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Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder of the autonomic nervous system resulting in decreased brain sensitivity to hypercapnia and hypoxia characterized by a genetic abnormality in the pair-like homeobox 2B (PHOX2B) gene. Most patients have a heterozygous expansion of the polyalanine repeat in exon 3 (PARM), while 10 % of patients have non-PARM (NPARM) mutations that can span the entire gene. The majority of pathogenic variants are de novo, but variants with incomplete penetrance can be identified in the heterozygous state. In the present report, CCHS was diagnosed in a symptomatic 3-month-old infant with neonatal respiratory distress. Genetic analysis revealed a new mutation in exon 1 of the PHOX2B gene - p.Ser28* (c.83C>G) - which was further identified in two family members, one minimally symptomatic and one asymptomatic. The identification of this new mutation supports the importance of sequencing the entire gene even when the classic PARM mutation is not found and highlights the phenotypic variability of CCHS., Competing Interests: Declaration of competing interest There is no financial support and no conflict of interest to declare for all the authors., (Copyright © 2024 Société française de pédiatrie. Published by Elsevier Masson SAS. All rights reserved.)

Pathogens such as bacteria, fungi and viruses are important components of soil and aquatic communities, where they can benefit from decaying and living organic matter, and may opportunistically infect human and animal hosts. One-third of human infectious diseases is constituted by sapronotic disease agents that are natural inhabitants of soil or aquatic ecosystems. They are capable of existing and reproducing in the environment outside of the host for extended periods of time. However, as ecological research on sapronosis is infrequent and epidemiological models are even rarer, very little information is currently available. Their importance is overlooked in medical and veterinary research, as well as the relationships between free environmental forms and those that are pathogenic. Here, using dynamical models in realistic aquatic metacommunity systems, we analyze sapronosis transmission, using the human pathogen Mycobacterium ulcerans that is responsible for Buruli ulcer. We show that the persistence of bacilli in aquatic ecosystems is driven by a seasonal upstream supply, and that the attachment and development of cells to aquatic living forms is essential for such pathogen persistence and population dynamics. Our work constitutes the first set of metacommunity models of sapronotic disease transmission, and is highly flexible for adaptation to other types of sapronosis. The importance of sapronotic agents on animal and human disease burden needs better understanding and new models of sapronosis disease ecology to guide the management and prevention of this important group of pathogens., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Nanomedicines have created a paradigm shift in healthcare. Yet fundamental barriers still exist that prevent or delay the clinical translation of nanomedicines. Critical hurdles inhibiting clinical success include poor understanding of nanomedicines' physicochemical properties, limited exposure in the cell or tissue of interest, poor reproducibility of preclinical outcomes in clinical trials, and biocompatibility concerns. Barriers that delay translation include industrial scale-up or scale-down and good manufacturing practices, funding and navigating the regulatory environment. Here we propose the DELIVER framework comprising the core principles to be realized during preclinical development to promote clinical investigation of nanomedicines. The proposed framework comes with design, experimental, manufacturing, preclinical, clinical, regulatory and business considerations, which we recommend investigators to carefully review during early-stage nanomedicine design and development to mitigate risk and enable timely clinical success. By reducing development time and clinical trial failure, it is envisaged that this framework will help accelerate the clinical translation and maximize the impact of nanomedicines., (© 2024. Springer Nature Limited.)

Carbyne free radicals RC⋮ (RC) are usually associated with high-energy processes, thus research on their preparation, chemical reactivity, and prevalence under mild conditions is scarce. Recently, it was reported that metallo-complexes containing CR ligands may undergo spontaneous degradation in aqueous solutions to produce free RC radicals. These highly reactive species may react with each other to form the corresponding alkyne and other products. The reaction of 1,1,1 halo-carbo-hydrates with Cr(II) ions also forms RC radicals under mild conditions. Herein, we report two additional synthetic routes that produce free RC radicals under mild conditions. First, the reaction between metallic zinc and acetic anhydride produces 2-butyne and several other C2, C3, and C4 compounds. Isotopic-labeling experiments indicate that the formation of 2-butyne results from an inter-molecular reaction in which two RC moieties from two acetic anhydride molecules combine in solution. In addition, the degradation of the tri-molybdenum complex [Mo3(H3CC≡CCH3)(OAc)(H2O)2Br7], in which a 2-butyne ligand is coordinated to the Mo3 framework in a μ3-η2 (⊥) binding mode in aqueous solution produces several C2, C3, C4 and C5 molecules. This indicates the formation of free CH3C radicals by a homolytic cleavage of the carbon-carbon triple bond., (© 2024 Wiley‐VCH GmbH.)

Foot-and-mouth disease (FMD) is an important endemic disease in livestock in Southeast Asia. Transboundary movement of animals may result in the transnational disease spread. A major cattle market is located at the Thailand-Myanmar border, where most cattle imported from Myanmar are traded. In this study, we built a stochastic susceptible-exposed-infectious-recovered (SEIR) model to investigate the effectiveness of a private animal quarantine service center in preventing FMDV from entering the major cattle market. We computed with different parameters and found that, with 50 % vaccine effectiveness, the risk of releasing infected cattle to the market per batch was generally low during the quarantine period of 21 and 28 days, with the risk ranging from 0.071 to 0.078 and 0.032 to 0.036, respectively. Despite the best scenario, the zero-risk state is difficult to attain. The sensitivity analysis highlights that the percentage of immune animals before entering the quarantine centers and the vaccine effectiveness are important factors. In conclusion, the 21-day quarantine period mitigates the risk of FMDV introduction into the cattle market. This control measure should be rigorously maintained to sustainably prevent FMDV outbreaks through transboundary animal movements, especially among countries in FMD-endemic regions., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Electrochemotherapy (ECT) with intravenous (IV) and/or intratumoral (IT) bleomycin has shown considerable efficacy in the treatment of non-resectable feline cutaneous squamous cell carcinoma (cSCC), boasting response rates of up to 95%, but other chemotherapy protocols have not yet been investigated. The objective of this prospective multicentre study was to compare the overall response rate (ORR) and progression-free interval (PFI) between cats with cSCC treated with ECT using IT and IV carboplatin (IV + IT), IV carboplatin (IV) or IV bleomycin (IV). A total of 44 cats with unresectable cSCC across three centres were enrolled and treated with ECT using carboplatin IV + IT (n = 10), carboplatin IV (n = 11) or bleomycin IV (n = 23). Treatment response according to RECIST criteria was recorded at 2 and 4 weeks post-treatment, and patients were followed until disease progression and/or death. All three groups were comparable regarding age, sex, weight, and lesion size. Adverse events were generally mild, localised and similar between groups. ORRs were 90.0% (carboplatin IV + IT), 90.9% (carboplatin IV) and 95.6% (bleomycin IV) and were not significantly different (p = 0.79). Median PFI was not reached for carboplatin IV + IT or carboplatin IV and was 566 days for bleomycin IV, with no significant difference between the three groups (p = 0.81). This study suggests that ECT using IV or IV + IT carboplatin is a reasonable alternative therapeutic option for managing cSCC, and further studies are warranted to compare outcomes between treatment protocols., (© 2024 The Author(s). Veterinary and Comparative Oncology published by John Wiley & Sons Ltd.)

Antimicrobial resistance has emerged as a significant health problem worldwide, including in Bangladesh, where chickens are an important protein source for human nutrition. One of the factors accelerating the development of antimicrobial resistance is the inappropriate use of antimicrobials on commercial chicken farms. A cross-sectional study was conducted in 2019 on 140 commercial chicken farms in the Chattogram district of Bangladesh to investigate the association between antimicrobial use and resistance in Escherichia coli and Salmonella spp. cultured from cloacal swabs of chickens and from the poultry shed environment. All E. coli and Salmonella spp. isolates were resistant to multiple antimicrobial classes, including those categorized as "Highest Priority Critically Important Antimicrobials" for human medicine. Notably, resistance was observed in E. coli isolates from farms that did not use these antimicrobial classes in the current production cycle. For example, although quinolones were not used on 43.9% of E. coli positive farms, 95.7% of these farms had quinolone-resistant E. coli isolates. The results of the path analysis revealed that there was a "direct effect" of the frequency of antimicrobial usage on "high" resistance, with resistance increasing when antimicrobials were administered more frequently ( β  = 0.28, p  = 0.002). There was a "direct effect" of the purpose of antimicrobial use on "low" resistance, with resistance marginally decreasing when antimicrobials were administered solely for therapeutic use ( β  = -0.17, p  = 0.062), but increasing when they were used prophylactically. Overall, the study results could be used to educate farmers on better practices for antimicrobial administration, and to guide government agencies to update policies on antimicrobial use and resistance surveillance in the poultry sector of Bangladesh., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Foysal, Imam, Das, Gibson, Mahmud, Gupta, Fournié, Hoque and Henning.)

In April 2024, the manuscript by Cuesta et al [...].

