B cell homeostasis and follicle confines are governed by fibroblastic reticular cells.

Fibroblastic reticular cells (FRCs) are known to inhabit T cell-rich areas of lymphoid organs, where they function to facilitate interactions between T cells and dendritic cells. However, in vivo manipulation of FRCs has been limited by a dearth of genetic tools that target this lineage. Here, using a mouse model to conditionally ablate FRCs, we demonstrated their indispensable role in antiviral T cell responses. Unexpectedly, loss of FRCs also attenuated humoral immunity due to impaired B cell viability and follicular organization. Follicle-resident FRCs established a favorable niche for B lymphocytes via production of the cytokine BAFF. Thus, our study indicates that adaptive immunity requires an intact FRC network and identifies a subset of FRCs that control B cell homeostasis and follicle identity.

Different methods of 3D QRS area calculation from vectorcardiographic X, Y, and Z Leads.

3DQRSarea is a strong marker for cardiac resynchronization therapy and can be obtained by taking the (i) summation or the (ii) difference of the areas subtended by positive and negative deflections in X, Y, Z vectorcardiographic electrocardiogram (ECG) leads. We correlated both methods with the instantaneous-absolute-3D-voltage-time-integral (VTIQRS-3D). 3DQRSarea consistently underestimated the VTIQRS -3D, but the summation method was a closer and more reliable approximation. The dissimilarity was less apparent in left bundle branch block (r2 summation .996 vs. difference .972) and biventricular paced ECGs (r2 .996 vs. .957) but was more apparent in normal ECGs (r2 .988 vs. .653).

Electrocardiographic Z-axis QRS-T voltage-time-integral in patients with typical right bundle branch block - Correlation with echocardiographic right ventricular size and function.

BACKGROUND: Right bundle branch block (RBBB) can be benign or associated with right ventricular (RV) functional and structural abnormalities. Our aim was to evaluate QRS-T voltage-time-integral (VTI) compared to QRS duration and lead V1 R' as markers for RV abnormalities. METHODS: We included adults with an ECG demonstrating RBBB and echocardiogram obtained within 3 months of each other, between 2010 and 2020. VTIQRS and VTIQRST were obtained for 12 standard ECG leads, reconstructed vectorcardiographic X, Y, Z leads and root-mean-squared (3D) ECG. Age, sex and BSA-adjusted linear regressions were used to assess associations of QRS duration, amplitudes, VTIs and lead V1 R' duration/VTI with echocardiographic tricuspid annular plane systolic excursion (TAPSE), RV tissue Doppler imaging S', basal and mid diameter, and systolic pressure (RVSP). RESULTS: Among 782 patients (33% women, age 71 ± 14 years) with RBBB, R' duration in lead V1 was modestly associated with RV S', RV diameters and RVSP (all p ≤ 0.03). QRS duration was more strongly associated with RV diameters (both p < 0.0001). AmplitudeQRS-Z was modestly correlated with all 5 RV echocardiographic variables (all p ≤ 0.02). VTIR'-V1 was more strongly associated with TAPSE, RV S' and RVSP (all p ≤ 0.0003). VTIQRS-Z and VTIQRST-Z were among the strongest correlates of the 5 RV variables (all p < 0.0001). VTIQRST-Z.√BSA cutoff of ≥62 µVsm had sensitivity 62.7% and specificity 65.7% for predicting ≥3 of 5 abnormal RV variables (AUC 0.66; men 0.71, women 0.60). CONCLUSION: In patients with RBBB, VTIQRST-Z is a stronger predictor of RV dysfunction and adverse remodeling than QRS duration and lead V1 R'.

Evaluation of electrocardiographic criteria for predicting left ventricular hypertrophy and dilation in presence of left bundle branch block.

