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A novel organic–inorganic hybrid, based on SiO2-CaO-ZnO bioactive glass (BG) and polycaprolactone (PCL), associating the highly bioactive and versatile bioactive glass with clinically established PCL was examined. The BG–PCL hybrid is obtained by acid-catalyzed silica sol–gel process inside PCL solution either by direct or indirect printing. Apatite-formation tests in simulated body fluid (SBF) confirm the ion release along with the hybrid’s bone-like apatite forming. Kinetics differ significantly between directly and indirectly printed scaffolds, the former requiring longer periods to degrade, while the latter demonstrates faster calcium phosphate (CaP) formation. Remarkably, Zn diffusion and accumulation are observed at the surface within the newly formed active CaP layer. Zn release is found to be dependent on printing method and immersion medium. Investigation of BG at the atomic scale reveals the ambivalent role of Zn, capable of acting both as a network modifier and as a network former linking the BG silicate network. In addition, hMSCs viability assay proves no cytotoxicity of the Zn hybrid. LIVE/DEAD staining demonstrated excellent cell viability and proliferation for over seven weeks. Overall, this hybrid material either non-doped or doped with a metal trace element is a promising candidate to be translated to clinical applications for bone regeneration.

The feasibility of a newly developed augmentation of ventral fixation technique for surgical stabilization of atlantoaxial instability was clinically evaluated in a cohort of eleven dogs, and long-term clinical outcomes were retrospectively analyzed. The new technique combines wire/suture fixation through a transverse hole in the axis anchored by two screws placed in the alae atlantis or at the cranial end of plates used to bridge the atlantoaxial joint ventrally. A previous biomechanical study demonstrated good stability of this technique during shear loading, comparable to the stability achieved with other standard techniques. Ten dogs improved clinically after surgery and returned to a normal life within 3–6 months of surgery. One dog developed aphonia, dysphagia, and died of aspiration pneumonia three days after surgery. The augmentation of conventional ventral atlantoaxial fixation with the transverse bony corridor of the proximal axis body may be a valuable way to enhance stabilization of the atlantoaxial joint.

Critical bone defect repair remains a major medical challenge. Developing biocompatible materials with bone-healing ability is a key field of research, and calcium-deficient apatites (CDA) are appealing bioactive candidates. We previously described a method to cover activated carbon cloths (ACC) with CDA or strontium-doped CDA coatings to generate bone patches. Our previous study in rats revealed that apposition of ACC or ACC/CDA patches on cortical bone defects accelerated bone repair in the short term. This study aimed to analyze in the medium term the reconstruction of cortical bone in the presence of ACC/CDA or ACC/10Sr-CDA patches corresponding to 6 at.% of strontium substitution. It also aimed to examine the behavior of these cloths in the medium and long term, in situ and at distance. Our results at day 26 confirm the particular efficacy of strontium-doped patches on bone reconstruction, leading to new thick bone with high bone quality as quantified by Raman microspectroscopy. At 6 months the biocompatibility and complete osteointegration of these carbon cloths and the absence of micrometric carbon debris, either out of the implantation site or within peripheral organs, was confirmed. These results demonstrate that these composite carbon patches are promising biomaterials to accelerate bone reconstruction.

Purpose: The classic heuristic miner algorithm has received lots of attention in the healthcare sector for discovering patient pathways. The extraction of these pathways provides more transparency about patient activities. The previous versions of this algorithm receive an event log and discover several process models by using manually adjustable thresholds. Then, the expert is left with the difficult task of deciding which discovered model can serve as the descriptive reference process model. Such a decision is completely arbitrary and it has been seen as a major structural issue in the literature of process mining. This paper tackles this problem by proposing a new process discovery algorithm to facilitate patient pathways diagnosis.Approach: To address this scientific challenge, this paper proposes to consider the statistical stability phenomenon in an event log, and it introduces the stable heuristic miner algorithm as its contribution. To evaluate the applicability of the proposed algorithm, a case study has been presented to monitor patient pathways in a medical consultation platform.Originality: Thanks to this algorithm, the value of thresholds will be automatically calculated at the statistically stable limits. Hence, instead of several models, only one process model will be discovered. To the best of our knowledge, applying the statistical stability phenomenon in the context of process mining to discover a reference process model from location event logs has not been addressed before.Findings/Practical implications: The results enabled to remove the uncertainty to determine the threshold that represents the common patient pathways and consequently, leaving some room for potential diagnosis of the pathways.

