Surface instabilities generated by a slider pulled across a granular bed.

We report an instability of a slider slowly dragged at the surface of a granular bed in a quasistatic regime. The boat-shaped slider sits on the granular medium under its own weight and is free to translate vertically and to rotate around the pitch axis while a constant horizontal speed is imposed. For a wide range of parameters (mass, length, shape, velocity) a regular pattern of peaks and troughs spontaneously emerges as the slider travels forward. This instability is studied through experiments using a conveyor belt and by means of two-dimensional discrete elements method simulations. We show that the wavelength and amplitude of the pattern scale as the length of the slider. We also observe that the ripples disappear for low and high masses, indicating an optimal confining pressure. The effect of the shape, more specifically the inclination of the front spatula, is studied and found to drastically influence both the wavelength and the amplitude. Finally, we show that the mechanical details (friction, cohesion) of the contact point between the slider and the pulling device is critical and remains to be fully understood.

Real-world study of the efficacy and safety of belantamab mafodotin (GSK2857916) in relapsed or refractory multiple myeloma based on data from the nominative ATU in France: the IFM 2020-04 study.

Belantamab mafodotin (BM) is an anti-BCMA antibody-drug conjugate (GSK2857916) that represents an alternative option in multiple myeloma. We sought to assess the efficacy and safety of BM in a real-world setting in patients who benefited from an early access program. We conducted an observational, retrospective, multicenter study. Eligibility criteria were treatment of relapsed or refractory multiple myeloma (RRMM) in monotherapy in adult patients who have received at least three lines of therapy previously, including at least one immunomodulatory agent (IMiD), a proteasome inhibitor (PI) and an anti-CD38 monoclonal antibody, and whose disease progressed during the last treatment period. The primary endpoint of the study is to assess the overall survival (OS). Between November 2019 and December 2020, 106 patients were treated with BM; 97 were eligible for the efficacy evaluation and 104 for safety. The median age was 66 (range, 37-82) years. High-risk cytogenetics were identified in 40.9% of patients. Fifty-five (56.7%) patients were triple-class refractory and 11 (11.3%) were penta-class refractory. The median number of prior lines of treatment was five (range, 3-12). The median number of BM cycles administered was three (range, 1-22). The overall response rate at best response was 38.1% (37/97). The median OS was 9.3 months (95% confidence interval [CI]: 5.9-15.3), and median progression-free survival was 3.5 months (95% CI: 1.9-4.7). The median duration of response was 9 months (range, 4.65-10.4). Treatment was delayed for 55 (52.9%) patients including 36.5% for treatment-related toxicity. Ophthalmic adverse events, mainly grade ≤2, were the most common toxicity (48%). The occurrence of keratopathy was 37.5%. Overall, our data are concordant with the results from DREAMM-2 in terms of efficacy and safety on a non-biased population.

Identification of Key Factors Influencing the Choice of the Type of Vaginal Pessary for Women Presenting with Pelvic Organ Prolapse: Semi-Directive Interviews and Development of an Algorithm.

(1) Background: Pelvic organ prolapse (POP) can be managed using a vaginal pessary. However, the decision-making process whereby health professionals choose the right pessary is unclear. The objective of this study was to focus on the experience of experts in pessary use and to propose an algorithm. (2) Methods: A prospective study, based on face-to-face semi-directive interviews and group discussions, was conducted on a multidisciplinary panel of professional experts specialized in pessary prescriptions. A consensual algorithm was established, and its accuracy was assessed by expert and non-expert panels. The Consolidated Criteria for Reporting Qualitative Studies (COREQ) were used. (3) Results: 17 semi-directive interviews were conducted. The parameters involved in the decision-making process regarding the choice of vaginal pessaries were: desire for self-management (65%), associated urinary stress incontinence (47%), POP type (41%), and POP stage (29%). The algorithm was developed step by step (4 iterations) using the Delphi technique. Most of the expert panel (76%) rated the relevance of the algorithm as 7 or more out of 10 on a visual analog scale according to their own experience (reference activity). Finally, most (81%) of the non-expert panel (n = 230) rated the usefulness of this algorithm as 7 or more out of 10 on a visual analog scale. (4) Conclusions: This study provides an expert panel-based algorithm that may help in the prescription of pessaries for POP.

