Initial experience with vNOTES hysterectomy for benign conditions in a French university hospital.

Background: Natural orifice transluminal endoscopic surgery by the vaginal route (vNOTES) is a new approach to performing hysterectomy. Clinical outcomes must be evaluated in centres that have started performing this technique. Objectives: To compare operative outcomes between vNOTES hysterectomy and laparoscopic hysterectomy during the introduction of the vNOTES approach in a teaching hospital. Material and Methods: A retrospective study was conducted from November 2019 to May 2021 at a French academic hospital in Marseille. The included patients underwent total hysterectomy for benign indications by vNOTES or conventional laparoscopy. Main outcome measures: Operative time, uterus weight, intraoperative complications, and postoperative complications according to the Clavien-Dindo classification. Results: Eighty-six patients underwent hysterectomy according to the selected criteria: 36 procedures were performed by vNOTES and 50 by laparoscopy. The mean operative time was shorter in the vNOTES group than in the laparoscopy group [116 min versus 149 min; p=0.003]. The mean uterus weight was not different between the vNOTES group and the laparoscopy group (238g versus 281g; p=0.572). Laparo-conversion occurred in one case in the vNOTES group (2.7%) and three cases in the laparoscopy group (3.4%). One Grade III postoperative complication occurred in the laparoscopy group, and no severe complication occurred in the vNOTES group. Conclusion: Operative outcomes of the vNOTES hysterectomy were favourable and support good feasibility without additional morbidity compared to laparoscopy. What is new?: During the introduction period of the vNOTES hysterectomy technique in a teaching hospital, reassuring operative outcomes and a low rate of complications were observed.

IMM-BCP-01, a patient-derived anti-SARS-CoV-2 antibody cocktail, is active across variants of concern including Omicron BA.1 and BA.2.

Monoclonal antibodies are an efficacious therapy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, rapid viral mutagenesis led to escape from most of these therapies, outlining the need for an antibody cocktail with a broad neutralizing potency. Using an unbiased interrogation of the memory B cell repertoire of patients with convalescent COVID-19, we identified human antibodies with broad antiviral activity in vitro and efficacy in vivo against all tested SARS-CoV-2 variants of concern, including Delta and Omicron BA.1 and BA.2. Here, we describe an antibody cocktail, IMM-BCP-01, that consists of three patient-derived broadly neutralizing antibodies directed at nonoverlapping surfaces on the SARS-CoV-2 Spike protein. Two antibodies, IMM20184 and IMM20190, directly blocked Spike binding to the ACE2 receptor. Binding of the third antibody, IMM20253, to its cryptic epitope on the outer surface of RBD altered the conformation of the Spike Trimer, promoting the release of Spike monomers. These antibodies decreased Omicron SARS-CoV-2 infection in the lungs of Syrian golden hamsters in vivo and potently induced antiviral effector response in vitro, including phagocytosis, ADCC, and complement pathway activation. Our preclinical data demonstrated that the three-antibody cocktail IMM-BCP-01 could be a promising means for preventing or treating infection of SARS-CoV-2 variants of concern, including Omicron BA.1 and BA.2, in susceptible individuals.

Monitoring of in-vitro ultrasonic stimulation of cells by numerical modeling.

Ultrasound stimulation of living tissues is a promising technique that can be safely applied for regenerative treatments. However, the ultrasound-induced mechanotransduction is still not well understood because of the large number of parameters involved at different scales and their difficult experimental accessibility. In this context, in-vitro studies may help to gain insight into the interaction between ultrasound and cells. Nevertheless, to conduct a reliable analysis of ultrasound effects on cell culture, the monitoring of the acoustic intensity delivered to the cells is of prime interest. Thanks to the development of an innovative custom experimental set-up inspired from ultrasound stimulation of bone regeneration conditions, major disturbing phenomena such as multiple reflections and standing wave formation inside the Petri dish are eliminated. Thus, the level of ultrasound stimulation, especially, in terms of spatial average temporal average intensity (ISATA), delivered to the cells can be monitored. Then, to properly estimate the level of ultrasound stimulation, a finite element model representing the experimental in-vitro configuration is developed. The numerical model manages on capturing the characteristics of the experimentally measured acoustic intensity distribution as illustrated by the experimental and numerical ISATA values of 42.3 and 45.8 mW/cm2 respectively, i.e. a relative difference of 8%. The numerical model would therefore allow exploring data inaccessible to experimental measurement and parametric studies to be carried out and facilitates the investigation of different virtual experimental configurations.