Two-component regulatory systems (TCS) are among the most widespread mechanisms that bacteria use to sense and respond to environmental changes. In the human pathogen Streptococcus pneumoniae, a total of 13 TCS have been identified and many of them have been linked to pathogenicity. Notably, TCS01 strongly contributes to pneumococcal virulence in several infection models. However, it remains one of the least studied TCS in pneumococci and its functional role is still unclear. In this study, we demonstrate that TCS01 cooperates with a BceAB-type ABC transporter to sense and induce resistance to structurally-unrelated antimicrobial peptides of bacterial origin that all target undecaprenyl-pyrophosphate or lipid II, which are essential precursors of cell wall biosynthesis. Even though tcs01 and bceAB genes do not locate in the same gene cluster, disruption of either of them equally sensitized the bacterium to the same set of antimicrobial peptides. We show that the key function of TCS01 is to upregulate the expression of the transporter, while the latter appears the main actor in resistance. Electrophoretic mobility shift assays further demonstrated that the response regulator of TCS01 binds to the promoter region of the bceAB genes, implying a direct control of these genes. The BceAB transporter was overexpressed and purified from E. coli. After reconstitution in liposomes, it displayed substantial ATPase and GTPase activities that were stimulated by antimicrobial peptides to which it confers resistance to, revealing new functional features of a BceAB-type transporter. Altogether, this inducible defense mechanism likely contributes to the survival of the opportunistic microorganism in the human host, in which competition among commensal microorganisms is a key determinant for effective host colonization and invasive path.

In an effort to reduce CO2emissions, many countries throughout the world are initiating plans to transition to more sustainable forms of energy. Nuclear energy would appear to be a powerful contender to replace fossil fuels, or at least be an unavoidable option, from an energy-mix perspective. However, nuclear energy suffers from a poor image among certain populations, especially the young, who favor the development of renewable energies. We wanted to get a more accurate read of what was happening in France, one of the most nuclearized countries in the world, where the share of nuclear energy is greater than 70%. Since plans are underway to reduce this level to 50% by 2035, understanding popular perceptions on this matter is even more important. In order to gain a better understanding, we interviewed an “expert” population and compared the results obtained with a so-called young “non-expert” student population. The first group is composed of firefighters, about half of whom have attended training in radiological risks, and the other, a non-expert population, composed of students from Université Côte d’Azur (UCA), who are potentially influenced (for better or worse) by social media. The aim of this study is to compare and contrast any differences in perception that these two distinct populations may have on the subject of nuclear energy.

Abstract Background Reports of osteoblastic tumours are limited to a few case reports in veterinary medicine. Osteoblastoma-like osteosarcoma has been accepted by the World Health Organization as an intermediate form between an osteosarcoma and osteoblastoma. This type of tumour indicates an osteosarcoma, that may resemble osteoblastoma clinically, histologically, and radiologically and have the capability for metastasis. Osteoblastoma-like osteosarcoma has not been described in veterinary medicine so far. Case presentation An eight-year old cat was presented due to progressive ataxia and paraparesis of the pelvic limbs. Imaging confirmed a well-defined, extradural mass originating from the spinous process of the second thoracic vertebra (T2) leading to severe compression of the spinal cord. Decompressive cytoreduction was achieved by removal of the mass after dorsal laminectomy of T1. After recovering from an acute worsening 3.5 weeks after surgery, the cat had an improved neurological status and the dorsal compression was resolved at follow-up 8 months later. A focal contrast enhancing lesion was still evident at the base of T2 spinous process and lung metastasis was additionally suspected. Based on histopathological, radiographic, and clinical features, an “osteoblastoma-like osteosarcoma” was suspected. Conclusions To the best of our knowledge, this is the first description of this tumour in veterinary medicine. In addition, this case report highlights the difficulty in the diagnosis and definition of osseous neoplasia in cats and provides a literature review.

rsEGFP2 is a reversibly photoswitchable fluorescent protein used in super-resolution light microscopy. Here the authors present the structure of an rsEGFP2 ground-state intermediate after excited state-decay that was obtained by nanosecond time-resolved serial femtosecond crystallography at an X-ray free electron laser, and time-resolved absorption spectroscopy measurements complement their structural analysis.