Oscillations of a particle-laden fountain.

Different regimes are usually observed for fluid migration through an immersed granular layer. In this work, we report a puzzling behavior when injecting water at a constant flow rate through a nozzle at the bottom of an immersed granular layer in a Hele-Shaw cell. In a given range of parameters (granular layer height and fluid flow rate) the granular bed is not only fluidized, but the particle-laden jet also exhibits periodic oscillations. The frequency and amplitude of the oscillations are quantified. The Strouhal number displays a power-law behavior as a function of a nondimensional parameter, J, defined as the ratio between the jet velocity at the initial granular bed height and the inertial particle velocity. Fluid-particle coupling is responsible for the jet oscillations. This mechanism could be at the origin of the cyclic behavior of pockmarks and mud volcanoes in sedimentary basins.

One Year Assessment of the Hearing Preservation Potential of the EVO Electrode Array.

BACKGROUND: A prospective longitudinal multicentre study was conducted to assess the one-year postsurgical hearing preservation profile of the EVOTM electrode array. METHODS: Fifteen adults presenting indications of electro-acoustic stimulation (pure-tone audiometry (PTA) thresholds ≤70 dB below 750 Hz) were implanted with the EVO™ electrode array. Hearing thresholds were collected at five time-points from CI activation to twelve months (12M) after activation. Hearing thresholds and hearing preservation profiles (HEARRING group classification) were assessed. RESULTS: All subjects had measurable hearing thresholds at follow-up. No case of complete loss of hearing or minimal hearing preservation was reported at any time point. At activation (Nact = 15), five participants had complete hearing preservation, and ten participants had partial hearing preservation. At the 12M time point (N12m = 6), three participants had complete hearing preservation, and three participants had partial hearing preservation. Mean hearing loss at activation was 11 dB for full range PTA and 25 dB for PTAs low-frequency (125-500 Hz). CONCLUSIONS: This study provides the first longitudinal follow-up on associated hearing profiles to the EVO™ electrode array, which are comparable to the literature. However, other studies on larger populations should be performed.

Mitotic WNT signalling orchestrates neurogenesis in the developing neocortex.

The role of WNT/ß-catenin signalling in mouse neocortex development remains ambiguous. Most studies demonstrate that WNT/ß-catenin regulates progenitor self-renewal but others suggest it can also promote differentiation. Here we explore the role of WNT/STOP signalling, which stabilizes proteins during G2/M by inhibiting glycogen synthase kinase (GSK3)-mediated protein degradation. We show that mice mutant for cyclin Y and cyclin Y-like 1 (Ccny/l1), key regulators of WNT/STOP signalling, display reduced neurogenesis in the developing neocortex. Specifically, basal progenitors, which exhibit delayed cell cycle progression, were drastically decreased. Ccny/l1-deficient apical progenitors show reduced asymmetric division due to an increase in apical-basal astral microtubules. We identify the neurogenic transcription factors Sox4 and Sox11 as direct GSK3 targets that are stabilized by WNT/STOP signalling in basal progenitors during mitosis and that promote neuron generation. Our work reveals that WNT/STOP signalling drives cortical neurogenesis and identifies mitosis as a critical phase for neural progenitor fate.

Ultrarare heterozygous pathogenic variants of genes causing dominant forms of early-onset deafness underlie severe presbycusis.