Pregnant women are daily exposed to environmental contaminants, including endocrine disruptors that can impact the offspring's health. This study aimed to evaluate the effects of maternal oral exposure to a mixture of contaminants at a dose mimicking women's exposure, during folliculogenesis and/or preimplantation period (FED and ED groups, respectively) on the fetoplacental phenotype in a rabbit model. The mixture (DEHP, pp'DDE, β-HCH, HCB, BDE-47, BPS, PFOS, PFOA) was defined based on data from HELIX and INMA cohorts. FED and ED females or unexposed females (control) were inseminated, their embryos were collected and transferred to unexposed control recipient rabbits at 80 h post-insemination. The effects of maternal FED and ED exposure were evaluated on fetoplacental growth and development by ultrasound, fetoplacental biometry, fetal metabolism, placental structure and function. The results demonstrated that the mixture weakly affected ultrasound measurements, as only placental volume increased significantly in FED vs ED. Analysis of placental structure demonstrated that the volume fraction of the maternal blood space was increased in FED vs control. Pre- and/or periconception exposure did not affect biometric at the end of gestation, but affected FED fetal biochemistry. Plasma triglyceride concentration was reduced compared to control. However, total cholesterol, urea, ASAT and ALAT in fetal blood were affected in both exposed groups. Multiple factor analysis, including biometric, biochemical, and stereological datasets, indicated that the three groups were significantly different. Additionally, several placental genes were differentially expressed between groups, compared two by two, in a sex-specific manner, with more difference in females than in males. The differentially expressed genes were involved in lipid, cholesterol, and drug/xenobiotic metabolism in both sexes. These results indicate that maternal exposure to environmental contaminants during crucial developmental windows only mildly impaired fetoplacental development but disturbed fetal blood biochemistry and placental gene expression with potential long-term effects on offspring phenotype., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

mRNA-based vaccines and therapeutics are gaining popularity and usage across a wide range of conditions. One of the critical issues when designing such mRNAs is sequence optimization. Even small proteins or peptides can be encoded by an enormously large number of mRNAs. The actual mRNA sequence can have a large impact on several properties, including expression, stability, immunogenicity, and more. To enable the selection of an optimal sequence, we developed CodonBERT, a large language model (LLM) for mRNAs. Unlike prior models, CodonBERT uses codons as inputs, which enables it to learn better representations. CodonBERT was trained using more than 10 million mRNA sequences from a diverse set of organisms. The resulting model captures important biological concepts. CodonBERT can also be extended to perform prediction tasks for various mRNA properties. CodonBERT outperforms previous mRNA prediction methods, including on a new flu vaccine data set., (© 2024 Li et al.; Published by Cold Spring Harbor Laboratory Press.)

Lassa Fever is a deadly viral haemorrhagic disease, causing annually several hundreds of deaths in West Africa. This zoonotic disease is primarily transmitted to humans by rodents of the genus Mastomys , even though other rodents reportedly carry the Lassa virus, while secondary interhuman transmission accounts for approximately 20% of cases. Although this disease has been endemic in rural zones of Nigeria, Sierra Leone, Liberfia, and Guinea for hundreds of years, it is also characterised by epidemic outbreaks in the dry season, responsible for heavy death tolls. No licensed vaccine or satisfying treatment is currently available. Disease management is hindered by the incomplete knowledge of the epidemiology and distribution of the disease, resulting from an inadequate health and surveillance system. Additional scientific constraints such as the genetic diversity of the virus and the lack of understanding of the mechanisms of immune protection complexify the development of a vaccine. The intricate socio-economic context in the affected regions, and the lack of monetary incentive for drug development, allow the disease to persist in some of West Africa's poorest communities. The increase in the number of reported cases and in the fatality rate, the expansion of the endemic area, as well as the threat Lassa Fever represents internationally should urge the global community to work on the disease control and prevention. The disease control requires collaborative research for medical countermeasures and tailored public health policies. Lassa Fever, created by the interconnection between animals, humans, and ecosystems, and embedded in an intricate social context, should be addressed with a 'One Health' approach. This article provides an overview of Lassa Fever, focusing on Nigeria, and discusses the perspectives for the control of disease.

Background: Recent outbreaks between 2015-17 and production delays have led to a yellow fever vaccine shortage. Therefore, there is an urgent need for new yellow fever vaccines with improved production scalability. A next-generation live-attenuated yellow fever vaccine candidate (vYF), produced in a Vero cell line has shown similar immunogenicity to licensed yellow fever vaccines in preclinical studies. In this study, we aimed to report the safety and immunogenicity of vYF in human clinical trial participants., Methods: In this first in-human, phase 1 randomised, observer-blind, active-controlled, dose-ranging clinical trial conducted at a single centre in the USA (Walter Reed Army Institute of Research, Silver Spring, MD, USA), 72 healthy adults (aged 18-60 years), without a known history of flavivirus infection or vaccination were randomly assigned (1:1:1:1) using interactive response technology to receive one dose of either vYF at 4, 5 or 6 Log CCID 50 or the licensed YF-VAX (18 individuals per group). The primary outcomes were safety, neutralising antibody (NAb) titres through D180 post-vaccination in the per-protocol analysis set (comprised of yellow fever-naive participants who received their intended vaccine and provided a valid post-vaccination blood sample), and occurrence, and level of yellow fever viraemia in each vaccine group through D14 post-vaccination., Findings: All vYF doses had a safety and tolerability profile similar to YF-VAX. The most frequently reported solicited injection site reactions (vYF groups vs YF-VAX group) were pain (22% [12 of 54 participants, 95% CI 12-36] vs 28% [five of 18 participants, 10-54]), and erythema (13% [seven of 54 participants, 5-25] vs 39% [seven of 18 participants, 17-64]), with headache (32% [17 of 54 participants, 20-46] vs 44% [eight of 18 participants, 22-69]) and malaise (26% [14 of 54 participants, 15-40] vs 33% [six of 18 participants, 13-59]) as the most frequently reported solicited systemic reactions. One grade 3 solicited reaction (erythema) reported in the YF-VAX group resolved spontaneously. No serious unsolicited adverse events or deaths were reported. Viraemia was transiently detected in 50 participants between D4 and D10 in all groups and was observed in more participants or for a longer time in the vYF 6 Log CCID 50 and YF-VAX groups. All yellow fever-naive vaccine recipients across the study groups seroconverted yielding four-fold increase from baseline in yellow fever NAb titres measured by yellow fever microneutralisation assay by D28 and were seroprotected with yellow fever NAb titres of at least 10 [1/dil]). Overall, 100% (18 of 18 participants, 95% CI 82-100), 89% (16 participants, 65-99), 100% (18 participants, 82-100), and 94% (17 participants, 73-100) of participants in the vYF 4 Log, vYF 5 Log, vYF 6 Log CCID 50 groups, and YF-VAX group, respectively, remained seroprotected through D180., Interpretation: vYF has a similar safety and immunogenicity profile to YF-VAX. In general, the vYF 5 Log CCID 50 dose appeared to show optimal viraemia, safety, and immunogenicity, and was chosen for subsequent development., Funding: Sanofi., Competing Interests: Declaration of interests A-MM, HA, YW, ARP, VD, NM, MV, and EF are Sanofi employees and hold shares and stock options in the company. KM and PTS were employed by the Walter Reed Army Institute of Research at the time of this study. MM, BO-S, ES, MFA, APP, BO, MNM, KSK, MEM, IG, MEG, JMD, MAK, MJH, CEL, JNH, SAP, and MLR received funds from Sanofi through their institutions to support their work in the VYF01 trial (NCT04142086)., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

We report the existence of a working memory system in the nematode C. elegans that is employed for deferred action in a sensory-guided decision-making process. We find that the turn direction of discrete reorientations during navigation is under sensory-guided control and relies on a working memory that can persist over an intervening behavioral sequence. This memory system is implemented by the phasic interaction of two distributed oscillatory dynamical components. The interaction of oscillatory neural ensembles may be a conserved primitive of cognition across the animal kingdom.

