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Animating gaze behavior is crucial for creating believable virtual characters, providing insights into their perception and interaction with the environment. In this paper, we present an efficient yet natural‐looking gaze animation model applicable to real‐time walking characters exploring natural environments. We address the challenge of dynamic gaze adaptation by combining findings from neuroscience with a data‐driven saliency model. Specifically, our model determines gaze focus by considering the character's locomotion, environment stimuli, and terrain conditions. Our model is compatible with both automatic navigation through pre‐defined character trajectories and user‐guided interactive locomotion, and can be configured according to the desired degree of visual exploration of the environment. Our perceptual evaluation shows that our solution significantly improves the state‐of‐the‐art saliency‐based gaze animation with respect to the character's apparent awareness of the environment, the naturalness of the motion, and the elements to which it pays attention. [ABSTRACT FROM AUTHOR]

Tensor fields are useful for modeling the structure of biological tissues. The challenge to measure tensor fields involves acquiring sufficient data of scalar measurements that are physically achievable and reconstructing tensors from as few projections as possible for efficient applications in medical imaging. In this paper, we present a filtered back-projection algorithm for the reconstruction of a symmetric second-rank tensor field from directional X-ray projections about three axes. The tensor field is decomposed into a solenoidal and irrotational component, each of three unknowns. Using the Fourier projection theorem, a filtered back-projection algorithm is derived to reconstruct the solenoidal and irrotational components from projections acquired around three axes. A simple illustrative phantom consisting of two spherical shells and a 3D digital cardiac diffusion image obtained from diffusion tensor MRI of an excised human heart are used to simulate directional X-ray projections. The simulations validate the mathematical derivations and demonstrate reasonable noise properties of the algorithm. The decomposition of the tensor field into solenoidal and irrotational components provides insight into the development of algorithms for reconstructing tensor fields with sufficient samples in terms of the type of directional projections and the necessary orbits for the acquisition of the projections of the tensor field.

Mycosis fungoides (MF) is a subtype of CTCL with a low incidence and high medical need for novel treatments. The objective of this randomized, placebo-controlled, double-blinded, first-in-human study was to evaluate safety, efficacy, cutaneous and systemic pharmacokinetics (PK) of topical bimiralisib in healthy volunteers (HVs) and MF patients. In this trial, a total of 6 HVs and 19 early-stage MF patients were treated with 2.0% bimiralisib gel and/or placebo. Drug efficacy was assessed by the Composite Assessment of Index Lesion Severity (CAILS) score, supported by objective measuring methods to quantify lesion severity. PK blood samples were collected frequently and cutaneous PK was investigated in skin punch biopsies on the last day of treatment. Local distribution of bimiralisib in HVs showed a mean exposure of 2.54 µg/g in the epidermis. A systemic concentration was observed after application of a target dose of 2 mg/cm 2 on 400 cm 2 , with a mean C avg of 0.96 ng/mL. Systemic exposure of bimiralisib was reached in all treated MF patients, and normalized plasma concentrations showed a 144% increased exposure compared to HVs, with an observed mean C avg of 4.49 ng/mL and a mean cutaneous concentration of 5.3 µg/g. No difference in CAILS or objective lesion severity quantification upon 42 days of once-daily treatment was observed in the MF patient group. In general, the treatment was well tolerated in terms of local reactions as well as systemic adverse events. In conclusion, we showed that topical bimiralisib treatment leads to (i) meaningful cutaneous drug levels and (ii) well-tolerated systemic drug exposure in MF patients and (iii) a lack of clinical efficacy, in need of further exploration due to numerous unknown factors, before depreciation of topical bimiralisib as a novel therapeutic drug for CTCLs.