Presbycusis, or age-related hearing loss (ARHL), is a major public health issue. About half the phenotypic variance has been attributed to genetic factors. Here, we assessed the contribution to presbycusis of ultrarare pathogenic variants, considered indicative of Mendelian forms. We focused on severe presbycusis without environmental or comorbidity risk factors and studied multiplex family age-related hearing loss (mARHL) and simplex/sporadic age-related hearing loss (sARHL) cases and controls with normal hearing by whole-exome sequencing. Ultrarare variants (allele frequency [AF] < 0.0001) of 35 genes responsible for autosomal dominant early-onset forms of deafness, predicted to be pathogenic, were detected in 25.7% of mARHL and 22.7% of sARHL cases vs. 7.5% of controls (P = 0.001); half were previously unknown (AF < 0.000002). MYO6, MYO7A, PTPRQ, and TECTA variants were present in 8.9% of ARHL cases but less than 1% of controls. Evidence for a causal role of variants in presbycusis was provided by pathogenicity prediction programs, documented haploinsufficiency, three-dimensional structure/function analyses, cell biology experiments, and reported early effects. We also established Tmc1N321I/+ mice, carrying the TMC1:p.(Asn327Ile) variant detected in an mARHL case, as a mouse model for a monogenic form of presbycusis. Deafness gene variants can thus result in a continuum of auditory phenotypes. Our findings demonstrate that the genetics of presbycusis is shaped by not only well-studied polygenic risk factors of small effect size revealed by common variants but also, ultrarare variants likely resulting in monogenic forms, thereby paving the way for treatment with emerging inner ear gene therapy.

Invasive Infections with Nannizziopsis obscura Species Complex in 9 Patients from West Africa, France, 2004-20201.

Nine new human invasive infections caused by the keratinophilic fungi Nannizziopsis obscura have been reported in France since 2004. The patients had variable clinical manifestations, had frequent dissemination, were mainly T-cell immunocompromised, and all originated from sub-Saharan West Africa. Before collection of the isolates, the etiologies of these infections were often misidentified, underscoring the extent of microscopic and cultural polymorphisms. All isolates but 1 had low MICs for the 8 antifungal drugs tested. When treated, patients received mainly azole therapy. Two of 7 patients with a known outcome died. We performed multilocus sequence analysis of N. obscura clinical strains and several strains of Nannizziopsis spp. isolated from reptiles. The human strains were clearly differentiated from the animal strains. N. obscura might be endemic to West Africa and responsible for undetected infections, which might become reactivated when immunosuppression occurs. N. obscura infection is probably underestimated because only sequencing enables proper identification.

Stability of a Liquid Jet Impinging on Confined Saturated Sand.

This Letter focuses on the dynamics of a liquid jet impacting the surface of a confined, immersed granular bed. Although previous works have considered the erosion process and surface morphology, less attention has been given to the jet hydrodynamics. Based on laboratory experiments, we show that when the liquid jet forms a crater, two situations arise. For weak or no erosion and for open craters, the jet is stationary. For vertical or overhanging crater walls, the jet displays a wide range of behaviors, from quasiperiodic oscillations to symmetry breaking and exploration of different states in time. An analysis of the different system states leads to the emergence of a bifurcation diagram depending on a dimensionless parameter, J, comparing the jet impact force to the force necessary to eject a grain. The frequency of the jet oscillations depends on the inertial velocity, the jet dispersion and the ratio between the injector cross section and the confinement length.

R-spondin signalling is essential for the maintenance and differentiation of mouse nephron progenitors.

During kidney development, WNT/ß-catenin signalling has to be tightly controlled to ensure proliferation and differentiation of nephron progenitor cells. Here, we show in mice that the signalling molecules RSPO1 and RSPO3 act in a functionally redundant manner to permit WNT/ß-catenin signalling and their genetic deletion leads to a rapid decline of nephron progenitors. By contrast, tissue specific deletion in cap mesenchymal cells abolishes mesenchyme to epithelial transition (MET) that is linked to a loss of Bmp7 expression, absence of SMAD1/5 phosphorylation and a concomitant failure to activate Lef1, Fgf8 and Wnt4, thus explaining the observed phenotype on a molecular level. Surprisingly, the full knockout of LGR4/5/6, the cognate receptors of R-spondins, only mildly affects progenitor numbers, but does not interfere with MET. Taken together our data demonstrate key roles for R-spondins in permitting stem cell maintenance and differentiation and reveal Lgr-dependent and independent functions for these ligands during kidney formation.