Predicting the outbreak of infectious diseases and designing appropriate preventive health actions require interdisciplinary research into the processes that drive exposure to and transmission of disease agents. In the case of mycobacterial diseases, the epidemiological understanding of the scientific community hitherto was based on the clinical studies of infections in vertebrates. To evaluate the information gained by comprehensively accounting for the ecological and evolutionary constraints, we conducted literature searches assessing the role of mycobacteria interactions with non-vertebrate species in the origin of their pathogenicity and variations in disease risk. The reviewed literature challenges the current theory of person-to-person transmission for several mycobacterial infections. Furthermore, the findings suggest that diverse non-vertebrate organisms influence virulence, mediate transmission, and contribute to pathogen abundance in relation to vertebrate exposure. We advocate that an ecological and evolutionary framework provides novel insights to support a more comprehensive understanding of the prevention and management of diseases in vertebrates., Competing Interests: Declaration of interests We declare no competing interests. The content of the article is the sole responsibility of the authors, with no role played by the funding agencies., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Postoperative bacterial infections are prevalent complications in both human and veterinary orthopedic surgery, particularly when a biofilm develops. These infections often result in delayed healing, early revision, permanent functional loss, and, in severe cases, amputation. The diagnosis and treatment pose significant challenges, and bacterial biofilm further amplifies the therapeutic difficulty as it confers protection against the host immune system and against antibiotics which are usually administered as a first-line therapeutic option. However, the inappropriate use of antibiotics has led to the emergence of numerous multidrug-resistant organisms, which largely compromise the already imperfect treatment efficiency. In this context, the study of bacterial biofilm formation allows to better target antibiotic use and to evaluate alternative therapeutic strategies. Exploration of the roles played by mechanical factors on biofilm development is of particular interest, especially because cartilage and bone tissues are reactive environments that are subjected to mechanical load. This review delves into the current landscape of biofilm mechanobiology, exploring the role of mechanical factors on biofilm development through a multiscale prism starting from bacterial microscopic scale to reach biofilm mesoscopic size and finally the macroscopic scale of the fracture site or bone-implant interface., (© 2024 Orthopaedic Research Society.)

The aim of this prospective clinical study was to evaluate the efficacy of the Surgical Pleth Index (SPI), a validated nociception monitor in human anaesthesia, in dogs. The technology uses a plethysmographic signal from a specific pulse oximetry probe to analyse pulse wave amplitudes and heartbeat intervals. Twenty-six healthy dogs anaesthetised for castration were included. SPI, invasive mean arterial pressure (MAP) and heart rate (HR) were continuously monitored. The occurrence or resolution of a haemodynamic reaction (HDR), defined as a > 20% increase in HR and/or MAP, was assessed at predefined times: cutaneous incision, testicles' exteriorization, cutaneous suture, and fentanyl administration. Following nociceptive events, the dogs presenting a HDR showed a significant 8% and 10% increase in SPI at 3 and 5 min respectively, whereas after fentanyl administration, a 13% and 16% significant decrease in SPI were noted. Receiver operating characteristic curves analysis indicated a moderate performance for the dynamic variations of SPI over 1 min to predict a HDR (AUC: 0.68, threshold value: +15%) or its resolution after fentanyl administration (AUC of 0.72, threshold value: -15%) within 3 min. The SPI varied according to perioperative nociceptive events and analgesic treatment; however, its performance to anticipate a HDR was limited with high specificity but low sensivity. Refinement of the algorithm to specifically accommodate for the canine species may be warranted. Further studies are required to evaluate the influence of other factors on the performance of this index., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The author reports equipment, drugs, or supplies was provided by General Electric Healthcare, Limonest, France., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objectives: The Choosing Wisely campaign recommends against the routine use of erythrocyte sedimentation rate (ESR) for the assessment of acute undiagnosed inflammation or infection. We examined ESR and C-reactive protein (CRP) ordering practices at a large, freestanding children's hospital. We found that 80% of ESR orders were placed concurrently with a CRP order. We aimed to reduce the ESR testing rate by 20% within 6 months in both inpatient and emergency department (ED) settings., Methods: Applying Lean process improvement principles, we interviewed stakeholders from multiple subspecialties and engaged the institutional laboratory stewardship committee to identify the root causes of ESR ordering and design interventions. We conducted provider education (November 2020) and employed clinical decision support through an order panel in the electronic health record (April 2021). The outcome measures were monthly ESR testing rate per 1000 patient days (inpatient) and per 1000 ED visits, analyzed using statistical process control charts. CRP testing rate was a balancing measure., Results: After intervention implementation, the ESR testing rate decreased from 11.4 to 8.9 tests per 1000 inpatient patient days (22% decrease) and from 49.4 to 29.5 tests per 1000 ED visits (40% decrease). This change has been sustained for >1 year postintervention. Interventions were effective even during the coronavirus disease 2019 pandemic when there was a rise in baseline ED ESR ordering rate. CRP testing rates did not increase after the interventions., Conclusions: Education and clinical decision support were effective in reducing the ESR ordering rate in both inpatient and ED settings., (Copyright © 2024 by the American Academy of Pediatrics.)

Synchrotron Microbeam Radiation Therapy (MRT) has repeatedly proven its superiority compared with conventional radiotherapy for glioma control in preclinical research. The clinical transfer phase of MRT has recently gained momentum; seven dogs with suspected glioma were treated under clinical conditions to determine the feasibility and safety of MRT. We administered a single fraction of 3D-conformal, image-guided MRT. Ultra-high-dose rate synchrotron X-ray microbeams (50 µm-wide, 400 µm-spaced) were delivered through five conformal irradiation ports. The PTV received ~25 Gy peak dose (within microbeams) per port, corresponding to a minimal cumulated valley dose (diffusing between microbeams) of 2.8 Gy. The dogs underwent clinical and MRI follow-up, and owner evaluations. One dog was lost to follow-up. Clinical exams of the remaining six dogs during the first 3 months did not indicate radiotoxicity induced by MRT. Quality of life improved from 7.3/10 [±0.7] to 8.9/10 [±0.3]. Tumor-induced seizure activity decreased significantly. A significant tumor volume reduction of 69% [±6%] was reached 3 months after MRT. Our study is the first neuro-oncologic veterinary trial of 3D-conformal Synchrotron MRT and reveals that MRT does not induce acute to subacute radiotoxicity in normal brain tissues. MRT improves quality of life and leads to remarkable tumor volume reduction despite low valley dose delivery. This trial is an essential step towards the forthcoming clinical application of MRT against deep-seated human brain tumors.

The intra-articular reconstruction of the cranial cruciate ligament (CrCL) by an organic graft or a synthetic implant allows the restoration of physiological stifle stability. This treatment is still marginal in routine practice. A Rottweiler presented an acute complete CrCL rupture treated using an ultra-high-molecular-weight polyethylene (UHMWPE) implant. The latter was positioned under arthroscopic guidance and fixed with interference screws through femoral and tibial bone tunnels. The dog was weight-bearing just after surgery and resumed normal standing posture and gait after one month, with mild signs of pain upon stifle manipulation. At three months postoperatively, minimal muscle atrophy and minimal craniocaudal translation were noted on the operated hindlimb, with no effects on the clinical outcome. The stifle was painless. At six months postoperatively, standing posture and gait were normal, muscle atrophy had decreased, the stifle was painless, and the craniocaudal translation was stable. On radiographs, congruent articular surfaces were observed without worsening of osteoarthrosis over the follow-up, as well as stable moderate joint effusion. Replacement of a ruptured CrCL with a UHMWPE ligament yielded good functional clinical outcome at six months postoperatively. This technique could be considered an alternative for the treatment of CrCL rupture in large dogs, but it needs confirmation from a prospective study with more dogs.

Implementation of biomarkers in sepsis and septic shock in emergency situations, remains highly challenging. This viewpoint arose from a public-private 3-day workshop aiming to facilitate the transition of sepsis biomarkers into clinical practice. The authors consist of international academic researchers and clinician-scientists and industry experts who gathered (i) to identify current obstacles impeding biomarker research in sepsis, (ii) to outline the important milestones of the critical path of biomarker development and (iii) to discuss novel avenues in biomarker discovery and implementation. To define more appropriately the potential place of biomarkers in sepsis, a better understanding of sepsis pathophysiology is mandatory, in particular the sepsis patient's trajectory from the early inflammatory onset to the late persisting immunosuppression phase. This time-varying host response urges to develop time-resolved test to characterize persistence of immunological dysfunctions. Furthermore, age-related difference has to be considered between adult and paediatric septic patients. In this context, numerous barriers to biomarker adoption in practice, such as lack of consensus about diagnostic performances, the absence of strict recommendations for sepsis biomarker development, cost and resources implications, methodological validation challenges or limited awareness and education have been identified. Biomarker-guided interventions for sepsis to identify patients that would benefit more from therapy, such as sTREM-1-guided Nangibotide treatment or Adrenomedullin-guided Enibarcimab treatment, appear promising but require further evaluation. Artificial intelligence also has great potential in the sepsis biomarker discovery field through capability to analyse high volume complex data and identify complex multiparametric patient endotypes or trajectories. To conclude, biomarker development in sepsis requires (i) a comprehensive and multidisciplinary approach employing the most advanced analytical tools, (ii) the creation of a platform that collaboratively merges scientific and commercial needs and (iii) the support of an expedited regulatory approval process., (© 2024. The Author(s).)