Bimiralisib is an orally bioavailable pan-phosphatidylinositol 3-kinase and mammalian target of rapamycin inhibitor which has shown activity against lymphoma in preclinical models. This phase I/II study evaluated the response rate to bimiralisib at 2 continuous dose levels (60 mg and 80 mg) in patients with relapsed/refractory lymphoma. Fifty patients were enrolled and started treatment. The most common histologies were diffuse large B-cell lymphoma (n = 17), follicular lymphoma (n = 9), T-cell lymphoma (n = 8), and others (mostly indolent). Patients had been treated with a median of 5 prior lines of treatment and 44% were considered refractory to their last treatment. Mean duration of treatment (and standard deviations) with 60 mg once daily (o.d.) was 1.3 ± 1.2 months, and with 80 mg o.d. 3.7 ± 3.9 months. On an intention to treat analysis, the overall response rate was 14% with 10% achieving a partial response and 4% a complete response. Thirty-six percent of patients were reported as having stable disease. No dose-limiting toxicities were observed during the phase I portion of the study. Overall, 70% of patients had a grade 3 treatment emergent adverse events (TEAE) and 34% had a grade 4 TEAE; 28% of patients discontinued treatment due to toxicity. The most frequent TEAEs grade ≥3 was hyperglycemia (24%), neutropenia (20%), thrombocytopenia (22%), and diarrhea (12%). Per protocol, hyperglycemia required treatment with oral antihyperglycemic agents in 28% and with insulin in 14%. At 60 mg or 80 mg continuous dosing, bimiralisib showed modest efficacy with significant toxicity in heavily pretreated patients with various histological subtypes of lymphoma., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

Introduction: According to the literature and our recent experience, even if patients present with symptoms strongly suggestive of benign paroxysmal positional vertigo (BPPV), the observed positional nystagmus does not always correspond to any previously described typical location. The aim of this multicentric study was to evaluate the frequency of both typical and less common forms of BPPV., Material and Methods: All consecutive patients presenting with BPPV in two hospitals between November 2016 and October 2017 were included. For each subject, answers to a standardized evaluation form and a recorded videonystagmoscopy were obtained by two otorhinolaryngologists. Appropriate diagnostic and therapeutic maneuvers were performed., Results: A total of 532 patients were studied and 491 cases of typical BPPV were found: 370 cases of canalolithiasis of the posterior semicircular canal (SCC), 3 cases of canalolithiasis of the anterior SCC, 107 cases of canalolithiasis of the lateral SCC, and 11 cases of cupulolithiasis of the lateral SCC. Fourty one patients reported symptoms suggestive of BPPV with positional nystagmus that could correspond to unusual locations of otoconia in the SCC: 18 cases of canalolithiasis in the anterior ampulla of the lateral SCC, 16 cases of posterior short arm canalolithiasis, four cases of pseudo-spontaneous nystagmus in canalolithiasis of the lateral SCC, and three cases of canalolithiasis of the posterior third of SCC., Discussion: Unusual BPPV accounted for almost 8% of BPPV treated in our clinics; it is paramount to know how to diagnose them, to carry out the appropriate therapeutic maneuvers and relieve these patients.

Background: We evaluated the usefulness of CT and MRI for the diagnosis of perilymphatic fistula (PLF) of the round (RW) and/or oval (OW) windows, with surgery as gold standard., Methods: We retrospectively enrolled 17 patients who presented a surgically confirmed PLF of the round (RW) or oval (OW) windows. All patients were imaged by CT + MRI (T2W SSFP without contrast) prior to surgery (= gold standard). Two radiologists, analyzed the RW and OW on the side of the clinical symptoms and sensitivity (Se) + Specificity (Sp) were calculated., Results: Round window fistula was the most frequent (71%). The best sign of PLF on imaging was a fluid filling of the window niches, which had good Se (83-100% for RW, 66-83% for OW) and Sp (60% for RW, 91-100% for OW). Disorientation of the footplate and pneumolabyrinth were also only observed in 50% of OW PLF., Conclusion: The combination of CT and MRI is a reliable tool for a fast and accurate diagnosis of round and oval window perilymphatic fistula, with good sensitivity (> 80%). The most common sign of PLF on imaging is the presence of a fluid-filling in the RW (especially if > 2/3 of the RW niche) or in the OW niches on both CT and MRI. A disorientation of the footplate or the presence of a pneumolabyrinth are clearly in favor of an oval window perilymphatic fistula.