Kidneys filter waste out of the bloodstream to produce urine. Each kidney contains many structures called nephrons which separate the waste from the blood. The number of nephrons in a kidney varies between people, and those with low numbers have a higher risk of chronic kidney disease. Nephrons are formed before birth from a specific group of so-called progenitor cells. Each of these cells can either divide to make others like itself, or it can specialize to make nephron cells. At the end of embryonic kidney development, all the progenitor cells become nephron cells. Cells that specialize to become part of a nephron first go through a change called a mesenchyme-to-epithelial transition. Epithelial cells move less than mesenchymal cells, and also develop a clear structure where the two ends of the cell adapt to different roles. Evidence suggests that a cell communication process called WNT/ß-catenin signaling controls this transition. Yet the details of how this transition is controlled are not fully understood. One way to activate WNT/ß-catenin signaling is with R-spondin proteins, which have been found in developing kidneys. Vidal et al. studied R-spondins during the embryonic development of kidneys in mice. Removing R-spondins stopped the progenitor cells from producing more of themselves and increased the number that died. The R-spondins were also needed for the progenitor cells to specialize as nephron cells through the mesenchyme-to-epithelial transition. Further results revealed that R-spondins activate WNT/ß-catenin signaling in these cells, even though the proteins that usually act as R-spondin receptors (called LGR4/5/6) could be removed without affecting the results. This suggests that R-spondins interact with different receptor proteins during kidney development. These findings highlight the role of R-spondins and WNT/ß-catenin signaling in kidney development. Future studies will seek the receptor proteins that R-spondins interact with in kidneys. They may also look to understand how R-spondins balance their different roles in progenitor cells and during cell specialization. These results in mice could also be extended to determine their relevance in human health and disease, including chronic kidney disease, which is responsible for more deaths than breast or prostate cancer.

The Oticon Medical Neuro Zti cochlear implant and the Neuro 2 sound processor: multicentric evaluation of outcomes in adults and children.

Objective: This study evaluated the outcomes of the Oticon Medical Neuro Zti cochlear implant and the Neuro 2 sound processor.Design: Neuro One users were upgraded to Neuro 2. Monosyllabic word identification was evaluated in adults with Neuro One after ≥5 months, with Neuro 2 at upgrade, and with Neuro 2 after 3 months. Self-reported listening ability, satisfaction, and usability were measured in adults and children.Study sample: Participants were 44 adults and 26 children.Results: Speech identification scores in quiet and noise were 58% and 45% with Neuro One and 67% and 55% with Neuro 2 after 3 months, respectively. Hearing impairment duration and number of active electrodes significantly predicted speech identification in noise with Neuro 2. Significantly higher questionnaire ratings were obtained for Neuro 2 than Neuro One regarding listening ability in complex listening situations, comfort and music, as well as nine aspects of satisfaction and usability.Conclusion: This study demonstrates the clinical superiority of the Neuro 2 sound processor over Neuro One in terms of speech identification in quiet and in noise and reported patient benefit and satisfaction. Given the study design, sources of improvement may include factors unrelated to the sound processor itself.

Nonlinear denoising for characterization of solid friction under low confinement pressure.

The present work investigates paper-paper friction dynamics by pulling a slider over a substrate. It focuses on the transition between stick-slip and inertial regimes. Although the device is classical, probing solid friction with the fewest contact damage requires that the applied load should be small. This induces noise, mostly impulsive in nature, on the recorded slider motion and force signals. To address the challenging issue of describing the physics of such systems, we promote here the use of nonlinear filtering techniques relying on recent nonsmooth optimization schemes. In contrast to linear filtering, nonlinear filtering captures the slider velocity asymmetry and, thus, the creep motion before sliding. Precise estimates of the stick and slip phase durations can thus be obtained. The transition between the stick-slip and inertial regimes is continuous. Here we propose a criterion based on the probability of the system to be in the stick-slip regime to quantify this transition. A phase diagram is obtained that characterizes the dynamics of this frictional system under low confinement pressure.

[A primitive plasma cell leukemia with immunoglobulin (Ig) E]. / À propos d'un cas de leucémie plasmocytaire primitive à IgE.