Preclinical Efficacy of IMM-BCP-01, a Highly Active Patient-Derived Anti-SARS-CoV-2 Antibody Cocktail

Using an unbiased interrogation of the memory B cell repertoire of convalescent COVID-19 patients, we identified human antibodies that demonstrated robust antiviral activity in vitro and efficacy in vivo against all tested SARS-CoV-2 variants. Here, we describe the pre-clinical characterization of an antibody cocktail, IMM-BCP-01, that consists of three unique, patient-derived recombinant neutralizing antibodies directed at non-overlapping surfaces on the SARS-CoV-2 spike protein. Two antibodies, IMM20184 and IMM20190 directly block spike binding to the ACE2 receptor. Binding of the third antibody, IMM20253, to its unique epitope on the outer surface of RBD, alters the conformation of the spike trimer, promoting release of spike monomers. These antibodies decreased SARS-CoV-2 infection in the lungs of Syrian golden hamsters, and efficacy in vivo efficacy was associated with broad antiviral neutralizing activity against multiple SARS-CoV-2 variants and robust antiviral effector function response, including phagocytosis, ADCC, and complement pathway activation. Our pre-clinical data demonstrate that the three antibody cocktail IMM-BCP-01 shows promising potential for preventing or treating SARS-CoV-2 infection in susceptible individuals. One sentence summaryIMM-BCP-01 cocktail triggers Spike Trimer dissociation, neutralizes all tested variants in vitro, activates a robust effector response and dose-dependently inhibits virus in vivo.

Unbiased interrogation of memory B cells from convalescent COVID-19 patients reveals a broad antiviral humoral response targeting SARS-CoV-2 antigens beyond the spike protein.

Patients who recover from SARS-CoV-2 infections produce antibodies and antigen-specific T cells against multiple viral proteins. Here, an unbiased interrogation of the anti-viral memory B cell repertoire of convalescent patients has been performed by generating large, stable hybridoma libraries and screening thousands of monoclonal antibodies to identify specific, high-affinity immunoglobulins (Igs) directed at distinct viral components. As expected, a significant number of antibodies were directed at the Spike (S) protein, a majority of which recognized the full-length protein. These full-length Spike specific antibodies included a group of somatically hypermutated IgMs. Further, all but one of the six COVID-19 convalescent patients produced class-switched antibodies to a soluble form of the receptor-binding domain (RBD) of S protein. Functional properties of anti-Spike antibodies were confirmed in a pseudovirus neutralization assay. Importantly, more than half of all of the antibodies generated were directed at non-S viral proteins, including structural nucleocapsid (N) and membrane (M) proteins, as well as auxiliary open reading frame-encoded (ORF) proteins. The antibodies were generally characterized as having variable levels of somatic hypermutations (SHM) in all Ig classes and sub-types, and a diversity of VL and VH gene usage. These findings demonstrated that an unbiased, function-based approach towards interrogating the COVID-19 patient memory B cell response may have distinct advantages relative to genomics-based approaches when identifying highly effective anti-viral antibodies directed at SARS-CoV-2.

Rapid microscopic fractional anisotropy imaging via an optimized linear regression formulation.

Water diffusion anisotropy in the human brain is affected by disease, trauma, and development. Microscopic fractional anisotropy (µFA) is a diffusion MRI (dMRI) metric that can quantify water diffusion anisotropy independent of neuron fiber orientation dispersion. However, there are several different techniques to estimate µFA and few have demonstrated full brain imaging capabilities within clinically viable scan times and resolutions. Here, we present an optimized spherical tensor encoding (STE) technique to acquire µFA directly from the 2nd order cumulant expansion of the powder averaged dMRI signal obtained from direct linear regression (i.e. diffusion kurtosis) which requires fewer powder-averaged signals than other STE fitting techniques and can be rapidly computed. We found that the optimal dMRI parameters for white matter µFA imaging were a maximum b-value of 2000 s/mm2 and a ratio of STE to LTE tensor encoded acquisitions of 1.7 for our system specifications. We then compared two implementations of the direct regression approach to the well-established gamma model in 4 healthy volunteers on a 3 Tesla system. One implementation used mean diffusivity (D) obtained from a 2nd order fit of the cumulant expansion, while the other used a linear estimation of D from the low b-values. Both implementations of the direct regression approach showed strong linear correlations with the gamma model (ρ = 0.97 and ρ = 0.90) but mean biases of -0.11 and - 0.02 relative to the gamma model were also observed, respectively. All three µFA measurements showed good test-retest reliability (ρ ≥ 0.79 and bias = 0). To demonstrate the potential scan time advantage of the direct approach, 2 mm isotropic resolution µFA was demonstrated over a 10 cm slab using a subsampled data set with fewer powder-averaged signals that would correspond to a 3.3-min scan. Accordingly, our results introduce an optimization procedure that has enabled nearly full brain µFA in only several minutes.