Introduction: Vestibular neuritis is the second cause of vertigo and new imaging protocols using delayed FLAIR with double-dose of gadolinium are proposed for its diagnosis. Our aim is to demonstrate that a single dose of gadolinium is sufficient., Methods: Thirty-three patients with a unilateral vestibular neuritis are compared to a control group. All patients underwent a FLAIR sequence, 1 hour after intravenous injection of a single dose of gadolinium, on a 1.5 Tesla MRI. Two radiologists analyzed the enhancement intensity of the superior (sup VN) and inferior vestibular nerve (inf VN) and ratios to the signal of the cerebellum were calculated (supVN/C). The statistics were performed using Bayesian analysis., Results: A strong enhancement of the sup VN was observed on the pathological side in 85% of patients with vestibular neuritis. The average signal intensity of the pathological sup VN (139 units ± 44) was more than two times the average intensity in the control group (58.5 units ± 5). The average ratios supVN/C were significantly different between the pathological side in vestibular neuritis (2.43 units ± 0.63) and the control group [1.16 ± 0.14 (Pr(diff > 0) = 1)]. A delayed enhancement > 71.5 units had a sensitivity of 96% and a specificity of 100% for the diagnosis of superior vestibular neuritis., Conclusion: A delayed FLAIR sequence, acquired 1 hour after a single dose of gadolinium injection, is a useful method for the diagnosis of vestibular neuritis. An enhancement of the sup VN > 71.5 units was in favor of the diagnosis.

Objective: Vestibular schwannomas (VS) may present with similar symptoms endolymphatic hydrops. Association between hydrops and internal auditory canal VS has been described by Naganawa et al. (Neuroradiology 53:1009-1015, 2011), but has never been confirmed since. The aim of this work was to study the prevalence of a saccular dilation on a T2-weighted sequence at 3 T MRI in VS compared to a control group., Materials and Methods: All patients presenting with typical VS between May 2009 and July 2018 were included (n = 183) and compared to a control group (n = 53). All underwent a high-resolution T2-weighted 3D sequence (FIESTA-C). The height and width of the saccule were measured on a coronal plane by two radiologists., Results: The saccule was dilated on the side of the schwannoma in 28% of the cases (p = 2.81 × 10 - 5 ), with 15.7% of bilateral dilation. Saccular dilation was correlated to sensorineural hearing loss (OR 3.26, p = 0.02). There was also a significant correlation between saccular hydrops on the normal contralateral side of patients with VS and vertigo (p = 0.049), and between saccular hydrops on the side of the tumour and tinnitus (p = 0.006)., Conclusion: A third (29%) of VS are associated with a saccular dilation on the side of the tumour, which is an MR sign of endolymphatic hydrops (bilateral in 15.7% of the cases) and it appears related to sensorineural hearing loss and tinnitus, as well as vertigo if a contralateral dilation is present. This opens new therapeutic potentialities with the use of anti-vertiginous drugs, which could have a beneficial effect on the clinical symptoms.

Objectives: Lateral semicircular canal (LSCC) malformations  are one of the most common inner ear malformations. The purpose of this study is to analyze the prevalence and type of hearing losses associated with LSCC malformations, compared to a control group., Materials and Methods: We retrospectively included 109 patients (166 ears) presenting with a CT-confirmed LSCC malformation, compared to a control group (24 patients). The bony island surface and the width of the inner portion of the LSCC were measured to confirm the malformation. There results were correlated to audiogram data: sensorineural (SHNL), mixed (MHL) or conductive hearing loss (CHL) by an otologist., Results: In the LSCC group, 60.9% of patients presented with an audiogram-confirmed hearing loss, especially SNHL (39.2%, n = 65) and MHL (12.7%, n = 21). Hearing was normal in 39.2% (n = 65) of the cases. Bilateral LSCC malformations (n = 57) were frequently associated with hearing loss (80.7%), SNHL in most of the cases (33.3%). Unilateral LSCC malformations were associated with hearing alterations (51.9%, n = 27), but we also observed a high rate (81%, n = 42) of contralateral abnormalities of the audiogram., Conclusion: LSCC malformations are commonly associated with hearing loss (61%), especially SHNL (39%). The high rate (81%) of contralateral hearing disturbances in unilateral LSCC malformations should be taken into account in the patient's daily life to avoid triggering or exacerbating any hearing loss. Otologists and radiologists must cooperate to ensure that all malformations are correctly described on CT, especially to improve the patient's education regarding hearing preservation.