We report here a case of primitive plasma cell leukemia with immunoglobulin (Ig) E. IgE myeloma is an exceptional variant of multiple myeloma, with a very poor prognosis. Its biological diagnosis requires specific analyzes in order to detect IgE gammopathy. Plasma cell leukemia (PCL) is also a very rare and very severe form of multiple myeloma. There are two variants: primitive PCL (pPCL) occurring de novo and secondary PCL (sPCL), evolution of a preexisting myeloma. Its diagnosis is essentially biological since it is defined by a blood plasmocytosis greater than 2 G/L or 20% of the leucocytes.

Myocardial-specific R-spondin3 drives proliferation of the coronary stems primarily through the Leucine Rich Repeat G Protein coupled receptor LGR4.

Coronary artery anomalies are common congenital disorders with serious consequences in adult life. Coronary circulation begins when the coronary stems form connections between the aorta and the developing vascular plexus. We recently identified the WNT signaling modulator R-spondin 3 (Rspo3), as a crucial regulator of coronary stem proliferation. Using expression analysis and tissue-specific deletion we now demonstrate that Rspo3 is primarily produced by cardiomyocytes. Moreover, we have employed CRISPR/Cas9 technology to generate novel Lgr4-null alleles that showed a significant decrease in coronary stem proliferation and thus phenocopied the coronary artery defects seen in Rspo3 mutants. Interestingly, Lgr4 mutants displayed slightly hypomorphic right ventricles, an observation also made after myocardial specific deletion of Rspo3. These results shed new light on the role of Rspo3 in heart development and demonstrate that LGR4 is the principal R-spondin 3 receptor in the heart.

Transtympanic pseudoaneurysm of the internal carotid artery complicating a myringotomy in a four-year old child: Case report and literature review.

We report the first case of a transtympanic iatrogenic internal carotid artery (ICA) pseudoaneurysm diagnosed in a 4-year-old child following a myringotomy. An endovascular treatment with a covered-stent was decided; spontaneous thrombosis was found during the therapeutic arteriography, and the procedure was aborted. Otoscopy and computed tomography (CT) scan monitoring showed a prolonged thrombosis and the disappearance of the pseudoaneurysm 18months after the diagnostic arteriography. Based on literature review, endovascular techniques seem to be preferred to the surgical approach for treatment of intrapetrous ICA pseudoaneurysm, however clinical and CT scan monitoring may also be a valid option.

Stability of gas channels in a dense suspension in the presence of obstacles.

We investigate experimentally the influence of a fixed obstacle on gas rising in a dense suspension. Air is injected at a constant flow rate by a single nozzle at the bottom center of a Hele-Shaw cell. Without obstacles, previous works have shown that a fluidized zone is formed with a parabolic shape, with a central air channel and two granular convection rolls on its sides. Here, we quantify the influence of the obstacle's shape, size, and height on the location and dynamics of the central air channel. Different regimes are reported: the air channel can simply deviate (stable), or it can switch sides over time (unstable), leading to two signatures not only above the obstacle, but sometimes also below it. This feedback also influences the channel deviation when bypassing the obstacle. A wake of less or no motion is reported above the largest obstacles as well as the maximum probability of gas location, which can be interesting for practical applications. The existence of a critical height h_{c}≃7 cm is discussed and compared with the existence of an air finger that develops from the injection nozzle and is stable in time. A dimensionless number describing the transition between air fingering and fracturing makes it possible to predict the channel's stability.

Assessment of citalopram and escitalopram on neuroblastoma cell lines. Cell toxicity and gene modulation.

