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Background: During the first wave of the coronavirus disease-2019 (COVID-19) pandemic, it was necessary to prepare for the possibility of triaging patients who could benefit from access to an intensive care unit (ICU). In our neuroscience institution, the challenge was to continue to manage usual neurological emergencies as well as the influx of COVID-19 patients., Methods: We report the experience of an ethical consulting unit to support care clinical decisions during the first wave of the pandemic (March 16 to April 30, 2020). Three objective evaluation criteria were defined: 2 of these criteria, patient's factors and general disease severity (Simplified Acute Physiology Score II), were common to all patients, and the third was the specific severity of the disease (neurological for brain injury, respiratory for COVID-19). Given our scarce resources, we used a high probability of a 3-month modified Rankin Scale ≤3 as the criterion for further resuscitation and management., Results: A total of 295 patients were admitted during the first pandemic wave; 111 with COVID-19 and 184 with neurological emergencies. The ethical unit's expertise was sought for 75 clinical situations in 56 patients (35 COVID-19 and 21 neurological). Decisions were as follows: 11% no limitation on care, 5% expectant care with reassessment (maximum therapy to assess possible progress pending decision), 67% partial limitation (no intensification of care or no transfer to ICU), and 17% limitation of curative care. At no time did a lack of availability of ICU beds require the ethical unit to advise against admission to the ICU., Conclusions: Our ethical consulting unit allowed for collegial ethical decision-making in line with international recommendations. This model could be easily transferred to other triage situations, provided it is adapted to the local context., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Posterior shoulder instability is becoming increasingly recognized in young active patient populations. Diagnosing posterior instability can be challenging because patients commonly present with a complaint of pain without a history of a dislocation or subluxation event. Additionally, a posterior labral tear is not always clearly visualized on advanced imaging studies. As such, physical examination is critical to the diagnosis. We report a simple physical examination maneuver for the diagnosis of symptomatic posterior shoulder instability. The thumb test attempts to replicate a posterior bone block procedure, helping to re-establish stability and relieve pain. The examiner places his or her thumb over the posterior glenohumeral joint line while the patient actively forward elevates the affected arm overhead. Improvement in pain and stability with this maneuver is diagnostic for symptomatic posterior shoulder instability. This test augments current physical examination maneuvers to assist with correctly diagnosing posterior shoulder instability., (© 2022 The Authors.)

Background: French Guiana (FG) is an ultra-peripheral European region in the Amazon, and the COVID-19 epidemic has had very different kinetics from both its giant neighbors, Brazil or mainland France., Methods: This study summarized the epidemics of COVID-19 in FG., Results: The tropical climate, multiethnicity, and remoteness of the population forced healthcare providers to accordingly adapt the management of the epidemic. Incidence and mortality have been lower than that in Europe and Latin America due to a combination of prevalence of the youth in the population and highly developed healthcare system., Conclusions: Currently, vaccine hesitancy hinders the rapid expansion of vaccine coverage.

Body-on-a-chip in vitro systems are a promising technology that aims to increase the predictive power of drug efficacy and toxicity in humans when compared to traditional animal models. Here, we developed a new heart-liver body-on-a-chip system with a skin surrogate to assess the toxicity of drugs that are topically administered. In order to test the utility of the system, diclofenac, ketoconazole, hydrocortisone and acetaminophen were applied topically through a synthetic skin surrogate (Strat-M membrane) and the toxicity results were compared to those of acute drug exposure from systemically applying the compounds. The heart-liver system was successful in predicting the effects for both cardiac and liver functions changes due to the compounds. The difference in the concentrations of drugs applied topically compared to systemically indicates that the barrier properties of the skin surrogate were efficient. One important advantage of this heart-liver system was the capability of showing differential effects of acute and chronic drug exposure which is necessary as part of the International Conference in Harmonisation (ICH) tri-partate guidelines. In conclusion, this work indicates a promising heart-liver body-on-a-chip system that can be used for the assessment of potential drug toxicity from dermal absorption as well as evaluate transport dynamics through the skin in the same system.