Regulatory T cells (Treg) play a prominent role in utero tolerating non-inherited maternal antigens and in regulating immune responses against pathogens at birth. This study investigates Treg immunity in newborns in West Africa, where sepsis remains a major public health problem. Treg phenotypes on neonates subgroups with early-onset sepsis (EOS), presumed sepsis, and healthy newborn with and without prenatal risk factors were evaluated. Treg phenotypes varied according to prenatal conditions, with increase in Treg frequency and Foxp3 expression in healthy newborns with prenatal risk factors compared to those with none risk. Compared to healthy newborns with prenatal risk factors, EOS neonates had a significantly reduced frequency of Treg and Foxp3 expression. In the Treg pool, higher frequency of activated Treg was observed in EOS neonates, suggesting an in-utero activation upstream of the sepsis onset. Their migration to the infection site may explain the reduced frequency of circulating Integrin α4β1 + Treg suggestive of homing to the endothelial tissue. EOS neonates show increases expression of CTLA-4, PD-1 and CD39 on Treg, which negatively regulate the activation of effector T cells (Teff) corroborating by the lower frequency of Teff in EOS neonates. The higher frequency of CD39 + Treg and the lower frequency of integrinα4β1 + Treg in EOS non-survivor suggests that Treg exhaustement and endothelial homing are associated with outcome severity. Neonates developing EOS are born with an altered Treg phenotypic profile. Treg expression of CTLA-4, PD-1, CD39, and integrinα4β1 cell markers can be considered as early warning or diagnostic markers of EOS., Competing Interests: Authors AP, LG, and KB-P were employed by the company bioMérieux. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from bioMerieux. The funder had the following involvement in the study: design, analysis, interpretation of data, the writing of this article., (Copyright © 2024 Sossou, Ezinmegnon, Agbota, Gbedande, Accrombessi, Massougbodji, d’Almeida, Alao, Dossou-Dagba, Pachot, Vachot, Brengel-Pesce, Cottrell, Yessoufou, Briand, Tissières and Fievet.)

Trichuris vulpis is a parasite of the large intestine of canids and has a global distribution. Despite its well-established epidemiology, the question of its pathogenicity in dogs remains debated. It has been suggested that younger age and concurrent infection with Ancylostoma caninum may be responsible for more severe clinical presentations. This retrospective study aimed to describe the clinical and diagnostic features of T. vulpis -infected dogs and to compare these findings with dogs infected with both T. vulpis and other intestinal parasites (poly-infected dogs). Forty-five dogs were included, with twenty-five being solely infected by T. vulpis and twenty poly-infected dogs. Only weight loss was more frequent ( p = 0.006) in poly-infected dogs compared to T. vulpis mono-infected dogs. No significant differences were observed in laboratory abnormalities between mono-infected and poly-infected dogs. Only diarrhea was more frequent ( p = 0.007) in younger dogs compared to adults. The egg shedding pattern was significantly higher ( p = 0.04) among adult dogs compared to young ones, and there was a significant positive correlation between egg shedding and age (r = 0.41; p = 0.005). These findings suggest that T. vulpis might be responsible for both clinical signs and laboratory abnormalities in dogs, irrespective of the host's age and the presence of other intestinal parasites.

Objectives: This study was designed to prospectively evaluate the feasibility of an opioid-free anesthesia protocol and describe the quality of recovery and management of postoperative analgesia in dogs after a tibial plateau leveling osteotomy (TPLO)., Methods: In total, 20 dogs presented for TPLO were included. After premedication with intravenous (IV) medetomidine (0.005-0.007 mg/kg) and midazolam (0.2 mg/kg), the dogs were anesthetized using ketamine (2 mg/kg) and propofol and maintained with isoflurane and ketamine CRI (0.6 mg/kg/h). Sciatic and femoral nerve blocks were performed with bupivacaine 0.5% (0.087 +/- 0.01 and 0.09 +/- 0.02 mL/kg, respectively). Meloxicam (0.2 mg/kg IV) was administered intraoperatively, after osteotomy. Fentanyl (0.002 mg/kg IV) was administered intraoperatively, as rescue analgesia in the case of sustained increase in cardiorespiratory variables. Two pain scores (French 4A-VET and Glasgow short form) were performed at conscious sternal recumbency and 2, 4, 6, 8, 12, and 20 h after extubation and compared to baseline using a Friedman test followed by a Nemenyi post-hoc test. The time taken for the first food intake and urination was reported., Results: Intraoperative opioid-free anesthesia was feasible in 11 dogs, whereas 9 dogs received fentanyl once during arthrotomy. No opioid postoperative rescue analgesia was required. Food intake occurred within 6 h, and all dogs were discharged after 24 h without any complication., Conclusion: Total opioid-free postoperative analgesia was achieved in all dogs, with adequate recoveries. Although opioid-free anesthesia was feasible in 55% of the population, a single dose of fentanyl was necessary in 45% of the dogs during arthrotomy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Didier, Faucher, Sarra Ferrer, Lapouge, Junot and Jourdan.)

Pupillometry is used in humans to monitor pain, nociception and analgesia. This single-center, non-randomized, non-blinded intervention trial, evaluated the effect of nose twitching on the pupil size in awake, sedated, and anesthetized horses. Pupil height (H) and length (L) were measured before (Be) and after (Af) nose twitching in fourteen non-painful adult awake horses (T0). The percentage of variation (PSV) was calculated (PSVTn = [(TnAf-TnBe)/TnBe]*100). Measurements were repeated (Tn) after acepromazine (0.04 mg kg -1 IV) (T1), romifidine (0.04 mg kg -1 IV) (T2), morphine (0.1 mg kg -1 IV) (T3), after anesthesia induction with diazepam (0.05 mg kg -1 IV) and ketamine (2.2 mg kg -1 IV), at the time the horse was placed on the operating table (T4) and when the expiratory fraction of sevoflurane was 2% (T5). HAf vs. HBe, LAf vs. LBe as well as PSVH vs. PSVL at each time were compared with a Mann-Whitney Wilcoxon test. The PSVL and PSVH, as well as HBe and LBe over time were compared with the Skillings-Mack test followed by a Wilcoxon test for paired data to make pairwise comparisons (Tn + 1 vs. Tn). In non-sedated horses (T0), the application of the nose twitch induced a significant increase in pupil length (LT0Be: 17.09 [16.05; 19.67] mm versus LT0Af: 19.52 [18.74; 21.40]) mm ( p  = 0.004). Thirty minutes after acepromazine administration (T1), nose twitching induced a significant increase in pupil length (LT1Be: 16.45 [14.80; 18.66] mm versus LT1Af 18.31 [17.20; 20.52] mm) ( p  = 0.016) and height (HT1Be: 8.44 [5.68; 12.04] mm versus HT1Af: 11.09 [7.97; 14.3] mm) ( p  < 0.001). PSVHT1 was significantly greater than PSVLT1 ( p  = 0.025). PSVH was higher at T1 than at T0 ( p  = 0.04). It was also significantly higher at T1 than at T2 ( p  < 0.001). Romifidine induced mydriasis (HT2Be 16.95 [14.73; 18.77] mm versus HT1Be 8.44 [5.68; 12.04] mm) ( p  < 0,001) (LT2Be 19.66 [18.45; 20.41] mm versus LT1Be 16.45 [14.80; 18.66] mm) ( p  < 0.001). The results suggest that nose twitching induced a pupillary dilation in the awake horse. This effect was potentiated after the administration of acepromazine but disappeared after the administration of romifidine., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Mascaró Triedo, Karar, Abunemeh and Portier.)

Objectives: In the post-SARS-CoV-2 pandemic era, "breakthrough infections" are still documented, due to variants of concerns (VoCs) emergence and waning humoral immunity. Despite widespread utilization, the definition of the anti-Spike (S) immunoglobulin-G (IgG) threshold to define protection has unveiled several limitations. Here, we explore the advantages of incorporating T-cell response assessment to enhance the definition of immune memory profile., Methods: SARS-CoV-2 interferon-gamma release assay test (IGRA) was performed on samples collected longitudinally from immunocompetent healthcare workers throughout their immunization by infection and/or vaccination, anti-receptor-binding domain IgG levels were assessed in parallel. The risk of symptomatic infection according to cellular/humoral immune capacities during Omicron BA.1 wave was then estimated., Results: Close to 40% of our samples were exclusively IGRA-positive, largely due to time elapsed since their last immunization. This suggests that individuals have sustained long-lasting cellular immunity, while they would have been classified as lacking protective immunity based solely on IgG threshold. Moreover, the Cox regression model highlighted that Omicron BA.1 circulation raises the risk of symptomatic infection while increased anti-receptor-binding domain IgG and IGRA levels tended to reduce it., Conclusion: The discrepancy between humoral and cellular responses highlights the significance of assessing the overall adaptive immune response. This integrated approach allows the identification of vulnerable subjects and can be of interest to guide antiviral prophylaxis at an individual level., (© 2024 The Authors. European Journal of Immunology published by Wiley‐VCH GmbH.)