Selective serotonin reuptake inhibitors (SSRI) are common antidepressants which cytotoxicity has been assessed in cancers notably colorectal carcinomas and glioma cell lines. We assessed and compared the cytotoxicity of 2 SSRI, citalopram and escitalopram, on neuroblastoma cell lines. The study was performed on 2 non-MYCN amplified cell lines (rat B104 and human SH-SY5Y) and 2 human MYCN amplified cell lines (IMR32 and Kelly). Citalopram and escitalopram showed concentration-dependent cytotoxicity on all cell lines. Citalopram was more cytotoxic than escitalopram. IMR32 was the most sensitive cell line. The absence of toxicity on human primary Schwann cells demonstrated the safety of both molecules for myelin. The mechanisms of cytotoxicity were explored using gene-expression profiles and quantitative real-time PCR (qPCR). Citalopram modulated 1 502 genes and escitalopram 1 164 genes with a fold change ≥ 2. 1 021 genes were modulated by both citalopram and escitalopram; 481 genes were regulated only by citalopram while 143 genes were regulated only by escitalopram. Citalopram modulated 69 pathways (KEGG) and escitalopram 42. Ten pathways were differently modulated by citalopram and escitalopram. Citalopram drastically decreased the expression of MYBL2, BIRC5 and BARD1 poor prognosis factors of neuroblastoma with fold-changes of -107 (p<2.26 10-7), -24.1 (p<5.6 10-9) and -17.7 (p<1.2 10-7). CCNE1, AURKA, IGF2, MYCN and ERBB2 were more moderately down-regulated by both molecules. Glioma markers E2F1, DAPK1 and CCND1 were down-regulated. Citalopram displayed more powerful action with broader and distinct spectrum of action than escitalopram.

BCL2L10 positive cells in bone marrow are an independent prognostic factor of azacitidine outcome in myelodysplastic syndrome and acute myeloid leukemia.

Azacitidine (AZA), the reference treatment for most higher-risk myelodysplastic (MDS) patients can also improve overall survival (OS) in elderly acute myeloid leukemia (AML) patients ineligible for intensive chemotherapy, but reliable biological markers predicting response and OS in patients treated with AZA are lacking. In a preliminary study, we found that an increase of the percentage of BCL2L10, an anti-apoptotic member of the bcl-2 family, was correlated with AZA resistance. In this study, we assessed prospectively by flow cytometry the prognostic value of BCL2L10 positive bone marrow mononuclear cells in 70 patients (42 MDS and 28 AML), prior to AZA treatment.In patients with baseline marrow blasts below 30%, the baseline percentage of bone marrow BCL2L10 positive cells inversely correlated with response to AZA and OS independently of the International Prognostic Scoring System (IPSS) and IPSS-revised (IPSS-R). Specifically, OS was significantly lower in patients with more than 10% BCL2L10 positive cells (median 8.3 vs 22.9 months in patients with less than 10% positivity, p = 0,001). In summary, marrow BCL2L10 positive cells may be a biomarker for azacitidine response and OS, with a potential impact in clinical practice.

The adrenal capsule is a signaling center controlling cell renewal and zonation through Rspo3.

Adrenal glands are zonated endocrine organs that are essential in controlling body homeostasis. How zonation is induced and maintained and how renewal of the adrenal cortex is ensured remain a mystery. Here we show that capsular RSPO3 signals to the underlying steroidogenic compartment to induce ß-catenin signaling and imprint glomerulosa cell fate. Deletion of RSPO3 leads to loss of SHH signaling and impaired organ growth. Importantly, Rspo3 function remains essential in adult life to ensure replenishment of lost cells and maintain the properties of the zona glomerulosa. Thus, the adrenal capsule acts as a central signaling center that ensures replacement of damaged cells and is required to maintain zonation throughout life.

Bubbles trapped in a fluidized bed: Trajectories and contact area.

This work investigates the dynamics of bubbles in a confined, immersed granular layer submitted to an ascending gas flow. In the stationary regime, a central fluidized zone of parabolic shape is observed, and the bubbles follow different dynamics: either the bubbles are initially formed outside the fluidized zone and do not exhibit any significant motion over the experimental time or they are located inside the fluidized bed, where they are entrained downwards and are, finally, captured by the central air channel. The dependence of the air volume trapped inside the fluidized zone, the bubble size, and the three-phase contact area on the gas injection flow rate and grain diameter are quantified. We find that the volume fraction of air trapped inside the fluidized region is roughly constant and of the order of 2%-3% when the gas flow rate and the grain size are varied. Contrary to intuition, the gas-liquid-solid contact area, normalized by the air injected into the system, decreases when the flow rate is increased, which may have significant importance in industrial applications.