Unbiased interrogation of memory B cells from convalescent COVID-19 patients reveals a broad antiviral humoral response targeting SARS-CoV-2 antigens beyond the spike protein

Patients who recover from SARS-CoV-2 infections produce antibodies and antigen-specific T cells against multiple viral proteins. Here, an unbiased interrogation of the anti-viral memory B cell repertoire of convalescent patients has been performed by generating large, stable hybridoma libraries and screening thousands of monoclonal antibodies to identify specific, high-affinity immunoglobulins (Igs) directed at distinct viral components. As expected, a significant number of antibodies were directed at the Spike (S) protein, a majority of which recognized the full-length protein. These full-length Spike specific antibodies included a group of somatically hypermutated IgMs. Further, all but one of the six COVID-19 convalescent patients produced class-switched antibodies to a soluble form of the receptor-binding domain (RBD) of S protein. Functional properties of anti-Spike antibodies were confirmed in a pseudovirus neutralization assay. Importantly, more than half of all of the antibodies generated were directed at non-S viral proteins, including structural nucleocapsid (N) and membrane (M) proteins, as well as auxiliary open reading frame-encoded (ORF) proteins. The antibodies were generally characterized as having variable levels of somatic hypermutations (SHM) in all Ig classes and sub-types, and a diversity of VL and VH gene usage. These findings demonstrated that an unbiased, function-based approach towards interrogating the COVID-19 patient memory B cell response may have distinct advantages relative to genomics-based approaches when identifying highly effective anti-viral antibodies directed at SARS-CoV-2.

[Endometrial receptivity in assisted reproductive techniques: An aspect to investigate in embryo implantation failure]. / La réceptivité endométriale en aide médicale à la procréation : Une piste à ne pas oublier devant un échec d'implantation.

Infertility affects between 8 and 12% of reproductive-age couples worldwide. Despite improvements in assisted reproductive techniques (ART), live birth rates are still limited. In clinical practice, imaging and microscopy are currently widely used, but their diagnostic effectiveness remains limited. In research, the emergence of innovative techniques named OMICS would improve the identification of the implantation window, while progressing in the understanding of the pathophysiological mechanisms involved in embryo implantation failures. To date, transcriptomic analysis seems to be the most promising approach in clinical research. The objective of this review is to present the results obtained with the different approaches available in clinical practice and in research to assess endometrial receptivity in patients undergoing ART.

Efficacy and safety of rituximab in myasthenia gravis: a French multicentre real-life study.

BACKGROUND AND PURPOSE: Fifteen percent of patients with myasthenia gravis (MG) are refractory to conventional treatment. Case reports and a few studies show probable benefit of rituximab in these cases. Our objective was to assess the efficacy and the safety of rituximab in patients with MG, in a multicentric real-life study. METHOD: Inclusion criteria were: age > 18 years; MG with anti-acetylcholine receptor (AChR) antibodies, anti-muscle-specific kinase (MuSk) antibodies or significant decrement after repetitive nerve stimulation; Myasthenia Gravis Foundation of America (MGFA) class >II; refractory or steroid-dependent MG; and treatment with rituximab. Efficacy was assessed at 6 months using the MGFA-post-intervention status (PIS) score, the myasthenic muscle score (MMS) and the number of patients receiving steroids <10 mg/day. Data on adverse events were collected. RESULTS: Twenty-nine patients were included: 20 with anti-AChR MG, five with anti-MuSK MG and four with seronegative MG. MGFA-PIS score was improved or better (improved, minimal manifestations or remission) in 86.2% of patients after 6 months of treatment (P < 0.0001). The mean MMS increased from 68.8 to 83.1 (P < 0.0001). A decrease in steroid dosage (<10 mg/day) was effective in 57.9% of treated patients. In all, 42.8% of patients experienced adverse events: infections (21.4% of patients); infusion reaction (7%); bradycardia (3.7%); and cytopenia (7%). CONCLUSION: The present study demonstrates the efficacy and safety of rituximab in patients with MG. Additional studies remain necessary to determine the role of rituximab in the pharmacopeia of MG treatment and to establish precise recommendations for the infusion protocol.