The aim of the present study was to evaluate the use of a novel intraoperative cone-beam computed tomography (CBCT)-based automated registration system for frameless stereotactic brain biopsy in companion animals. An experimental cadaveric study evaluated thalamic and piriform lobe target site needle placement error in three dogs and three cats without a history of intracranial disease. Diagnostic accuracy and diagnostic yield were prospectively evaluated in twenty-four client-owned dogs and four cats with intracranial disease. Twenty-one procedures were performed post mortem (eighteen dogs and three cats), and seven biopsy procedures were performed in alive patients (six dogs and one cat). Procedural duration was evaluated in ten post mortem and four living patients. Outcome was evaluated in six dogs and one cat. In dogs, the calculated median needle placement error was 1.8 mm (range 0.71–2.84 mm) and 1.53 mm (range 1.45–1.99 mm) for piriform lobe and thalamus target sites, respectively. In cats, the calculated median needle placement error was 0.79 mm (range 0.6–1.91 mm) for the piriform lobe target site and 1.29 mm (range 0.47–2.69 mm) for the thalamic target site. The diagnostic yield was 96.4% (95% CI 0.81–0.99), the diagnostic accuracy was 94.4% (95% CI 0.72–0.99). Median total procedural duration for post mortem biopsies was 57.5 min (range 41–69 min). Median total procedural duration for intra vitam biopsies was 122.5 min (range 103–136 min). Three dogs were discharged 1 day after biopsy and one dog after 6 days. Two dogs and one cat were euthanized 24 and 48 h after biopsy. Intraoperative CBCT-based automated image registration for frameless stereotactic biopsies in companion animals is capable of providing diagnostic brain biopsy specimens independent of skull size and morphology with diagnostic yield and accuracy comparable to published values for diverse frameless and frame-based stereotaxy systems used in veterinary medicine. Duration of the procedure is not negatively affected and within the published range with other systems. Mobile intraoperative CBCT-based registration combined with neuronavigation delivers diagnostic brain biopsies in companion animals.

Cancer is the leading cause of death in dogs, yet there are no established screening paradigms for early detection. Liquid biopsy methods that interrogate cancer-derived genomic alterations in cell-free DNA in blood are being adopted for multi-cancer early detection in human medicine and are now available for veterinary use. The CANcer Detection in Dogs (CANDiD) study is an international, multi-center clinical study designed to validate the performance of a novel multi-cancer early detection “liquid biopsy” test developed for noninvasive detection and characterization of cancer in dogs using next-generation sequencing (NGS) of blood-derived DNA; study results are reported here. In total, 1,358 cancer-diagnosed and presumably cancer-free dogs were enrolled in the study, representing the range of breeds, weights, ages, and cancer types seen in routine clinical practice; 1,100 subjects met inclusion criteria for analysis and were used in the validation of the test. Overall, the liquid biopsy test demonstrated a 54.7% (95% CI: 49.3–60.0%) sensitivity and a 98.5% (95% CI: 97.0–99.3%) specificity. For three of the most aggressive canine cancers (lymphoma, hemangiosarcoma, osteosarcoma), the detection rate was 85.4% (95% CI: 78.4–90.9%); and for eight of the most common canine cancers (lymphoma, hemangiosarcoma, osteosarcoma, soft tissue sarcoma, mast cell tumor, mammary gland carcinoma, anal sac adenocarcinoma, malignant melanoma), the detection rate was 61.9% (95% CI: 55.3–68.1%). The test detected cancer signal in patients representing 30 distinct cancer types and provided a Cancer Signal Origin prediction for a subset of patients with hematological malignancies. Furthermore, the test accurately detected cancer signal in four presumably cancer-free subjects before the onset of clinical signs, further supporting the utility of liquid biopsy as an early detection test. Taken together, these findings demonstrate that NGS-based liquid biopsy can offer a novel option for noninvasive multi-cancer detection in dogs.

Polymorphism has long been recognized as a crucial dimension of the nature of language. One of the merits of dialectology and dialectologists is emphasis on the inherently variable and polymorphic nature of linguistic systems, which are always in a state of relative equilibrium and stability. The most striking features of the Occitan data that will be discussed lies in the possibility of finding various forms in a given cell in certain paradigms; more strikingly, it will be shown that two or three (even four) paradigms for one and the same (tense) verb may coexist in the same variety. It will be argued that if polymorphism is the natural state of linguistic systems, it is also anti-economic from a cognitive and processing point of view. It follows that the diachronic evolution of languages tends to develop adaptive solutions to circumvent the potential drawbacks of extreme polymorphism: “natural selection” leads to the reduction or elimination of morphological proliferation. Of course, before reduction or elimination take place, a more or less extended period of time may elapse during which a preference for some paradigmatic options may arise.