The interrogation and the clinical examination are critical in the research of vertigo etiology. In the context of vertigo, the vital emergencies are of neurological and vascular origins. It is therefore necessary to be able to identify them quickly and simply. Vertigo is a symptom to relieve and the cause is to be diagnosed. Careful questioning combined with neurological examination, nystagmus study, Halmagyi test and skew deviation search are more reliable than imaging in the first 48hours to detect a stroke. There are 12% false negatives in cerebral MRI and 74% false negative in cerebral CT-scan in the first 48hours of an ischemic stroke. Labyrinth emergencies are infectious labyrinthitis, perilymphatic fistula and aeroembolism of the vestibule., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Background: Endolymphatic hydrops can be studied on magnetic resonance imaging (MRI) using images acquired 4 h after intravenous injection of Gd-chelate. Our aim was to compare high-resolution T2-weighted images of the saccule in normal subjects with histological sections from cadavers and to identify its changes in Meniere disease, compared to healthy volunteers., Methods: Sixty-four healthy volunteers without any otologic disease and 64 patients who fulfilled all the criteria for unilateral Meniere disease underwent 3 T MRI using a T2-weighted steady state free precession (SSFP) sequence, without contrast material injection. Images of healthy volunteers were compared with histological sections of normal inner ears from premature foetuses and compared with volunteers., Results: The normal saccule was easily visible on T2-weighted images in volunteers, with a normal maximal height of 1.6 mm (1.4 ± 0.1 mm, mean ± standard deviation) and a good correlation with reference histological sections, while in Meniere disease the saccule was dilated in 52/62 patients (84%), with a saccular height greater than 1.6 mm (1.69 ± 0.24 mm, p  = 0.001), found in 45/52 patients (86%). An associated increased width (greater than 1.4 mm) was found in 23/52 patients (44%). A round shape or the non-visualisation of the saccule were also found in 2/52 (4%) and in 5/62 patients (8%), respectively., Conclusions: A T2-weighted sequence is an easy method to diagnose Meniere disease. Saccular abnormalities were found in 84% of the cases: elongation (height > 1.6 mm) in 86%, increased saccular width in 44%, or a missing saccule in 8%., Competing Interests: The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Objectives: Since 1996, 1 to 4 annual training missions have been carried out to train Haitian otorhinolaryngology (ENT) and cervicofacial surgery residents by the association Liens Otorhinolaryngology Ayti (LOA). Until 1996, ENT was practiced and taught by ophthalmologists. The aim of this article is to describe the contributions and limitations of LOA in training of Haitian resident physicians and the creation of the ENT specialty in Haiti., Design: Retrospective analysis of clinical consultation and surgical interventions records and didactics carried out during missions from 1996 through 2014., Participants: A total of 37 missions were made during the 19-year period in which 29 senior ENT specialists participated, with an average of 3.37 missions per physician., Results: A total of 10,300 consultations and 173 surgical procedures were made jointly by a senior LOA physician and a Haitian resident physician. Totally 16 Haitian ENT residents were trained, 81% of whom are still practicing in Haiti. ENT became a surgical specialty in 2001 after the nomination of a Haitian ENT specialist as Assistant Director of the ENT-Ophthalmology service. The latter benefitted from dual training by LOA in Haiti and abroad., Conclusion: The Haitian population experiences significant difficulties with access to medical care owing to very low number of resident medical personnel. LOA's work has contributed over 19 years to the training of ENT physicians now practicing in Haiti and to the creation of a local ENT specialty., (Copyright © 2015 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