Sepsis is associated with hypoperfusion and organ failure. The aims of the study were: 1) to assess the effect of pimobendan on macrocirculation and perfusion and 2) to describe a multimodal approach to the assessment of perfusion in sepsis and compare the evolution of the perfusion parameters. Eighteen anaesthetized female piglets were equipped for macrocirculation monitoring. Sepsis was induced by an infusion of Pseudomonas aeruginosa. After the occurrence of hypotension, animals were resuscitated. Nine pigs received pimobendan at the start of resuscitation maneuvers, the others received saline. Tissue perfusion was assessed using temperature gradients measured with infrared thermography (TG = core temperature - tarsus temperature), urethral perfusion index (uPI) derived from photoplethysmography and sublingual microcirculation (Sidestream dark field imaging device): De Backer score (DBs), proportion of perfused vessels (PPV), microvascular flow index (MFI) and heterogeneity index (HI). Arterial lactate and ScvO 2 were also measured. Pimobendan did not improve tissue perfusion nor macrocirculation. It did not allow a reduction in the amount of noradrenaline and fluids administered. Sepsis was associated with tissue perfusion disorders: there were a significant decrease in uPI, PPV and ScvO 2 and a significant rise in TG. TG could significantly predict an increase in lactate. Resuscitation was associated with a significant increase in uPI, DBs, MFI, lactate and ScvO 2 . There were fair correlations between the different perfusion parameters. In this model, pimobendan did not show any benefit. The multimodal approach allowed the detection of tissue perfusion alteration but only temperature gradients predicted the increase in lactatemia., Competing Interests: Declaration of competing interest Boehringer Ingelheim Animal Health France (Lyon, France) provided the drugs necessary for the study. The authors declare that they have no other competing financial interests or personal relationships that could have influenced the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Case Series Summary: This case series describes seven cats that were treated with high-flow nasal cannula oxygen therapy (HFNOT). Seven cats were prospectively (n = 5) or retrospectively (n = 2) included from three veterinary university referral centers between March 2020 and September 2023. Data on signalment, medical history, clinical and diagnostic findings, treatment administered, response to HFNOT and outcomes were recorded. All cats included in this case series failed to respond to oxygen cage or flow-by oxygen therapy and were subsequently transitioned to HFNOT. After this transition, these cats demonstrated a marked improvement in respiratory parameters, including respiratory rate, effort and oxygen saturation measured by pulse oximetry, within 1 h of initiating HFNOT. All cats tolerated HFNOT well without any complications., Relevance and Novel Information: There is limited literature reporting the use of HFNOT in feline patients. This is the first case series in the literature of HFNOT utilized as an advanced oxygen delivery method for feline respiratory failure. This case series indicates that HFNOT improves oxygenation in feline patients that fail to respond to conventional oxygen therapy., Competing Interests: Conflict of interestThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

As lyophilization continues to be a critical step in the manufacturing of sensitive biopharmaceuticals, challenges often arise during the scale up to commercial scale or the transfer from one manufacturing site to another. While data from the small-scale development of the lyophilization cycle is abundant it is typically much more difficult to extract important information from commercial scale cycles, due to the lack of process analytical technologies available on the commercial line. There is often a reluctance to include wireless temperature or pressure probes during GMP operations due to the additional contamination risk, and retrofitting equipment such as the TDLAS can be prohibitively expensive. Further, as products become more advanced, the cost of consuming the product or even the availability of material may limit the opportunities to run commercial scale trials. This paper presents two novel methods to garner critical cycle information to allow for the evaluation of cycle performance without the need for expensive analytical equipment, costly revalidation and line downtime. Critically, this can be achieved using commonly available temperature and capacitance probes on existing commercial scale equipment. The first method is a calorimetric method, based on quantifying the differences in heat transfer liquid temperature between the shelf inlet and shelf outlet. This change in temperature results from the on-going sublimation, an endo-thermic reaction occurring during lyophilization. The second method uses the differential pressure between the chamber and condenser resulting from the vapor flow from vial to condenser during primary drying. As stated by the authors both methods align well and provide valuable cycle characterization data., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Motivation: Lipid nanoparticles (LNPs) are the most widely used vehicles for mRNA vaccine delivery. The structure of the lipids composing the LNPs can have a major impact on the effectiveness of the mRNA payload. Several properties should be optimized to improve delivery and expression including biodegradability, synthetic accessibility, and transfection efficiency., Results: To optimize LNPs, we developed and tested models that enable the virtual screening of LNPs with high transfection efficiency. Our best method uses the lipid Simplified Molecular-Input Line-Entry System (SMILES) as inputs to a large language model. Large language model-generated embeddings are then used by a downstream gradient-boosting classifier. As we show, our method can more accurately predict lipid properties, which could lead to higher efficiency and reduced experimental time and costs., Availability and Implementation: Code and data links available at: https://github.com/Sanofi-Public/LipoBART., (© The Author(s) 2024. Published by Oxford University Press.)

Reliable detection of bacteria belonging to the Borrelia burgdorferi sensu lato species complex in vertebrate reservoirs, tick vectors, and patients is key to answer questions regarding Lyme borreliosis epidemiology. Nevertheless, the description of characteristics of qPCRs for the detection of B. burgdorferi s. l. are often limited. This study covers the development and validation of two duplex taqman qPCR assays used to target four markers on the chromosome of genospecies of B. burgdorferi s. l. Analytical specificity was determined with a panel of spirochete strains. qPCR characteristics were specified using water or tick DNA spiked with controlled quantities of the targeted DNA sequences of B. afzelii, B. burgdorferi sensu stricto or B. bavariensis. The effectiveness of detection results was finally evaluated using DNA extracted from ticks and biopsies from mammals whose infectious status had been determined by other detection assays. The developed qPCR assays allow exclusive detection of B. burgdorferi s. l. with the exception of the M16 marker which also detect relapsing fever Borreliae. The limit of detection is between 10 and 40 copies per qPCR reaction depending on the sample type, the B. burgdorferi genospecies and the targeted marker. Detection tests performed on various kind of samples illustrated the accuracy and robustness of our qPCR assays. Within the defined limits, this multi-target qPCR method allows a versatile detection of B. burgdorferi s. l., regardless of the genospecies and the sample material analyzed, with a sensitivity that would be compatible with most applications and a reproducibility of 100% under measurement conditions of limits of detection, thereby limiting result ambiguities., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The hygienic quality of urban surfaces can be impaired by multiple sources of microbiological contaminants. These surfaces can trigger the development of multiple bacterial taxa and favor their spread during rain events through the circulation of runoff waters. These runoff waters are commonly directed toward sewer networks, stormwater infiltration systems or detention tanks prior a release into natural water ways. With water scarcity becoming a major worldwide issue, these runoffs are representing an alternative supply for some usage like street cleaning and plant watering. Microbiological hazards associated with these urban runoffs, and surveillance guidelines must be defined to favor these uses. Runoff microbiological quality from a recently implemented city center rainwater harvesting zone was evaluated through classical fecal indicator bacteria (FIB) assays, quantitative PCR and DNA meta-barcoding analyses. The incidence of socio-urbanistic patterns on the organization of these urban microbiomes were investigated. FIB and DNA from Human-specific Bacteroidales and pathogens such as Staphylococcus aureus were detected from most runoffs and showed broad distribution patterns. 16S rRNA DNA meta-barcoding profilings further identified core recurrent taxa of health concerns like Acinetobacter, Mycobacterium, Aeromonas and Pseudomonas, and divided these communities according to two main groups of socio-urbanistic patterns. One of these was highly impacted by heavy traffic, and showed recurrent correlation networks involving bacterial hydrocarbon degraders harboring significant virulence properties. The tpm-based meta-barcoding approach identified some of these taxa at the species level for more than 30 genera. Among these, recurrent pathogens were recorded such as P. aeruginosa, P. paraeruginosa, and Aeromonas caviae. P. aeruginosa and A. caviae tpm reads were found evenly distributed over the study site but those of P. paraeruginosa were higher among sub-catchments impacted by heavy traffic. Health risks associated with these runoff P. paraeruginosa emerging pathogens were high and associated with strong cytotoxicity on A549 lung cells. Recurrent detections of pathogens in runoff waters highlight the need of a microbiological surveillance prior allowing their use. Good microbiological quality can be obtained for certain typologies of sub-catchments with good hygienic practices but not all. A reorganization of Human mobility and behaviors would likely trigger changes in these bacterial diversity patterns and reduce the occurrences of the most hazardous groups., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Enhanced Passive Safety Surveillance (EPSS) was conducted for quadrivalent inactivated split-virion influenza vaccines (IIV4) in Germany (high dose [HD]) and Finland (standard dose [SD]) for the northern hemisphere (NH) 2022/23 influenza season. The primary objective was to assess adverse events following immunization (AEFI) occurring ≤7 days post-vaccination. In each country, the EPSS was conducted at the beginning of the NH influenza season. Exposure information was documented using vaccination cards (VC), and AEFI were reported via an electronic data collection system or telephone. AEFI were assessed by seriousness and age group (Finland only). The vaccinee reporting rate (RR) was calculated as the number of vaccinees reporting ≥ 1 AEFI divided by the total vaccinees. In Germany, among 1041 vaccinees, there were 31 AEFI (ten vaccinees) during follow-up, including one serious AEFI. Of 16 AEFI (six vaccinees) with reported time of onset, 15 occurred ≤7 days post-vaccination (RR 0.58%, 95% confidence interval [CI] 0.21, 1.25), which was lower than the 2021/22 season (RR 1.88%, 95% CI: 1.10, 3.00). In Finland, among 1001 vaccinees, there were 142 AEFI (51 vaccinees) during follow-up, none of which were serious. Of 133 AEFI (48 vaccinees) with time of onset reported, all occurred ≤7 days post-vaccination (RR 4.80%, 95% CI: 3.56, 6.31), which was similar to the 2021/22 season (RR 4.90%, 95% CI: 3.65, 6.43). The EPSS for HD-IIV4 and for SD-IIV4 in the 2022/23 influenza season did not suggest any clinically relevant changes in safety beyond what is known/expected for IIV4s.