Skin sensitization is an important toxicological endpoint in the safety assessment of chemicals and cosmetic ingredients. Driven by ethical considerations and European Union (EU) legislation, its assessment has progressed from the reliance on traditional animal models to the use of non-animal test methods. It is generally accepted that the assessment of skin sensitization requires the integration of various non-animal test methods in defined approaches (DAs), to cover the mechanistic key events of the adverse outcomes pathway (AOP) (OECD, 2014). Several case studies for DAs predicting skin sensitization hazard or potency have been submitted to the OECD, including a stacking meta-model developed by L'Oréal Research & Innovation (OECD, 2017b; Del Bufalo et al., 2018; Noçairi et al., 2016). The present study evaluated the predictive performance of the defined approach integrating a stacking meta-model incorporating in silico, in chemico and in vitro assays, using the Cosmetics Europe (CE) skin sensitization database. Based on the optimized prediction cut-offs, the defined approach provided a hazard prediction for 97 chemicals with a sensitivity of 91%, a specificity of 76% and accuracy of 86% (kappa of 0.67) against human skin sensitization hazard data and a sensitivity of 85%, specificity of 91% and accuracy of 87% (kappa of 0.67) against Local Lymph Node Assay (LLNA) hazard data. A comparison of the in vivo LLNA with human hazard data for the same 97 chemicals showed a sensitivity of 92%, specificity of 51% and accuracy of 78% (kappa of 0.48). Thus, the defined approach showed a higher degree of concordance, as compared to the LLNA for predicting human skin sensitization hazard. Moreover, a comparison with the six DAs selected for evaluation of their predictivity in the study by Kleinstreuer et al. (2018) showed a similar high accuracy of 86% for 97 overlapping chemicals. The next step will be an independent evaluation of the DA for its integration in the performances based test guidelines (PBTG) for skin sensitization., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The goal of human-on-a-chip systems is to capture multi-organ complexity and predict the human response to compounds within physiologically relevant platforms. The generation and characterization of such systems is currently a focal point of research given the long-standing inadequacies of conventional techniques for predicting human outcome. Functional systems can measure and quantify key cellular mechanisms that correlate with the physiological status of a tissue, and can be used to evaluate therapeutic challenges utilizing many of the same endpoints used in animal experiments or clinical trials. Culturing multiple organ compartments in a platform creates a more physiologic environment (organ-organ communication). Here is reported a human 4-organ system composed of heart, liver, skeletal muscle and nervous system modules that maintains cellular viability and function over 28 days in serum-free conditions using a pumpless system. The integration of non-invasive electrical evaluation of neurons and cardiac cells and mechanical determination of cardiac and skeletal muscle contraction allows the monitoring of cellular function especially for chronic toxicity studies in vitro . The 28 day period is the minimum timeframe for animal studies to evaluate repeat dose toxicity. This technology could be a relevant alternative to animal testing by monitoring multi-organ function upon long term chemical exposure., Competing Interests: Disclosure of Potential Conflict of Interest The authors confirm that competing financial interests exist but there has been no financial support for this research that could have influenced its outcome. However, JJH and MLS have a potential competing financial interest, in that a company has been formed to market services for types of cells like this in body-on-a-chip devices.

Background: Despite the context of several national warnings, antipsychotics drugs are commonly used to treat behavioural and psychological symptoms in dementia (BPSD)., Aim: To observe a decrease of antipsychotic drug prescription, in old NH (nursing homes) residents with dementia, after an awareness of their general practitioner., Methods: Observational, prospective, multicenter study. The study population corresponds to NH residents with dementia, and antipsychotic drug consumption, in nursing homes volunteered to participate. Awareness-raising is carried out through information documents. The evaluation criteria is the proportion of residents under antipsychotics after sensitization., Results: out of the 30 nursing homes included, 26.7% of the patients were prescribed at least one antipsychotic and 15% were both demented and under antipsychotics. A total of 317 residents with dementia and antipsychotics were included 15% of the total NH population. Psychotropic drug co-prescriptions was very frequent 43.2% also used benzodiazepines, 37.2% anxiolytics and 33.1% antidepressants. Agitation, aggressiveness, opposition to care and wandering were the most commonly BPSD encountered. After a first sensitization, we obtained a 15.5% decrease of antipsychotic prescriptions., Conclusion: A personalized sensitization towards GP allowed a reduction of antipsychotic drugs prescription in NH residents with dementia and BPSD.