BACKGROUND: The utility of standard published electrocardiographic (ECG) criteria for left ventricular hypertrophy (LVH) in patients with left bundle branch block (LBBB) is not established. We have previously shown that in ECGs demonstrating LBBB, QRS duration outperforms vectorcardiographic X, Y, Z lead and root-mean-squared (3D) amplitudes and voltage-time-integrals in diagnosing LVH and dilation. We sought to evaluate diagnostic yields of published LVH criteria versus QRS duration for ECG based diagnosis of LVH and dilation in presence of LBBB. METHODS: We included adult patients with typical LBBB having ECG and transthoracic echocardiogram performed within 3 months of each other in 2010-2020. We obtained area under receiver-operator characteristic curve (AUC) for QRS duration and each of the published ECG LVH criteria to predict increased LV mass indexed (↑LVMi, women >95 g/m2, men >115 g/m2) and LV end diastolic volume indexed (↑LVEDVi, women >61 mL/m2, men >74 mL/m2). RESULTS: Among 413 adults (53 % women, age 73 ± 12 yr) with LBBB, the traditional LVH criteria performed poorly to detect ↑LVMi or ↑LVEDVi. Cornell voltage-duration product had the highest AUCs (↑LVMi 0.634, ↑LVEDVi 0.580). QRS duration had a higher AUC for diagnosing ↑LVMi (women 0.657, men 0.703) and ↑LVEDVi (women 0.668, men 0.699) compared to any other criteria. CONCLUSIONS: In patients with LBBB, prolonged QRS duration (women ≥150 ms, men ≥160 ms) is a superior predictor of LVH and dilation than traditional ECG-based LVH criteria.

Electrocardiographic prediction of left ventricular hypertrophy in women and men with left bundle branch block - Comparison of QRS duration, amplitude and voltage-time-integral.

BACKGROUND: Standard ECG criteria for left ventricular (LV) hypertrophy rely on QRS amplitudes. However, in the setting of left bundle branch block (LBBB), ECG correlates of LV hypertrophy are not well established. We sought to evaluate quantitative ECG predictors of LV hypertrophy in the presence of LBBB. METHODS: We included adult patients with typical LBBB having ECG and transthoracic echocardiogram performed within 3 months of each other in 2010-2020. Orthogonal X, Y, Z leads were reconstructed from digital 12­lead ECGs using Kors's matrix. In addition to QRS duration, we evaluated QRS amplitudes and voltage-time-integrals (VTIs) from all 12 leads, X, Y, Z leads and 3D (root-mean-squared) ECG. We used age, sex and BSA-adjusted linear regressions to predict echocardiographic LV calculations (mass, end-diastolic and end-systolic volumes, ejection fraction) from ECG, and separately generated ROC curves for predicting echocardiographic abnormalities. RESULTS: We included 413 patients (53% women, age 73 ± 12 years). All 4 echocardiographic LV calculations were most strongly correlated with QRS duration (all p < 0.00001). In women, QRS duration ≥ 150 ms had sensitivity/specificity 56.3%/64.4% for increased LV mass and 62.7%/67.8% for increased LV end-diastolic volume. In men, QRS duration ≥ 160 ms had a sensitivity/specificity 63.1%/72.1% for increased LV mass and 58.3%/74.5% for increased LV end-diastolic volume. QRS duration was best able to discriminate eccentric hypertrophy (area under ROC curve 0.701) and increased LV end-diastolic volume (0.681). CONCLUSIONS: In patients with LBBB, QRS duration (≥ 150 in women and ≥ 160 in men) is a superior predictor of LV remodeling esp. eccentric hypertrophy and dilation.

EFSUMB 2020 Proposal for a Contrast-Enhanced Ultrasound-Adapted Bosniak Cyst Categorization - Position Statement.

The well-established Bosniak renal cyst classification is based on contrast-enhanced computed tomography determining the malignant potential of cystic renal lesions. Ultrasound has not been incorporated into this pathway. However, the development of ultrasound contrast agents coupled with the superior resolution of ultrasound makes it possible to redefine the imaging of cystic renal lesions. In this position statement, an EFSUMB Expert Task Force reviews, analyzes, and describes the accumulated knowledge and limitations and presents the current position on the use of ultrasound contrast agents in the evaluation of cystic renal lesions.

Plexin D1 determines body fat distribution by regulating the type V collagen microenvironment in visceral adipose tissue.