Immunosenescence corresponds to the progressive decline of immune functions with increasing age. Although it is critical to understand what modulates such a decline, the ecological and physiological drivers of immunosenescence remain poorly understood in the wild. Among them, the level of glucocorticoids (GCs) during early life are good candidates to modulate immunosenescence patterns because these hormones can have long-term consequences on individual physiology. Indeed, GCs act as regulators of energy allocation to ensure allostasis, are part of the stress response triggered by unpredictable events and have immunosuppressive effects when chronically elevated. We used longitudinal data collected over two decades in two populations of roe deer (Capreolus capreolus) to test whether higher baseline GC levels measured within the first year of life were associated with a more pronounced immunosenescence and parasite susceptibility. We first assessed immunosenescence trajectories in these populations facing contrasting environmental conditions. Then, we found that juvenile GC levels can modulate lymphocyte trajectory. Lymphocyte depletion was accelerated late in life when GCs were elevated early in life. Although the exact mechanism remains to be elucidated, it could involve a role of GCs on thymic characteristics. In addition, elevated GC levels in juveniles were associated with a higher abundance of lung parasites during adulthood for individuals born during bad years, suggesting short-term negative effects of GCs on juvenile immunity, having in turn long-lasting consequences on adult parasite load, depending on juvenile environmental conditions. These findings offer promising research directions in assessing the carry-over consequences of GCs on life-history traits in the wild., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Bradycardia and dysautonomia observed during SARS-Cov2 infection suggests involvement of the autonomic nervous system (ANS). Limited data exists on ANS dysregulation and its association with outcomes in patients with acute respiratory distress syndrome (ARDS) related to COVID-19 (C-ARDS) or other etiologies (NC-ARDS)., Objectives: We aimed to explore sympathovagal balance, assessed by heart rate variability (HRV), and its clinical prognostic value in C-ARDS compared with NC-ARDS., Methods: A single-center, prospective case-control study was conducted. Consecutive patients meeting ARDS criteria between 2020 and 2022 were included. HRV was assessed using 1-hour electrographic tracing during a stable, daytime period., Results: Twenty-four patients with C-ARDS and 19 with NC-ARDS were included. Age, sex and ARDS severity were similar between groups. The median heart rate was markedly lower in the C-ARDS group than in the NC-ARDS group (60 [53-72] versus 101 [91-112] bpm, p<.001). Most of HRV parameters were significantly increased in patients with C-ARDS. HRV correlated with heart rate only in patients with C-ARDS. A positive correlation was found between the low-to high-frequency ratio (LF/HF) and length of intensive care unit stay (r = 0.576, p<.001)., Conclusion: This study confirmed that C-ARDS was associated with marked bradycardia and severe ANS impairment, suggesting a sympathovagal imbalance with vagal overtone. Poor outcomes appeared to be more related to sympathetic rather than parasympathetic hyperactivation., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Motor vehicular trauma, bite wounds, high-rise syndrome, and trauma of unknown origin are common reasons cats present to the emergency service. In small animals, thoracic injuries are often associated with trauma. The objective of this retrospective study was to evaluate limits of agreement (LOA) between thoracic point-of-care ultrasound (thoracic POCUS) and thoracic radiography (TXR), and to correlate thoracic POCUS findings to animal trauma triage (ATT) scores and subscores in a population of cats suffering from recent trauma., Methods: Cats that had thoracic POCUS and TXR performed within 24 h of admission for suspected/witnessed trauma were retrospectively included. Thoracic POCUS and TXR findings were assessed as "positive" or "negative" based on the presence or absence of injuries. Cats positive on thoracic POCUS and TXR were assigned 1 to 5 tentative diagnoses: pulmonary contusions/hemorrhage, pneumothorax, pleural effusion, pericardial effusion, and diaphragmatic hernia. When available ATT scores were calculated. To express LOA between the two imaging modalities a kappa coefficient and 95% CI were calculated. Interpretation of kappa was based on Cohen values., Results: One hundred and eleven cats were included. 83/111 (74.4%) cats were assessed as positive based on thoracic POCUS and/or TXR. Pulmonary contusion was the most frequent diagnosis. The LOA between thoracic POCUS and TXR were moderate for all combined injuries, moderate for pulmonary contusions/hemorrhage, pneumothorax, diaphragmatic hernia, and fair for pleural effusion. Cats with positive thoracic POCUS had significantly higher median ATT scores and respiratory subscores compared to negative thoracic POCUS cats., Discussion: The frequency of detecting intrathoracic lesions in cats was similar between thoracic POCUS and TXR with fair to moderate LOA, suggesting thoracic POCUS is useful in cats suffering from trauma. Thoracic POCUS may be more beneficial in cats with higher ATT scores, particularly the respiratory score., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Vidal, Boysen, Fordellone, Nectoux, Allaouchiche and Pouzot-Nevoret.)

Background: A next-generation Vero cell rabies vaccine (PVRV-NG2) was developed using the same Pitman-Moore strain as in the licensed purified Vero cell vaccine (PVRV; Verorab) and the human diploid cell vaccine (HDCV; Imovax Rabies®)., Methods: This dual-center, modified, double-blind, phase 3 study evaluated the immunogenic non-inferiority and safety of PVRV-NG2 with and without concomitant intramuscular human rabies immunoglobulin (HRIG) versus PVRV + HRIG and HDCV + HRIG in a simulated post-exposure prophylaxis (PEP) regimen. Healthy adults ≥18 years old (N = 640) were randomized 3:1:1:1 to PVRV-NG2 + HRIG, PVRV + HRIG, HDCV + HRIG, or PVRV-NG2 alone (administered as single vaccine injections on days [D] 0, D3, D7, D14, and 28, with HRIG on D0 in applicable groups). Rabies virus neutralizing antibodies (RVNA) titers were assessed pre- (D0) and post-vaccination (D14, D28, and D42) using the rapid fluorescent focus inhibition test. Non-inferiority, based on the proportion of participants achieving RVNA titers ≥0.5 IU/mL (primary objective), was demonstrated if the lower limit of the 95% CI of the difference in proportions between PVRV-NG2 + HRIG and PVRV + HRIG/HDCV + HRIG was >-5% at D28. Safety was assessed up to 6 months after the last injection., Results: Non-inferiority of PVRV-NG2 + HRIG compared with PVRV + HRIG and HDCV + HRIG was demonstrated. Nearly all participants (99.6%, PVRV-NG2 + HRIG; 100%, PVRV + HRIG; 98.7%, HDCV + HRIG; 100%, PVRV-NG2 alone) achieved RVNA titers ≥0.5 IU/mL at D28. Geometric mean titers were similar between groups with concomitant HRIG administration at all time points. Safety profiles were similar between PVRV-NG2 and comparator vaccines., Conclusions: In a simulated PEP setting, PVRV-NG2 + HRIG showed comparable immunogenicity and safety to current standard-of-care vaccines., Clinical Trials Registration: NCT03965962., Competing Interests: Potential conflicts of interest. A. C. P. P., Q. J., C. P., J. K. P., V. B., S. B., S. P., F. G. M., and A. M. M. are employees of Sanofi and may hold shares and/or stock options in the company. Y. D. reports other financial or nonfinancial interests as investigator and CEO of 1 of the investigation sites. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

For drug delivery systems, the mechanical properties of drug carriers are suspected to play a crucial role in the delivery process. However, there is a lack of reliable methods available to measure the mechanical properties of drug carriers, which hampers the establishment of a link between delivery efficiency and the mechanical properties of carriers. Lipid nanoparticles (LNPs) are advanced systems for delivering nucleic acids to target cell populations for vaccination purposes (mRNA) or the development of new drugs. Hence, it is crucial to develop reliable techniques to measure the mechanical properties of LNPs. In this article, we used AFM to image and probe the mechanical properties of LNPs which are loaded with two different biopolymers either pDNA or mRNA. Imaging the LNPs before and after indentation, as well as recording the retraction curve, enables us to obtain more insight into how the AFM tip penetrates into the particle and to determine whether the deformation of the LNPs is reversible. For pDNA, the indentation by the tip leads to irreversible rupture of the LNPs, while the deformation is reversible for the mRNA-loaded LNPs. Moreover, the forces reached for pDNA are higher than for mRNA. These results pave the way toward the establishment of the link between the LNP formulation and the delivery efficiency.