Prevalence of dental anomalies in French orthodontic patients: A retrospective study.

OBJECTIVES: To investigate the prevalence and gender distributions of dental anomalies in French orthodontic patients. MATERIAL AND METHODS: A retrospective review of the dental files of orthodontic patients was conducted to investigate the frequencies of dental anomalies. Pretreatment intraoral photographs and panoramic radiographs were analyzed. The occurrence rates of various dental anomalies (as determined by the numbers, shapes, structures, exfoliations, and eruptions of teeth) were calculated as percentages and differences in gender distribution using Chi2 and Fisher tests. RESULTS: Five hundred fifty-one patients receiving orthodontic treatment between 2003 and 2013 at a French hospital were included in the study: 45.74% of the patients (n=252) presented at least one dental anomaly. Taurodontism was the most common (15.06%), followed by ectopic eruption (11.43%). Odontoma, macrodontia, fusion, gemination, talon cusp, dentinogenesis imperfecta, regional odontodysplasia, premature tooth eruption, and premature exfoliation were not found. No statistically significant correlations were found between gender and the occurrence of dental anomalies. CONCLUSION: French orthodontic patients exhibit a high rate of dental anomalies, indicating that dental anomalies should be carefully considered in the orodental management of French patients.

Effects of dietary supplementation with a mixed blueberry and grape extract on working memory in aged beagle dogs.

Cellular oxidative damage is thought to be one of the key mechanisms underlying age-related cognitive impairment in dogs. Several nutritional interventions to limit cognitive decline are reported in the literature. To our knowledge, the association of grape and blueberry extracts has never been tested in aged dogs. Our objective was to evaluate the effect of a polyphenol-rich extract from grape and blueberry (PEGB) on oxidative status and cognitive performances in aged dogs. A total of thirty-five beagle dogs (aged 8·0-14·5 years) were fed a basal diet with PEGB at either 0 parts per million (ppm) (n 11; control), 240 ppm (n 12; PEGB1) or 480 ppm (n 12; PEGB2) for 75 d. To investigate the effects of PEGB supplementation on cognition and oxidative status, a delayed non-matching to position (DNMP) test and RT-PCR on genes involved in oxidative stress were evaluated. The dogs fed PEGB1 showed a higher superoxide dismutase mRNA expression compared with dogs fed PEGB2 (P = 0·042) and with the control group (P = 0·014). Moreover, the dogs fed PEGB2 showed higher nuclear factor-like 2 (Nrf2) mRNA expression compared with the dogs fed PEGB1 (P = 0·027). Concerning the DNMP test, the proportion of dogs showing cognitive improvements relative to their baseline level was significantly higher in dogs fed the PEGB, regardless of the dosage, than in dogs receiving no supplementation (P = 0·030). The results obtained in the DNMP test suggested a potential benefit of the PEGB on working memory. However, this hypothesis should be further investigated to confirm this cognitive effect.

Properties of particle phases for metal-matrix-composite design.

Successful metallurgical design of metal-matrix-composites relies on the knowledge of the intrinsic property profiles of the metal matrix and especially the compounds employed for particles, whiskers or fibres. In this work we compiled the key properties melting point, bulk modulus, shear modulus, Young׳s modulus, density, hardness, Poisson׳s ratio and structure/space group from the widespread literature data for the most relevant compound types, i.e. borides, carbo-borides, carbides, oxides, nitrides and intermetallic phases.

Stiff, light, strong and ductile: nano-structured High Modulus Steel.

Structural material development for lightweight applications aims at improving the key parameters strength, stiffness and ductility at low density, but these properties are typically mutually exclusive. Here we present how we overcome this trade-off with a new class of nano-structured steel - TiB2 composites synthesised in-situ via bulk metallurgical spray-forming. Owing to the nano-sized dispersion of the TiB2 particles of extreme stiffness and low density - obtained by the in-situ formation with rapid solidification kinetics - the new material has the mechanical performance of advanced high strength steels, and a 25% higher stiffness/density ratio than any of the currently used high strength steels, aluminium, magnesium and titanium alloys. This renders this High Modulus Steel the first density-reduced, high stiffness, high strength and yet ductile material which can be produced on an industrial scale. Also ideally suited for 3D printing technology, this material addresses all key requirements for high performance and cost effective lightweight design.