Genome-wide association studies have implicated PLEXIN D1 (PLXND1) in body fat distribution and type 2 diabetes. However, a role for PLXND1 in regional adiposity and insulin resistance is unknown. Here we use in vivo imaging and genetic analysis in zebrafish to show that Plxnd1 regulates body fat distribution and insulin sensitivity. Plxnd1 deficiency in zebrafish induced hyperplastic morphology in visceral adipose tissue (VAT) and reduced lipid storage. In contrast, subcutaneous adipose tissue (SAT) growth and morphology were unaffected, resulting in altered body fat distribution and a reduced VAT:SAT ratio in zebrafish. A VAT-specific role for Plxnd1 appeared conserved in humans, as PLXND1 mRNA was positively associated with hypertrophic morphology in VAT, but not SAT. In zebrafish plxnd1 mutants, the effect on VAT morphology and body fat distribution was dependent on induction of the extracellular matrix protein collagen type V alpha 1 (col5a1). Furthermore, after high-fat feeding, zebrafish plxnd1 mutant VAT was resistant to expansion, and excess lipid was disproportionately deposited in SAT, leading to an even greater exacerbation of altered body fat distribution. Plxnd1-deficient zebrafish were protected from high-fat-diet-induced insulin resistance, and human VAT PLXND1 mRNA was positively associated with type 2 diabetes, suggesting a conserved role for PLXND1 in insulin sensitivity. Together, our findings identify Plxnd1 as a novel regulator of VAT growth, body fat distribution, and insulin sensitivity in both zebrafish and humans.

Machine learning to classify left ventricular hypertrophy using ECG feature extraction by variational autoencoder.

Background: Traditional ECG criteria for left ventricular hypertrophy (LVH) have low diagnostic yield. Machine learning (ML) can improve ECG classification. Methods: ECG summary features (rate, intervals, axis), R-wave, S-wave and overall-QRS amplitudes, and QRS/QRST voltage-time integrals (VTIs) were extracted from 12-lead, vectorcardiographic X-Y-Z-lead, and root-mean-square (3D) representative-beat ECGs. Latent features were extracted by variational autoencoder from X-Y-Z and 3D representative-beat ECGs. Logistic regression, random forest, light gradient boosted machine (LGBM), residual network (ResNet) and multilayer perceptron network (MLP) models using ECG features and sex, and a convolutional neural network (CNN) using ECG signals, were trained to predict LVH (left ventricular mass indexed in women >95 g/m², men >115 g/m²) on 225,333 adult ECG-echocardiogram (within 45 days) pairs. AUROCs for LVH classification were obtained in a separate test set for individual ECG variables, traditional criteria and ML models. Results: In the test set (n=25,263), AUROC for LVH classification was higher for ML models using ECG features (LGBM 0.790, MLP 0.789, ResNet 0.788) as compared to the best individual variable (VTIQRS-3D 0.677), the best traditional criterion (Cornell voltage-duration product 0.647) and CNN using ECG signal (0.767). Among patients without LVH who had a follow-up echocardiogram >1 (closest to 5) years later, LGBM false positives, compared to true negatives, had a 2.63 (95% CI 2.01, 3.45)-fold higher risk for developing LVH (p<0.0001). Conclusions: ML models are superior to traditional ECG criteria to classify-and predict future-LVH. Models trained on extracted ECG features, including variational autoencoder latent variables, outperformed CNN directly trained on ECG signal.

Predictors of left atrial appendage emptying velocity: Derivation and validation of CHIRP3(M-1) score.

BACKGROUND: Atrial fibrillation (AF) leads to impaired left atrial appendage contractility, increasing the risk of thromboembolic stroke. The left atrial appendage emptying velocity (LAAev) measured on transesophageal echocardiogram (TEE) is a marker of increased thromboembolic risk. OBJECTIVES: The purpose of this study was to evaluate predictors of reduced LAAev for identifying individuals at increased risk for cardiogenic stroke. METHODS: This was a single-center retrospective review of TEEs and clinical charts. Predictors of LAAev <30 cm/s were identified using logistic regression. A risk prediction model was created using stepwise selection in a derivation set (n = 695) and separately tested in a validated set (n = 300). RESULTS: We included TEEs on 995 patients (age 71.3±12.7 years; female 38.1%; history of AF 82.1%; in AF at evaluation 27.7%; CHA2DS2-VASc score 4.1 ± 1.9; LAAev 41.6 ± 21.0 cm/s). Significant multivariable predictors of LAAev <30 cm/s in derivation set were used to create the CHIRP3M-1 score containing 8 variables: Coronary artery disease (1), congestive Heart failure (1), Increased left atrial volume index ≥42 mL/m2 (1), current Rhythm AF (1), Paroxysmal AF (2), Persistent AF (3), longstanding Persistent/permanent AF (4), and greater than moderate Mitral regurgitation (-1). In the validation set, as compared to intermediate scores (3-4), those with low scores (≤2) and high scores (≥5) had odds ratios for LAAev <30 cm/s of 0.41 (0.21, 0.78, P = .007) and 2.58 (95% confidence interval 1.45-4.61, P = .001), respectively. CONCLUSION: We developed and validated a novel risk stratification system to predict reduced LAAev using clinical and echocardiographic variables. This may help refine the stratification of cardiogenic stroke risk.