Background: The anesthetic management of adrenalectomies for phaeochromocytoma excision, a catecholamine-secreting tumor, is challenging due to the potential for fatal complications following severe hemodynamic variations, including hypertensive crisis following tumor manipulation or sympathetic stimulation, but also severe hypotension and volume depletion post resection., Case Description: An 11 kg, 15-year-old male neutered Jack Russel Terrier, with mitral valve disease stage B2, was referred for adrenalectomy for phaeochromocytoma resection. The patient was administered per os prazosin 0.11 mg/kg twice a day and amlodipine 0.125 mg/kg once a day for preoperative stabilization. On the day of surgery, the dog received maropitant 1 mg/kg intravenously (IV) and was premedicated with 0.2 mg/kg methadone IV. Anesthesia was induced with alfaxalone 1 mg/kg IV and midazolam 0.2 mg/kg IV and maintained with partial intravenous anesthesia using sevoflurane in 70% oxygen and constant rate infusions of dexmedetomidine 0.5 μg/kg/hour and maropitant 100 μg/kg/hour. After induction of anesthesia, the dog was mechanically ventilated, and a transversus abdominal plane block was performed with ropivacaine 0.2%. The dog remained remarkably stable with a single, self-limiting, hypertension episode recorded intraoperatively. Postoperative rescue analgesia consisted of methadone and ketamine. The dog was discharged 48 hours after surgery, but persistent hypertension was reported at suture removal., Conclusion: The use of a low-dose dexmedetomidine CRI, a maropitant CRI, and a transversus abdominal plane block provided stable perioperative hemodynamic conditions for phaeochromocytoma excision in a dog., Competing Interests: The authors declare that there is no conflict of interest.

The pathogenesis of increased serum phosphate concentration and proteinuria in dogs with spontaneous hyperadrenocorticism (HAC) is unclear. A potential link between proteinuria and calcium/phosphate metabolism has never been studied in dogs with HAC. The aims of the study were: (1) To evaluate calcium/phosphate metabolism in dogs with spontaneous HAC and compare to healthy dogs as well as to dogs with non-HAC illness; (2) to look for associations between markers of calcium/phosphate metabolism and biomarkers of kidney disease in dogs with HAC. Fifty-four dogs were included in the study, classified as HAC (n=27), non-HAC disease (n=17), and healthy (n=10). Serum calcium, phosphate, 25(OH)Vitamin D, 1,25(OH) 2 Vitamin D, plasma intact parathyroid hormone concentration (iPTH), FGF23, and urinary fractional excretion of calcium and phosphate were evaluated in all dogs at diagnosis and compared between each group. The correlation between these variables and urine protein-to-creatinine ratio (UPC) and urinary N-acetylglucosaminidase-to-creatinine ratio (uNAG/C) was evaluated in the HAC group. Medians [range] of serum phosphate concentration, urinary fractional excretion of calcium (FE(Ca)), and iPTH were significantly higher in dogs with HAC than in dogs with non-HAC illness (P<0.01) and healthy dogs (P<0.01). Increased 1,25(OH) 2 Vitamin D/25(OH)Vitamin D was also observed (P<0.001). In HAC group, UPC was significantly negatively correlated with 25(OH)Vitamin D (r(s): -0.54; P<0.01). Urinary NAG/C was significantly positively correlated with serum phosphate (r(s): 0.46; P=0.019). Increased serum phosphate, urinary excretion of calcium, and hyperparathyroidism were observed in dogs with HAC. Vitamin D metabolism may be shifted towards increased 1-alpha hydroxylation., Competing Interests: Conflict of interest FGF23 analysis cost was supported by Royal Canin. Fiona Da Riz’s residency received financial support from Royal Canin. None of the authors has any financial or personal relationships that could inappropriately influence or bias the content of the paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Vaccination is one of the most important control tools to reduce Salmonella in poultry production. In order for a live vaccine to be licensed for field use it should be provided with the detection methods to differentiate it from field strains. This paper aims to describe the validation of an alternative method for the differentiation of the Salmonella 441/014 vaccine strain from field strains, using a chromogenic Media, ASAP from bioMérieux. The ASAP-based differentiation method was compared with already authorized methods, namely the Anicon SE Kylt PCR DIVA 1 assay and Ceva S-Check Salmonella differentiation kit, following the ISO 16140-6:2019 validation method guidelines. A Generalised Linear Model was fitted to the data to determine the inclusivity and exclusivity of differentiation methods (PCR Kylt vs. S-Check vs. ASAP TM ). Statistical differences were based on a P-value level of < 0.05 (SPSS Inc., Chicago, IL). In this study, we show that the ASAP media was able to differentiate Salmonella Enteritidis vaccine strains from field strains, obtaining 100% agreement between the three differentiation assays. This differentiation approach is quicker, easier to deploy and cheaper as compared to alternative methods., Competing Interests: Disclosures The study was conceived, developed, and analyzed by J.G.L, C.G, P.C-G, and S.S-N from CECAV which declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Specific data regarding outcome of cats with high-grade and large granular lymphocyte alimentary lymphoma (HGAL and LGL, respectively) treated with multi-agent chemotherapy are scarce. The aims of this multi-centric, retrospective study were to describe the outcome of cats with HGAL and LGL treated with COP- or CHOP-based chemotherapy and to identify potential prognostic factors. Cats with a cytological or histological diagnosis of HGAL or LGL lymphoma treated with COP- or CHOP-based protocol as first-line chemotherapy were included. Data regarding diagnosis, staging, treatment and follow-up were collected. Fifty-seven cats treated with CHOP (n = 37) or COP (n = 20) protocols were included. Complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) were observed in 20%, 22%, 36% and 22% of cats, respectively, for an overall response rate of 42%. Median progression-free interval (PFI) was 148 days and overall median survival time (OST) was 131 days. Cats achieving CR, PR or SD showed significantly longer PFI (p < .01) and OST (p < .015) compared with cats with PD. Other positive prognostic factors in multi-variate analysis were rescue treatment (p < .001) and absence of lymph node involvement (p < .03). Negative prognostic factors were diffuse infiltration of the gastrointestinal tract (p = .035) and infiltration of a non-haematopoietic organ (p < .01)., (© 2024 The Authors. Veterinary and Comparative Oncology published by John Wiley & Sons Ltd.)

Objectives: To evaluate the safety and feasibility of high flow oxygen therapy (HFOT), and to record SpO 2 and desaturation episodes in dogs and cats receiving HFOT or conventional oxygen therapy (COT) during bronchoscopy ± bronchoalveolar lavage (BAL)., Materials and Methods: Dogs and cats undergoing bronchoscopy ± BAL between January and May 2023 were included in the study. Patients were randomly allocated to two groups: HFOT (HFOT group; two cats and four dogs) and COT (COT group; one cat and five dogs). HFOT and COT were started at the beginning of the bronchoscopy. HFOT was delivered with a gas flow rate of 1 L/kg/min at an FiO 2 of 100% and a temperature of 34°C (pediatric mode) or 37°C (adult mode). COT was delivered through the working channel of the bronchoscope at a rate of 1.5 L/min. The safety and feasibility of HFOT were assessed, and peripheral oxygen saturation (SpO 2 ) was measured by pulse oximetry every 30 s throughout the procedure., Measurements and Main Results: HFOT was feasible and safe in both dogs and cats with no complications reported. While there was no significant difference in the number of desaturation episodes (SpO 2  < 94%) between the two groups, none of the patients in the HFOT group experienced severe desaturation (SpO 2  < 90%). In contrast, two patients in the COT group had an SpO 2  < 90%. Mean SpO 2 was significantly higher in the HFOT group compared to the COT group at T0 (98% ± 2% vs. 94 ± 2%), T0.5 (98% ± 2% vs. 94% ± 3%) and T1 (98% ± 2% vs. 94% ± 4%)., Conclusion: To the authors' knowledge, this is the largest study conducted to date using HFOT during bronchoscopy in dogs and cats. Our results suggest that HFOT is feasible and safe during bronchoscopy ± BAL. Furthermore, HFOT may reduce the risk of desaturation episodes in dogs and cats undergoing bronchoscopy and BAL., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Dartencet, Abunemeh, Junot, Nectoux, Allaouchiche, Krafft and Pouzot-Nevoret.)