Genome-Wide Association Study of Acute Renal Graft Rejection.

Acute renal rejection is a major risk factor for chronic allograft dysfunction and long-term graft loss. We performed a genome-wide association study to detect loci associated with biopsy-proven acute T cell-mediated rejection occurring in the first year after renal transplantation. In a discovery cohort of 4127 European renal allograft recipients transplanted in eight European centers, we used a DNA pooling approach to compare 275 cases and 503 controls. In an independent replication cohort of 2765 patients transplanted in two European countries, we identified 313 cases and 531 controls, in whom we genotyped individually the most significant single nucleotide polymorphisms (SNPs) from the discovery cohort. In the discovery cohort, we found five candidate loci tagged by a number of contiguous SNPs (more than five) that was never reached in iterative in silico permutations of our experimental data. In the replication cohort, two loci remained significantly associated with acute rejection in both univariate and multivariate analysis. One locus encompasses PTPRO, coding for a receptor-type tyrosine kinase essential for B cell receptor signaling. The other locus involves ciliary gene CCDC67, in line with the emerging concept of a shared building design between the immune synapse and the primary cilium.

Marine phospholipids: The current understanding of their oxidation mechanisms and potential uses for food fortification.

There is a growing interest in using marine phospholipids (PL) as ingredient for food fortification due to their numerous health benefits. However, the use of marine PL for food fortification is a challenge due to the complex nature of the degradation products that are formed during the handling and storage of marine PL. For example, nonenzymatic browning reactions may occur between lipid oxidation products and primary amine group from phosphatidylethanolamine or amino acid residues that are present in marine PL. Therefore, marine PL contain products from nonenzymatic browning and lipid oxidation reactions, namely, Strecker aldehydes, pyrroles, oxypolymers, and other impurities that may positively or negatively affect the oxidative stability and quality of marine PL. This review was undertaken to provide the industry and academia with an overview of the current understanding of the quality changes taking place in PL during their production and their storage as well as with regards to their utilization for food fortification.

Family physicians and HIV infection.

OBJECTIVE: We aimed to describe the current and desired involvement of family physicians (FPs) in the treatment of HIV patients (screening practices, potential training and patient follow-up) to reduce the duration and frequency of their hospital treatment. MATERIAL AND METHODS: We conducted a descriptive cross-sectional survey between 2011 and 2012 with the support of COREVIH (Regional Coordinating Committee on HIV). We sent a self-assessment questionnaire to all FPs of the Pays de la Loire region to enquire about their HIV screening practices and expectations for the management of HIV patients. RESULTS: A total of 871 FPs completed the questionnaire (response rate: 30.4%). A total of 54.2% said to provide care to HIV patients; the mean number of HIV patients per FP was estimated at 1.4. With regard to HIV screening, 12.2% systematically suggest an HIV serology to their patients and 72.7% always suggest it to pregnant women. About 45.4% of responding FPs said to be willing to manage HIV patients (clinical and biological monitoring, compliance checks and prescription renewal). FPs mainly reported the lack of training and the low number of HIV patients as a barrier to their further involvement in the management of HIV patients. CONCLUSION: The responding FPs provide care to very few HIV patients. They are, however, willing to be more involved in the routine care of these patients. Medical training provided by COREVIH would help improve HIV screening. The management of HIV patients could thus be handed over to willing FPs.

Analysis of protein carbonylation--pitfalls and promise in commonly used methods.

Oxidation of proteins has received a lot of attention in the last decades due to the fact that they have been shown to accumulate and to be implicated in the progression and the pathophysiology of several diseases such as Alzheimer, coronary heart diseases, etc. This has also resulted in the fact that research scientists are becoming more eager to be able to measure accurately the level of oxidized protein in biological materials, and to determine the precise site of the oxidative attack on the protein, in order to get insights into the molecular mechanisms involved in the progression of diseases. Several methods for measuring protein carbonylation have been implemented in different laboratories around the world. However, to date no methods prevail as the most accurate, reliable, and robust. The present paper aims at giving an overview of the common methods used to determine protein carbonylation in biological material as well as to highlight the limitations and the potential. The ultimate goal is to give quick tips for a rapid decision making when a method has to be selected and taking into consideration the advantage and drawback of the methods.