies. METHODS: We have established a novel mucus secreting tumor cell line (Cx-03) derived from a female patient who underwent radical hysterectomy after diagnosis of a large malignant carcino sarcoma (Muellerian mixed tumor). Via xenotransplantation in SCID beige mice, recultivation and subcloning a stable cell line was established from primary tumor cells. RESULTS: Human origin and novelty of the cell line was determined by karyotype analysis and STR fingerprint. During growth cells produce considerable amounts of a PAS positive viscoelastic mucus. Immunostaining revealed expression of mucins and the mucin modifier CLCA1. We demonstrate in initial electrophysiological experiments that confluent, polarized monolayers of Cx-03 are formed (on PCF-filter supports) that exhibit stable electrical resistance (> 600 Ω cm2). Confluent Cx-03 monolayers express barrier-forming tight junction proteins claudin-1 and -4 which co-localize with zonula occludens protein-1 (ZO-1) at cell-cell contacts. CONCLUSIONS: Mucus secretion is a rare property among mammalian cell lines. In combination with its ability to form polarized monolayers Cx-03 might contribute as a novel cell based model for drug absorption, transport and barrier studies.

Epidemiology of meningiomas.

Although they represent about a third of all the tumors of the central nervous system, knowledge concerning meningioma epidemiology (including incidence data and exploration of the risk factors) remains scarce compared to that of gliomas. A limited number of cancer registries worldwide only record malignant brain tumors, however their completeness and accuracy have been questioned. Even if comparisons are made difficult due to differences in methodologies, available annual incidence rates (sex- and age-standardized, generally on US or World standard population), provided by population-based registries range from 1.3/100,000 to 7.8/100,000 for cerebral meningiomas. An increase in the incidence of primary brain tumors in general and of meningiomas in particular has been observed during the past decades in several countries. It has been suggested that this trend could be artefactual and could be the resultant of an ageing population, improvement in health access and in diagnostic procedures, changes in coding classification for tumors recorded in registries, and/or an increase in the rate of histological confirmation, even in the elderly. All these factors are likely to play a role but they might not fully explain the increase in incidence, observed in most age groups. In addition to intrinsic risk factors (gender, ethnic groups, allergic conditions, familial and personal history, genetic polymorphisms), some exogenous risk factors have been suspected to play a role in the etiology of meningiomas and their changes with time is likely to impact incidence trends. A causal link has been established only for ionising radiation but the role of many other factors have been hypothesised: electromagnetic fields, nutrition, pesticides, hormonal as well as reproductive factors. Considering the serious or even lethal potentiality of some meningiomas and the apparent rise in their incidence, all practitioners involved in neuro-oncology should feel concerned today of the necessity to better assess their public health burden and to study their epidemiological features.

Concentrations of Cefuroxime in Brain Tissue of Neurointensive Care Patients.

Effective concentrations of antibiotics in brain tissue are essential for antimicrobial therapy of brain infections. However, data concerning cerebral penetration properties of antibiotics for treatment or prophylaxis of central nervous system infections are rare. Six patients suffering subarachnoid hemorrhage and requiring cerebral microdialysis for neurochemical monitoring were included in this study. Free interstitial concentrations of cefuroxime after intravenous application of 1,500 mg were measured by microdialysis in brain tissue, as well as in plasma at steady-state (n = 6) or after single-dose administration (n = 1). At steady state, free area under the concentration-time curve from 0 to 24 h (AUC0-24) values of 389.0 ± 210.3 mg/liter·h and 131.4 ± 72.8 mg/liter·h were achieved for plasma and brain, respectively, resulting in a brain tissue penetration ratio (AUC0-24 brain/AUC0-24 free plasma) of 0.33 ± 0.1. Plasma and brain tissue concentrations at individual time points correlated well (R = 0.59, P = 0.001). At steady-state time over MIC (t>MIC) values of >40% of dosing interval were achieved up to an MIC of 16 mg/liter for plasma and 4 mg/liter for brain tissue. Although MIC90 values could not be achieved in brain tissue for relevant bacteria, current dosing strategies of cefuroxime might be sufficient to treat pathogens with MIC values up to 4 mg/liter. The activity of cefuroxime in brain tissue might be overestimated when relying exclusively on plasma levels. Although currently insufficient data after single dose administration exist, lower brain-plasma ratios observed after the first dose might warrant a loading dose for treatment and perioperative prophylaxis.

Evaluation of clinical, laboratory, imaging findings and outcome in 99 dogs with leptospirosis.

OBJECTIVE: To report clinical, laboratory and diagnostic imaging features and prognostic factors in dogs with leptospirosis from North-East Germany. MATERIALS AND METHODS: Medical records of dogs diagnosed with leptospirosis from 2006 to 2013 were evaluated retrospectively. RESULTS: The study included 99 dogs. At initial presentation, the most common clinical signs were lethargy (96%), anorexia (88%), vomiting (85%), painful abdomen (39%), diarrhoea (38%), oliguria (27%) and tachypnoea (26%). Abnormal laboratory findings included anaemia (63%), thrombocytopenia (63%), leucocytosis (57%), increase of plasma urea (84%) and creatinine concentrations (81%), increased liver enzyme activities (80%), hyperbilirubinaemia (69%), hyperphosphataemia (67%), hyponatraemia (64%), hypoalbuminaemia (55%) and hypokalaemia (29%). Radiological pulmonary changes were detected in 57% of the dogs initially or during the course of disease. Severe dyspnoea, oliguria, azotaemia, hyperbilirubinaemia and severe radiological pulmonary changes were more often found in dogs that did not survive. There was renal, hepatic and pulmonary involvement in 95, 92 and 58% of the dogs, respectively, and multi-organ lesions in 98 dogs (98%); 32 dogs died or were euthanased. CONCLUSION: Several clinical and laboratory abnormalities were associated with a negative outcome; severe lung involvement was specifically associated with high mortality.

Reduced electrode arrays for the automated detection of rhythmic and periodic patterns in the intensive care unit: Frequently tried, frequently failed?

OBJECTIVE: To investigate the effect of systematic electrode reduction from a common 10-20 EEG system on pattern detection sensitivity (SEN). METHODS: Two reviewers rated 17130 one-minute segments of 83 prospectively recorded cEEGs according to the ACNS standardized critical care EEG terminology (CCET), including burst suppression patterns (BS) and unequivocal electrographic seizures. Consensus annotations between reviewers were used as a gold standard to determine pattern detection SEN and specificity (SPE) of a computational algorithm (baseline, 19 electrodes). Electrodes were than reduced one by one in four different variations. SENs and SPEs were calculated to determine the most beneficial assembly with respect to the number and location of electrodes. RESULTS: High automated baseline SENs (84.99-93.39%) and SPEs (90.05-95.6%) were achieved for all patterns. Best overall results in detecting BS and CCET patterns were found using the "hairline+vertex" montage. While the "forehead+behind ear" montage showed an advantage in detecting ictal patterns, reaching a 15% drop of SEN with 10 electrodes, all montages could detect BS sufficiently if at least nine electrodes were available. CONCLUSION: For the first time an automated approach was used to systematically evaluate the effect of electrode reduction on pattern detection SEN in cEEG. SIGNIFICANCE: Prediction of the expected detection SEN of specific EEG patterns with reduced EEG montages in ICU patients.