Sepsis induces intense, dynamic and heterogeneous host response modulations. Despite improvement of patient management, the risk of mortality and healthcare-associated infections remains high. Treatments to counterbalance immune response are under evaluation, but effective biomarkers are still lacking to perform patient stratification. The design of the present study was defined to alleviate the limitations of existing literature: we selected patients who survived the initial hyperinflammatory response and are still hospitalized at day 5-7 after ICU admission. Using the Immune Profiling Panel (IPP), a fully automated RT-qPCR multiplex prototype, we optimized a machine learning model combining the IPP gene expression levels for the identification of patients at high risk of worsening, a composite endpoint defined as death or secondary infection, within one week after sampling. This was done on 332 sepsis patients selected from two retrospective studies. The IPP model identified a high-risk group comprising 30% of patients, with a significant increased proportion of worsening events at day 28 compared to the low-risk group (49% vs. 28%, respectively). These preliminary results underline the potential clinical application of IPP for sepsis patient stratification in a personalized medicine perspective, that will be confirmed in a larger prospective multicenter study., (© 2024. The Author(s).)

Belgian blue (BB) cattle have an 11-bp deletion in myostatin that causes skeletal muscle hyperplasia and increased muscle mass, leading to a 'double-muscled' phenotype. Preliminary data suggest that this phenotype may be associated with breed-specific hematologic and biochemical values. Therefore, in this study, we sought to compare hematologic and serum biochemical parameters in healthy BB and Holstein Friesian (HF) cows and to propose breed-specific reference intervals for BB cows. Hematologic parameters, total protein, creatinine, creatine kinase (CK) and aspartate transaminase (AST) activities, albumin, and globulins were measured in 183 clinically healthy adult BB and HF cows. There were significant differences between BB and HF cows in 17 of 27 measured parameters. BB cows had significantly higher creatinine concentration and CK and AST activities ( p < 0.001). RBCs, hemoglobin, hematocrit ( p < 0.001), MCV and lymphocytes ( p < 0.05) were also significantly higher in BB cows compared with HF cows. The average N/L ratio was greater than 1 in both breeds. These results suggest that BB and HF cows have significantly different clinically relevant hematologic and serum biochemical values, and, therefore, breed-specific reference intervals should be used.

Introduction: In light of the burden of traumatic brain injury (TBI) in children and the excessive number of unnecessary CT scans still being performed, new strategies are needed to limit their use while minimising the risk of delayed diagnosis of intracranial lesions (ICLs). Identifying children at higher risk of poor outcomes would enable them to be better monitored. The use of the blood-based brain biomarkers glial fibrillar acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1) could help clinicians in this decision. The overall aim of this study is to provide new knowledge regarding GFAP and UCH-L1 in order to improve TBI management in the paediatric population., Methods and Analysis: We will conduct a European, prospective, multicentre study, the BRAINI-2 paediatric study, in 20 centres in France, Spain and Switzerland with an inclusion period of 30 months for a total of 2880 children and adolescents included. To assess the performance of GFAP and UCH-L1 used separately and in combination to predict ICLs on CT scans (primary objective), 630 children less than 18 years of age with mild TBI, defined by a Glasgow Coma Scale score of 13-15 and with a CT scan will be recruited. To evaluate the potential of GFAP and UCH-L1 in predicting the prognosis after TBI (secondary objective), a further 1720 children with mild TBI but no CT scan as well as 130 children with moderate or severe TBI will be recruited. Finally, to establish age-specific reference values for GFAP and UCH-L1 (secondary objective), we will include 400 children and adolescents with no history of TBI., Ethics and Dissemination: This study has received ethics approval in all participating countries. Results from our study will be disseminated in international peer-reviewed journals. All procedures were developed in order to assure data protection and confidentiality., Trial Registration Number: NCT05413499., Competing Interests: Competing interests: OM and VP are employees of bioMérieux. The other authors declare no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; and no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The non-human primate (NHP) model (specifically rhesus and cynomolgus macaques) has facilitated our understanding of the pathogenic mechanisms of yellow fever (YF) disease and allowed the evaluation of the safety and efficacy of YF-17D vaccines. However, the accuracy of this model in mimicking vaccine-induced immunity in humans remains to be fully determined. We used a systems biology approach to compare hematological, biochemical, transcriptomic, and innate and antibody-mediated immune responses in cynomolgus macaques and human participants following YF-17D vaccination. Immune response progression in cynomolgus macaques followed a similar course as in adult humans but with a slightly earlier onset. Yellow fever virus neutralizing antibody responses occurred earlier in cynomolgus macaques [by Day 7[(D7)], but titers > 10 were reached in both species by D14 post-vaccination and were not significantly different by D28 [plaque reduction neutralization assay (PRNT) 50 titers 3.6 Log vs 3.5 Log in cynomolgus macaques and human participants, respectively; P = 0.821]. Changes in neutrophils, NK cells, monocytes, and T- and B-cell frequencies were higher in cynomolgus macaques and persisted for 4 weeks versus less than 2 weeks in humans. Low levels of systemic inflammatory cytokines (IL-1RA, IL-8, MIP-1α, IP-10, MCP-1, or VEGF) were detected in either or both species but with no or only slight changes versus baseline. Similar changes in gene expression profiles were elicited in both species. These included enriched and up-regulated type I IFN-associated viral sensing, antiviral innate response, and dendritic cell activation pathways D3-D7 post-vaccination in both species. Hematological and blood biochemical parameters remained relatively unchanged versus baseline in both species. Low-level YF-17D viremia (RNAemia) was transiently detected in some cynomolgus macaques [28% (5/18)] but generally absent in humans [except one participant (5%; 1/20)].IMPORTANCECynomolgus macaques were confirmed as a valid surrogate model for replicating YF-17D vaccine-induced responses in humans and suggest a key role for type I IFN., Competing Interests: N.M., FP.-D., E.C., F.R., A.P., S.G., and V.C. are employees of Sanofi and may hold shares and/or stock options in the company. E.M.-L., C.L.B., A.C., N.D., S.H.E.K., K.P., D.J.M.L., F.M., N.D.-B., and R.L.G. declare no competing interest relevant to this report.

Background: The nerve growth factor (NGF) has been previously shown to be involved in cellular proliferation, differentiation, survival, or wound healing. This factor displays a variety of biological effects that yet remain to be explored. Previous data on cell lines show a pro-inflammatory role of NGF on monocytes., Objectives: The objective of the study was to investigate the pro-inflammatory effect of NGF, using a model of fresh human monocytes., Methods: Monocytes obtained from PBMC were exposed to NGF at various concentrations. Alternatively, monocytes were exposed to BSA, the NGF carrier protein without the NGF. Gene expression and cytokine release in the supernatant were monitored., Results: We found that NGF increased the expression of pro-inflammatory, chemotactic, and remodeling genes such as interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and C-X-C motif ligand (CXCL)8. The protein levels of CXCL8 and matrix metalloproteinase (MMP)-9 were also increased in the cell supernatants following NGF exposure. BSA alone was found to drive part of this response, bringing nuance to the inflammatory potential of the NGF., Conclusion: These data suggest that NGF is able to enhance monocyte inflammatory responses once cells are stimulated with another signal but is possibly not able to directly activate it. This could have implications for example in patients with bacterial infections, where NGF could worsen the local inflammation by over-activating immune cells., (© 2024 The Authors. Fundamental & Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of Société Française de Pharmacologie et de Thérapeutique.)

Background: Leptospirosis is a zoonotic disease. It is particularly prevalent in tropical countries and has major consequences for human and animal health. In Benin, the disease's epidemiology remains poorly understood, especially in livestock, for which data are lacking., Objectives: To characterise Leptospira seroprevalence and locally circulating serogroups in livestock from Cotonou and to estimate the prevalence of Leptospira renal carriage in cattle., Methods: We conducted a cross-sectional study in February 2020 during which livestock were sampled at an abattoir and in an impoverished city district. We analysed blood samples from 279 livestock animals (i.e. cattle, sheep, goats and pigs) using the microscopic agglutination test. Additionally, samples of renal tissue from 100 cattle underwent 16s rRNA (rrs) real-time PCR analysis., Results: For the 131 cattle, 85 sheep, and 50 goats tested, seroprevalence was 18% (95% confidence interval [CI] [12%, 26%]), 9% (95% CI [4%, 17%] and 2% (95% CI [0%, 9%]), respectively, and most of the seropositive animals were associated with 1:100 titres. All 13 pigs were seronegative. Leptospira DNA was found in the renal tissue of 10% (95% CI [5%, 18%]) of the cattle tested (n = 100). Leptospira borgpetersenii was the main species present (n = 7), but Leptospira interrogans (n = 2) and Leptospira kirschneri (n = 1) were also detected. Various serogroups (Canicola, Grippotyphosa, Sejroe, Icterohaemorrhagiae, Pomona, Pyrogenes, Australis and Autumnalis) were detected using microscopic agglutination test without a clear predominance of any of them., Conclusions: These results suggest that abattoir workers and people living in close contact with livestock in poor urban areas are exposed to the risk of Leptospira infection., (© 2024 The Authors. Veterinary Medicine and Science published by John Wiley & Sons Ltd.)