Bivalent intra-spike binding provides durability against emergent Omicron lineages: Results from a global consortium.

The SARS-CoV-2 Omicron variant of concern (VoC) and its sublineages contain 31-36 mutations in spike and escape neutralization by most therapeutic antibodies. In a pseudovirus neutralization assay, 66 of the nearly 400 candidate therapeutics in the Coronavirus Immunotherapeutic Consortium (CoVIC) panel neutralize Omicron and multiple Omicron sublineages. Among natural immunoglobulin Gs (IgGs), especially those in the receptor-binding domain (RBD)-2 epitope community, nearly all Omicron neutralizers recognize spike bivalently, with both antigen-binding fragments (Fabs) simultaneously engaging adjacent RBDs on the same spike. Most IgGs that do not neutralize Omicron bind either entirely monovalently or have some (22%-50%) monovalent occupancy. Cleavage of bivalent-binding IgGs to Fabs abolishes neutralization and binding affinity, with disproportionate loss of activity against Omicron pseudovirus and spike. These results suggest that VoC-resistant antibodies overcome mutagenic substitution via avidity. Hence, vaccine strategies targeting future SARS-CoV-2 variants should consider epitope display with spacing and organization identical to trimeric spike.

ICOS is upregulated on T cells following radiation and agonism combined with radiation results in enhanced tumor control.

Multiple preclinical studies have shown improved outcomes when radiation therapy is combined with immune modulating antibodies. However, to date, many of these promising results have failed to translate to successful clinical studies. This led us to explore additional checkpoint and co-stimulatory pathways that may be regulated by radiation therapy. Here, we demonstrate that radiation increases the expression of inducible T cell co-stimulator (ICOS) on both CD4 and CD8 T cells in the blood following treatment. Moreover, when we combined a novel ICOS agonist antibody with radiation we observed durable cures across multiple tumor models and mouse strains. Depletion studies revealed that CD8 T cells were ultimately required for treatment efficacy, but CD4 T cells and NK cells also partially contributed to tumor control. Phenotypic analysis showed that the combination therapy diminished the increased infiltration of regulatory T cells into the tumor that typically occurs following radiation alone. Finally, we demonstrate in a poorly immunogenic pancreatic tumor model which is resistant to combined radiation and anti-PD1 checkpoint blockade that the addition of this novel ICOS agonist antibody to the treatment regimen results in tumor control. These findings identify ICOS as part of a T cell pathway that is modulated by radiation and targeting this pathway with a novel ICOS antibody results in durable tumor control in preclinical models.

First-in-Human Phase I/II ICONIC Trial of the ICOS Agonist Vopratelimab Alone and with Nivolumab: ICOS-High CD4 T-Cell Populations and Predictors of Response.

PURPOSE: The first-in-human phase I/II ICONIC trial evaluated an investigational inducible costimulator (ICOS) agonist, vopratelimab, alone and in combination with nivolumab in patients with advanced solid tumors. PATIENTS AND METHODS: In phase I, patients were treated with escalating doses of intravenous vopratelimab alone or with nivolumab. Primary objectives were safety, tolerability, MTD, and recommended phase II dose (RP2D). Phase II enriched for ICOS-positive (ICOS+) tumors; patients were treated with vopratelimab at the monotherapy RP2D alone or with nivolumab. Pharmacokinetics, pharmacodynamics, and predictive biomarkers of response to vopratelimab were assessed. RESULTS: ICONIC enrolled 201 patients. Vopratelimab alone and with nivolumab was well tolerated; phase I established 0.3 mg/kg every 3 weeks as the vopratelimab RP2D. Vopratelimab resulted in modest objective response rates of 1.4% and with nivolumab of 2.3%. The prospective selection for ICOS+ tumors did not enrich for responses. A vopratelimab-specific peripheral blood pharmacodynamic biomarker, ICOS-high (ICOS-hi) CD4 T cells, was identified in a subset of patients who demonstrated greater clinical benefit versus those with no emergence of these cells [overall survival (OS), P = 0.0025]. A potential genomic predictive biomarker of ICOS-hi CD4 T-cell emergence was identified that demonstrated improvement in clinical outcomes, including OS (P = 0.0062). CONCLUSIONS: Vopratelimab demonstrated a favorable safety profile alone and in combination with nivolumab. Efficacy was observed only in a subset of patients with a vopratelimab-specific pharmacodynamic biomarker. A potential predictive biomarker of response was identified, which is being prospectively evaluated in a randomized phase II non-small cell lung cancer trial. See related commentary by Lee and Fong, p. 3633.