Neospora caninum is an apicomplexan parasite that causes abortion and stillbirth in cattle. We employed the pregnant neosporosis mouse model to investigate the efficacy of a modified version of the attenuated Listeria monocytogenes vaccine vector Lm3Dx_NcSAG1, which expresses the major N. caninum surface antigen SAG1. Multivalent vaccines were generated by the insertion of gra7 and/or rop2 genes into Lm3Dx_NcSAG1, resulting in the double mutants, Lm3Dx_NcSAG1_NcGRA7 and Lm3Dx_NcSAG1_NcROP2, and the triple mutant, Lm3Dx_NcSAG1_NcGRA7_NcROP2. Six experimental groups of female BALB/c mice were inoculated intramuscularly three times at two-week intervals with 1 × 107 CFU of the respective vaccine strains. Seven days post-mating, mice were challenged by the subcutaneous injection of 1 × 105N. caninum NcSpain-7 tachyzoites. Non-pregnant mice, dams and their offspring were observed daily until day 25 post-partum. Immunization with Lm3Dx_NcSAG1 and Lm3Dx_NcSAG1_NcGRA7_NcROP2 resulted in 70% postnatal pup survival, whereas only 50% and 58% of pups survived in the double mutant-vaccinated groups. Almost all pups had died at the end of the experiment in the infection control. The triple mutant was the most promising vaccine candidate, providing the highest rate of protection against vertical transmission (65%) and CNS infection. Overall, integrating multiple antigens into Lm3Dx_SAG1 resulted in lower vertical transmission and enhanced protection against cerebral infection in dams and in non-pregnant mice.

Objective: To objectively assess the cervical paraspinal musculature of French bulldogs (FBs) using computed tomography (CT) scan-based measurements, outline differences in other breeds published in the literature, and investigate the potential influence of its cervical paraspinal musculature on predisposed sites for intervertebral disk disease.Animals: Thirty FBs that underwent CT scans of the cervical spine from the skull to C7/T1 were enrolled. Fifteen dogs were patients suffering from intervertebral disk herniation (IVDH group), and 15 dogs underwent CT scans due to brachycephalic obstructive airway syndrome (BOAS group).Methods: At the level of each cervical intervertebral disk from C2/C3 to C7/T1, measurements were performed and statistically analyzed. On the sagittal CT scan reconstruction, the height ratio of the dorsal to ventral paraspinal musculature and the angle of the disk axis to vertebral body length were assessed. On the transverse plane, the area ratio of the dorsal and ventral paraspinal musculature and the ratio of force moments were determined at each intervertebral disk level. Finally, ratios were compared to the values of Labrador retrievers and dachshunds published by Hartmann et al. (1).Results: Comparing the two FB groups, one significant difference was detected in the mean height ratio of the dorsal to ventral paraspinal musculature at the level of C5/C6 (P = 0.0092) and C6/C7 (P = 0.0076), with IVDH FBs having the more prominent dorsal paraspinal musculature. At the level of C3/C4, a significantly less prominent dorsal paraspinal musculature in FBs than in dachshunds (P = 0.0058) and a significantly steeper disk to vertebral body angulation were observed (P = 0.0005).Conclusion: Although some incidental differences were found, most parameters did not significantly differ between the BOAS and IVDH FBs. Significant conformational differences in the cervical paraspinal musculature and disk to vertebral body length angulation were found between FBs and two other breeds (chondrodystrophic and non-chondrodystrophic). This study's findings suggest that the paraspinal musculature is an additional biomechanical influencing factor on the preferential sites of IVDH in the cervical spine and that other major factors exist in IVDH development, especially in FBs.

Virus-like particles constitute versatile vectors that can be used as vaccine platforms in many fields from infectiology and more recently to oncology. We previously designed non-infectious adenovirus-inspired 60-mer dodecahedric virus-like particles named ADDomers displaying on their surface either a short epitope or a large tumor/viral antigen. In this work, we explored for the first time the immunogenicity of ADDomers exhibiting melanoma-derived tumor antigen/epitope and their impact on the features of human dendritic cell (DC) subsets. We first demonstrated that ADDomers displaying tumor epitope/antigen elicit a strong immune-stimulating potential of human DC subsets (cDC2s, cDC1s, pDCs), which were able to internalize and cross-present tumor antigen, and subsequently cross-prime antigen-specific T-cell responses. To further limit off-target effects and enhance DC targeting, we engineered specific motifs to de-target epithelial cells and improve DCs’ addressing. The improved engineered platform making it possible to display large antigen represents a tool to overcome the barrier of immune allele restriction, broadening the immune response, and paving the way to its potential utilization in humans as an off-the-shelf vaccine.