The serine and threonine kinase MST1 is the mammalian homolog of Hippo. MST1 is a critical mediator of the migration, adhesion, and survival of T cells; however, these functions of MST1 are independent of signaling by its typical effectors, the kinase LATS and the transcriptional coactivator YAP. The kinase NDR1, a member of the same family of kinases as LATS, functions as a tumor suppressor by preventing T cell lymphomagenesis, which suggests that it may play a role in T cell homeostasis. We generated and characterized mice with a T cell-specific double knockout of Ndr1 and Ndr2 (Ndr DKO). Compared with control mice, Ndr DKO mice exhibited a substantial reduction in the number of naïve T cells in their secondary lymphoid organs. Mature single-positive thymocytes accumulated in the thymus in Ndr DKO mice. We also found that NDRs acted downstream of MST1 to mediate the egress of mature thymocytes from the thymus, as well as the interstitial migration of naïve T cells within popliteal lymph nodes. Together, our findings indicate that the kinases NDR1 and NDR2 function as downstream effectors of MST1 to mediate thymocyte egress and T cell migration., (Copyright © 2015, American Association for the Advancement of Science.)

Background: Embryology is a complex morphologic discipline involving a set of entangled mechanisms, sometime difficult to understand and to visualize. Recent computer based techniques ranging from geometrical to physically based modeling are used to assist the visualization and the simulation of virtual humans for numerous domains such as surgical simulation and learning. On the other side, the ontology-based approach applied to knowledge representation is more and more successfully adopted in the life-science domains to formalize biological entities and phenomena, thanks to a declarative approach for expressing and reasoning over symbolic information. 3D models and ontologies are two complementary ways to describe biological entities that remain largely separated. Indeed, while many ontologies providing a unified formalization of anatomy and embryology exist, they remain only descriptive and make the access to anatomical content of complex 3D embryology models and simulations difficult., Results: In this work, we present a novel ontology describing the development of the human embryology deforming 3D models. Beyond describing how organs and structures are composed, our ontology integrates a procedural description of their 3D representations, temporal deformation and relations with respect to their developments. We also created inferences rules to express complex connections between entities. It results in a unified description of both the knowledge of the organs deformation and their 3D representations enabling to visualize dynamically the embryo deformation during the Carnegie stages. Through a simplified ontology, containing representative entities which are linked to spatial position and temporal process information, we illustrate the added-value of such a declarative approach for interactive simulation and visualization of 3D embryos., Conclusions: Combining ontologies and 3D models enables a declarative description of different embryological models that capture the complexity of human developmental anatomy. Visualizing embryos with 3D geometric models and their animated deformations perhaps paves the way towards some kind of hypothesis-driven application. These can also be used to assist the learning process of this complex knowledge., Availability: http://www.mycorporisfabrica.org/.

Studies of mammalian tissue culture cells indicate that the conserved and distinct NDR isoforms, NDR1 and NDR2, play essential cell biological roles. However, mice lacking either Ndr1 or Ndr2 alone develop normally. Here, we studied the physiological consequences of inactivating both NDR1 and NDR2 in mice, showing that the lack of both Ndr1/Ndr2 (called Ndr1/2-double null mutants) causes embryonic lethality. In support of compensatory roles for NDR1 and NDR2, total protein and activating phosphorylation levels of the remaining NDR isoform were elevated in mice lacking either Ndr1 or Ndr2. Mice retaining one single wild-type Ndr allele were viable and fertile. Ndr1/2-double null embryos displayed multiple phenotypes causing a developmental delay from embryonic day E8.5 onwards. While NDR kinases are not required for notochord formation, the somites of Ndr1/2-double null embryos were smaller, irregularly shaped and unevenly spaced along the anterior-posterior axis. Genes implicated in somitogenesis were down-regulated and the normally symmetric expression of Lunatic fringe, a component of the Notch pathway, showed a left-right bias in the last forming somite in 50% of all Ndr1/2-double null embryos. In addition, Ndr1/2-double null embryos developed a heart defect that manifests itself as pericardial edemas, obstructed heart tubes and arrest of cardiac looping. The resulting cardiac insufficiency is the likely cause of the lethality of Ndr1/2-double null embryos around E10. Taken together, we show that NDR kinases compensate for each other in vivo in mouse embryos, explaining why mice deficient for either Ndr1 or Ndr2 are viable. Ndr1/2-double null embryos show defects in somitogenesis and cardiac looping, which reveals their essential functions and shows that the NDR kinases are critically required during the early phase of organogenesis.