Dissolution of cemented carbide powders in artificial sweat: implications for cobalt sensitization and contact dermatitis.

Skin exposure to cobalt-containing materials can cause systemic immune sensitization and upon repeat contact, elicitation of allergic contact dermatitis (ACD). Data on cobalt dissolution rates are needed to calculate uptake through skin and for development of models to understand risk of sensitization or dermatitis. The purpose of this research was to measure the dissolution kinetics of feedstock and process-sampled powders encountered in the production of hard metal alloys using artificial sweat. The physicochemical properties of each material were characterized prior to evaluation of dissolution behavior. Variations in artificial sweat solvent pH and chemistry were used to understand critical factors in dissolution. Dissolution of cobalt, tungsten, and tungsten carbide was often biphasic with the initial rapid phase being up to three orders of magnitude faster than the latter long-term phase. Artificial sweat pH did not influence dissolution of cobalt or tungsten carbide. Solvent composition had little influence on observed dissolution rates; however, vitamin E suppressed the dissolution of cobalt and tungsten carbide from sintered particles obtained from a chamfer grinder. There was no effect of particle size on dissolution of feedstock cobalt, tungsten, tungsten carbide, and admixture powders. Particle physicochemical properties influenced observed dissolution rates with more cobalt and tungsten carbide dissolving from chamfer grinder particles compared to the feedstock powders or admixture powder. Calculations using the observed dissolution rates revealed that skin exposure concentrations were similar to concentrations known to induce cobalt sensitization and elicit ACD. Observed dissolution rates for cobalt in artificial sweat indicate that dermal uptake may be sufficient to induce cobalt sensitization and allergic dermatitis.

Formulation and stability of a novel artificial sebum under conditions of storage and use.

Materials in contact with liquids on the human skin surface may dissolve and permeate into skin. Release and permeation of chemicals in contact with skin is often estimated in vitro using artificial skin liquids, although sebum lipids are generally not included in these models. The purposes of this research were to develop a representative artificial sebum that contains the appropriate types of lipids at levels that match human values and quantitatively characterize the model to understand its utility for in vitro testing. Artificial sebum that consisted of 10 lipids at proportions that closely resembled human sebum was characterized using thin layer chromatography under a variety of storage and use conditions (dry and liquid, 4°C and 32°C, with and without vitamin E) for 28 days. Levels of sebum constituents maintained in solution and dry at 4°C were stable through the duration of the test period. Levels of all sebum lipids maintained dry at 32°C were stable in the presence of vitamin E; however, squalene oxidized rapidly in the absence of vitamin E. Liquids on the human skin surface consist of sebum and sweat with minor amounts of cellular debris and intercellular lipid from the stratum corneum. The relative importance of each component for release of chemicals from materials in contact with skin will depend upon the type of material (metal, organic, etc.). A model artificial sebum was formulated and characterized to aid researchers in understanding potential release of chemicals from materials in contact with skin and subsequent partitioning and absorption.

Comparison of free radical generation by pre- and post-sintered cemented carbide particles.