Hepatic surgeries are often performed in cats to obtain a disease diagnosis, for the removal of masses, or for the treatment of shunts. Whereas the vascular anatomy of the liver has been studied in dogs, such evidence is lacking in cats. The current study used corrosion casts of portal and hepatic veins and computed tomography (CT) analysis of the casts to identify and describe the intrahepatic anatomy in healthy cat livers (n = 7). The results showed that feline livers had a consistent intrahepatic portal and venous anatomy, with only minor disparities in the numbers of secondary and tertiary branches. The feline portal vein consistently divided into two major branches and not three, as previously described in the literature for cats. The finding of a portal vein originating from the right medial lobe branch leading to the quadrate lobe in 4/7 specimens is a novelty of the feline anatomy that was not previously described in dogs. Partial to complete fusion of the caudate process of the caudate and the right lateral lobe, with a lack of clear venous separation between the lobes, was present in two specimens. These findings allowed a detailed description of the most common intrahepatic venous patterns in cats. Further anatomical studies should be encouraged to confirm the present findings and to investigate the utility of this information in surgical settings.

Listeria monocytogenes (LM) has been proposed as vaccine vector in various cancers and infectious diseases since LM induces a strong immune response. In this study, we developed a novel and safe LM-based vaccine vector platform, by engineering a triple attenuated mutant (Lm3Dx) (ΔactA, ΔinlA, ΔinlB) of the wild-type LM strain JF5203 (CC 1, phylogenetic lineage I). We demonstrated the strong attenuation of Lm3Dx while maintaining its capacity to selectively infect antigen-presenting cells (APCs) in vitro. Furthermore, as proof of concept, we introduced the immunodominant Neospora caninum (Nc) surface antigen NcSAG1 into Lm3Dx. The NcSAG1 protein was expressed by Lm3Dx_SAG1 during cellular infection. To demonstrate safety of Lm3Dx_SAG1 in vivo, we vaccinated BALB/C mice by intramuscular injection. Following vaccination, mice did not suffer any adverse effects and only sporadically shed bacteria at very low levels in the feces (

Abstract Background Serum thymidine kinase 1 (sTK1) activity is closely correlated with DNA synthesis. Objectives Evaluate sTK1 activity as a biomarker for treatment response and early detection of relapse in dogs with lymphoma. Animals Ninety‐seven client‐owned dogs with naive or relapsed lymphoma and 23 healthy dogs. Methods Prospective study. Serum TK1 activity measured by refined ELISA‐based method (DiviTum assay, Biovica International) before treatment, at clinical response, and every 4 weeks until relapse or last follow‐up. Results Serum TK1 activity was ≤20 Du/L in 96% (22/23) of healthy dogs. Pretreatment sTK1 activity was >20 Du/L in 88% (85/97) dogs with lymphoma. At clinical response, sTK1 activity was significantly lower in dogs with complete (CR, n = 36) versus partial (PR, n = 29) response (P 2.7‐fold value measured at clinical response) predicted relapse at subsequent 4‐week assessment with a Se 61% and Sp 88% (AUC, 0.79; 95%‐CI, 0.64‐0.95; P = .004). Conclusions and Clinical Importance Monitoring sTK1 activity could help to detect complete responders and early disease progression in dogs with lymphoma.

The efficient spread of SARS-CoV-2 resulted in a unique pandemic in modern history. Despite early identification of ACE2 as the receptor for viral spike protein, much remains to be understood about the molecular events behind viral dissemination. We evaluated the contribution of C-type lectin receptors (CLRS) of antigen-presenting cells, widely present in respiratory mucosa and lung tissue. DC-SIGN, L-SIGN, Langerin and MGL bind to diverse glycans of the spike using multiple interaction areas. Using pseudovirus and cells derived from monocytes or T-lymphocytes, we demonstrate that while virus capture by the CLRs examined does not allow direct cell infection, DC/L-SIGN, among these receptors, promote virus transfer to permissive ACE2+ Vero E6 cells. A glycomimetic compound designed against DC-SIGN, enable inhibition of this process. These data have been then confirmed using authentic SARS-CoV-2 virus and human respiratory cell lines. Thus, we described a mechanism potentiating viral spreading of infection.