Background: Phosphorylation of the transcriptional coactivator YAP1 is a key event in defining Hippo signaling outputs. Previous studies demonstrated that phosphorylation of YAP1 at serine 127 (S127) sequesters YAP1 in the cytoplasm and consequently inhibits YAP1 transcriptional activity. Mammalian tissue-culture experiments suggest that downstream of MST1/2 signaling, LATS1/2 function as YAP1-S127 kinases. However, studies of Mst1/2 knockout mouse models revealed that the identity of the physiological YAP1-S127 kinase(s) in certain tissues, such as the intestine, remains unknown., Results: We show that mammalian NDR1/2 kinases phosphorylate YAP1 on S127 and thereby negatively regulate YAP1 activity in tissue-cultured cells. By studying NDR1/2-deficient mice, we demonstrate the in vivo relevance of NDR1/2-mediated regulation of YAP1. Specifically, upon loss of NDR1/2 in the intestinal epithelium, endogenous S127 phosphorylation is decreased whereas total YAP1 levels are increased. Significantly, ablation of NDR1/2 from the intestinal epithelium renders mice exquisitely sensitive to chemically induced colon carcinogenesis. Analysis of human colon cancer samples further revealed that NDR2 and YAP1 protein expression are inversely correlated in the majority of samples with high YAP1 expression. Collectively, we report NDR1/2 as physiological YAP1-S127 kinases that might function as tumor suppressors upstream of YAP1 in human colorectal cancer., Conclusions: We establish mammalian NDR1/2 as bona fide kinases that target YAP1 on S127 in vitro and in vivo. Our findings therefore have important implications for a broad range of research efforts aimed at decoding and eventually manipulating YAP1 biology in cancer settings, regenerative medicine, and possibly also noncancer human diseases., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

New therapeutic targets are needed that circumvent inherent therapeutic resistance of glioblastoma multiforme (GBM). Here, we report such a candidate target in the uncharacterized adaptor protein hMOB3, which we show is upregulated in GBM. In a search for its biochemical function, we found that hMOB3 specifically interacts with MST1 kinase in response to apoptotic stimuli and cell-cell contact. Moreover, hMOB3 negatively regulated apoptotic signaling by MST1 in GBM cells by inhibiting the MST1 cleavage-based activation process. Physical interaction between hMOB3 and MST1 was essential for this process. In vivo investigations established that hMOB3 sustains GBM cell growth at high cell density and promotes tumorigenesis. Our results suggest hMOB3 as a candidate therapeutic target for the treatment of malignant gliomas., (©2014 American Association for Cancer Research.)

Objective: The human heart is composed of a helical network of muscle fibers organized to form sheets that are separated by cleavage planes responsible for the orthotropic mechanical properties of cardiac muscle. The purpose of this study is the reconstruction and visualization of these structures in 3 dimensions., Methods: Anisotropic least square filtering followed by fiber and sheet tracking techniques were applied to diffusion tensor magnetic resonance imaging data of the excised human heart. Fibers were reconstructed using the first eigenvectors of the diffusion tensors. The sheets were reconstructed using the second and third eigenvectors and visualized as surfaces., Results: The fibers are shown to lie in sheets that have transmural structure, which correspond to histologic studies published in the literature. Quantitative measurements show that the sheets as appose to the fibers are organized into laminar orientations without dominant populations., Conclusions: A visualization algorithm was developed to demonstrate the complex 3-dimensional orientation of the fibers and sheets in human myocardium.