Rapid generation of reactive oxygen species (ROS) may occur in response to cellular contact with metal particles. Generation of ROS by cobalt and/or tungsten carbide is implicated in causing hard metal lung disease (HMD) and allergic contact dermatitis (ACD). In this study, ROS generation and particle properties that influence radical generation were assessed for three sizes of tungsten, tungsten carbide, cobalt, admixture (tungsten carbide and cobalt powders), spray dryer, and post-sintered chamfer grinder powders using chemical (H(2)O(2) plus phosphate buffered saline, artificial lung surfactant, or artificial sweat) and cellular (RAW 264.7 mouse peritoneal monocytes plus artificial lung surfactant) reaction systems. For a given material, on a mass basis, hydroxyl (.OH) generation generally increased as particle size decreased; however, on a surface area basis, radical generation levels were more, but not completely, similar. Chamfer grinder powder, polycrystalline aggregates of tungsten carbide in a metallic cobalt matrix, generated the highest levels of .OH radicals (p < 0.05). Radical generation was not dependent on the masses of metals, rather, it involved surface-chemistry-mediated reactions that were limited to a biologically active fraction of the total available surface area of each material. Improved understanding of particle surface chemistry elucidated the importance of biologically active surface area in generation of ROS by particle mixtures.

ICOS agonism by JTX-2011 (vopratelimab) requires initial T cell priming and Fc cross-linking for optimal T cell activation and anti-tumor immunity in preclinical models.

Immunotherapy checkpoint inhibitors, such as antibodies targeting PD-1 and CTLA-4, have demonstrated the potential of harnessing the immune system to treat cancer. However, despite encouraging results particularly with respect to survival, only a minority of patients benefit from these therapies. In clinical studies aimed at understanding changes in the immune system following immunotherapy treatment, ICOS (Inducible T cell CO-Stimulator) was shown to be significantly up-regulated on CD4+ T cells and this was associated with clinical activity, indicating that ICOS stimulatory activity may be beneficial in the treatment of solid tumors. In this report, we describe the generation of specific, species cross-reactive, agonist antibodies to ICOS, including the humanized clinical candidate, JTX-2011 (vopratelimab). Preclinical studies suggest that the ICOS stimulating antibodies require Fc receptor cross-linking for optimal agonistic activity. Notably, the ICOS antibodies do not exhibit superagonist properties but rather require T cell receptor (TCR)-mediated upregulation of ICOS for agonist activity. Treatment with the ICOS antibodies results in robust anti-tumor benefit and long-term protection in preclinical syngeneic mouse tumor models. Additional benefit is observed when the ICOS antibodies are administered in combination with anti-PD-1 and anti-CTLA-4 therapies. Based on the preclinical data, JTX-2011 is currently being developed in the clinical setting for the treatment of solid tumors.

Effect of Prefrontal Cortex Stimulation on Regulation of Amygdala Response to Threat in Individuals With Trait Anxiety: A Randomized Clinical Trial.

Importance: Transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC) is under clinical investigation as a treatment for major depressive disorder. However, the mechanisms of action are unclear, and there is a lack of neuroimaging evidence, particularly among individuals with affective dysfunction. Furthermore, there is no direct causal evidence among humans that the prefrontal-amygdala circuit functions as described in animal models (ie, that increasing activity in prefrontal cortical control regions inhibits amygdala response to threat). Objective: To determine whether stimulation of the prefrontal cortex reduces amygdala threat reactivity in individuals with trait anxiety. Design, Setting, and Participants: This community-based randomized clinical trial used a double-blind, within-participants design (2 imaging sessions per participant). Eighteen women with high trait anxiety (age range, 18-42 years) who scored greater than 45 on the trait measure of State-Trait Anxiety Inventory were randomized to receive active or sham tDCS of the DLPFC during the first session and the other intervention during the next session. Each intervention was followed immediately by a functional imaging scan during which participants performed an attentional task requiring them to ignore threatening face distractors. Data were collected from May 7 to October 6, 2015. Main Outcomes and Measures: Amygdala threat response, measured with functional magnetic resonance imaging. Results: Data from 16 female participants (mean age, 23 years; range, 18-42 years), with 8 in each group, were analyzed. Compared with sham stimulation, active DLPFC stimulation significantly reduced bilateral amygdala threat reactivity (z = 3.30, P = .04) and simultaneously increased activity in cortical regions associated with attentional control (z = 3.28, P < .001). In confirmatory behavioral analyses, there was a mean improvement in task accuracy of 12.2% (95% CI, 0.30%-24.0%; mean [SD] difference in number of correct answers, 2.2 [4.5]; t15 = 1.94, P = .04) after active DLPFC stimulation. Conclusions and Relevance: These results reveal a causal role for prefrontal regulation of amygdala function in attentional capture by threat in individuals with high trait anxiety. The finding that prefrontal stimulation acutely increases attentional control signals and reduces amygdala threat reactivity may indicate a neurocognitive mechanism that could contribute to tDCS treatment effects in affective disorders. Trial Registration: isrctn.org Identifier: ISRCTN78638425.

Automatic volumetry on MR brain images can support diagnostic decision making.

BACKGROUND: Diagnostic decisions in clinical imaging currently rely almost exclusively on visual image interpretation. This can lead to uncertainty, for example in dementia disease, where some of the changes resemble those of normal ageing. We hypothesized that extracting volumetric data from patients' MR brain images, relating them to reference data and presenting the results as a colour overlay on the grey scale data would aid diagnostic readers in classifying dementia disease versus normal ageing. METHODS: A proof-of-concept forced-choice reader study was designed using MR brain images from 36 subjects. Images were segmented into 43 regions using an automatic atlas registration-based label propagation procedure. Seven subjects had clinically probable AD, the remaining 29 of a similar age range were used as controls. Seven of the control subject data sets were selected at random to be presented along with the seven AD datasets to two readers, who were blinded to all clinical and demographic information except age and gender. Readers were asked to review the grey scale MR images and to record their choice of diagnosis (AD or non-AD) along with their confidence in this decision. Afterwards, readers were given the option to switch on a false-colour overlay representing the relative size of the segmented structures. Colorization was based on the size rank of the test subject when compared with a reference group consisting of the 22 control subjects who were not used as review subjects. The readers were then asked to record whether and how the additional information had an impact on their diagnostic confidence. RESULTS: The size rank colour overlays were useful in 18 of 28 diagnoses, as determined by their impact on readers' diagnostic confidence. A not useful result was found in 6 of 28 cases. The impact of the additional information on diagnostic confidence was significant (p < 0.02). CONCLUSION: Volumetric anatomical information extracted from brain images using automatic segmentation and presented as colour overlays can support diagnostic decision making.

Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell-driven tumor immunity.

MICA and MICB are expressed by many human cancers as a result of cellular stress, and can tag cells for elimination by cytotoxic lymphocytes through natural killer group 2D (NKG2D) receptor activation. However, tumors evade this immune recognition pathway through proteolytic shedding of MICA and MICB proteins. We rationally designed antibodies targeting the MICA α3 domain, the site of proteolytic shedding, and found that these antibodies prevented loss of cell surface MICA and MICB by human cancer cells. These antibodies inhibited tumor growth in multiple fully immunocompetent mouse models and reduced human melanoma metastases in a humanized mouse model. Antitumor immunity was mediated mainly by natural killer (NK) cells through activation of NKG2D and CD16 Fc receptors. This approach prevents the loss of important immunostimulatory ligands by human cancers and reactivates antitumor immunity.

Characteristics of dusts encountered during the production of cemented tungsten carbides.

Inhalation of cobalt (Co) and tungsten carbide (WC) particles, but not Co or WC alone, may cause hard metal disease, risk of which does not appear to be uniform across cemented tungsten carbide (CTC) production processes. Inhalation of Co alone or in the presence of WC may cause asthma. Hypothesizing that aerosol size, chemical content, heterogeneity, and constituent compaction may be important exposure factors, we characterized aerosols from representative CTC manufacturing processes. Six work areas were sampled to characterize aerosol size distributions (dust, Co) and 12 work areas were sampled to characterize physicochemical properties (using scanning electron microscopy with energy dispersive x-ray spectrometry [SEM-EDX]). Bulk feedstock and process-generated powders were characterized with SEM-EDX and x-ray diffraction. The dust mass median diameter was respirable and the cobalt respirable mass fraction was highest (37%) in grinding. Morphology of particles changed with processing: individual, agglomerate, or aggregates (pre-sintered materials), then mostly compacted particles (subsequent to sintering). Elemental composition of particles became increasingly heterogeneous: mostly discrete Co or W particles (prior to spray drying), then heterogeneous W/Co particles (subsequent work areas). Variability in aerosol respirability and chemical heterogeneity could translate into differences in toxicity and support detailed characterization of physicochemical properties during exposure assessments.