Regulation of cosmetic testing and poor predictivity of preclinical drug studies has spurred efforts to develop new methods for systemic toxicity. Current in vitro assays do not fully represent physiology, often lacking xenobiotic metabolism. Functional human multi-organ systems containing iPSC derived cardiomyocytes and primary hepatocytes were maintained under flow using a low-volume pumpless system in a serum-free medium. The functional readouts for contractile force and electrical conductivity enabled the non-invasive study of cardiac function. The presence of the hepatocytes in the system induced cardiotoxic effects from cyclophosphamide and reduced them for terfenadine due to drug metabolism, as expected from each compound's pharmacology. A computational fluid dynamics simulation enabled the prediction of terfenadine-fexofenadine pharmacokinetics, which was validated by HPLC-MS. This in vitro platform recapitulates primary aspects of the in vivo crosstalk between heart and liver and enables pharmacological studies, involving both organs in a single in vitro platform. The system enables non-invasive readouts of cardiotoxicity of drugs and their metabolites. Hepatotoxicity can also be evaluated by biomarker analysis and change in metabolic function. Integration of metabolic function in toxicology models can improve adverse effects prediction in preclinical studies and this system could also be used for chronic studies as well., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Goal of the Study: The umbilicus has a major role in the aesthetics of the anterior abdominal wall. Many publications deal with abdominal dermolipectomies but few focus on umbilicoplasty. However, these are essential in assessing the aesthetic result. Umbilicoplasty in "aile de mouette" used in our service is reliable and easily reproducible. In this article, we evaluate the satisfaction of patients with abdominal dermolipectomy with this technique of transposition., Materials and Method: In the plastic surgery department of the Saint-Louis Hospital in Paris, we carried out a retrospective study of patients undergoing abdominal dermolipectomy with transposition of the umbilicus, between 1 January 2012 and 31 December 2012. All patients were operated according to our technique of umbilicoplasty: disinsertion of the umbilicus in V, reinsertion of the umbilic in "aile de mouette", a degreasing periumbilical associated with a plication of the umbilical stem. The complications identified in patients medical records and satisfaction were assessed by a telephone questionnaire., Results: Ninety-six patients were included. No patient presented umbilical necrosis. The overall result of umbilical transposition was considered good to excellent for 92.7% of patients., Conclusion: Umbilicoplasty in gull wing has many advantages: it is a simple, easily reproducible, reliable technique, the patients of which are for the most part very satisfied., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Cosmetics Europe, the European Trade Association for the cosmetics and personal care industry, is conducting a multi-phase program to develop regulatory accepted, animal-free testing strategies enabling the cosmetics industry to conduct safety assessments. Based on a systematic evaluation of test methods for skin sensitization, five non-animal test methods (DPRA (Direct Peptide Reactivity Assay), KeratinoSens TM , h-CLAT (human cell line activation test), U-SENS TM , SENS-IS) were selected for inclusion in a comprehensive database of 128 substances. Existing data were compiled and completed with newly generated data, the latter amounting to one-third of all data. The database was complemented with human and local lymph node assay (LLNA) reference data, physicochemical properties and use categories, and thoroughly curated. Focused on the availability of human data, the substance selection resulted nevertheless resulted in a high diversity of chemistries in terms of physico-chemical property ranges and use categories. Predictivities of skin sensitization potential and potency, where applicable, were calculated for the LLNA as compared to human data and for the individual test methods compared to both human and LLNA reference data. In addition, various aspects of applicability of the test methods were analyzed. Due to its high level of curation, comprehensiveness, and completeness, we propose our database as a point of reference for the evaluation and development of testing strategies, as done for example in the associated work of Kleinstreuer et al. We encourage the community to use it to meet the challenge of conducting skin sensitization safety assessment without generating new animal data.

Skin sensitization is a toxicity endpoint of widespread concern, for which the mechanistic understanding and concurrent necessity for non-animal testing approaches have evolved to a critical juncture, with many available options for predicting sensitization without using animals. Cosmetics Europe and the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods collaborated to analyze the performance of multiple non-animal data integration approaches for the skin sensitization safety assessment of cosmetics ingredients. The Cosmetics Europe Skin Tolerance Task Force (STTF) collected and generated data on 128 substances in multiple in vitro and in chemico skin sensitization assays selected based on a systematic assessment by the STTF. These assays, together with certain in silico predictions, are key components of various non-animal testing strategies that have been submitted to the Organization for Economic Cooperation and Development as case studies for skin sensitization. Curated murine local lymph node assay (LLNA) and human skin sensitization data were used to evaluate the performance of six defined approaches, comprising eight non-animal testing strategies, for both hazard and potency characterization. Defined approaches examined included consensus methods, artificial neural networks, support vector machine models, Bayesian networks, and decision trees, most of which were reproduced using open source software tools. Multiple non-animal testing strategies incorporating in vitro, in chemico, and in silico inputs demonstrated equivalent or superior performance to the LLNA when compared to both animal and human data for skin sensitization.

Significant progress has been made in the development and validation of non-animal test methods for skin sensitization assessment. At present, three of the four key events of the Adverse Outcome Pathway (AOP) are assessable by OECD-accepted in vitro methods. The fourth key event describes the immunological response in the draining lymph node where activated dendritic cells present major histocompatibility complex-bound chemically modified peptides to naive T cells, thereby priming the proliferation of antigen-specific T cells. Despite substantial efforts, modelling and assessing this adaptive immune response to sensitizers with in vitro T cell assays still represents a challenge. The Cosmetics Europe Skin Tolerance Task Force organized a workshop, bringing together academic researchers, method developers, industry representatives and regulatory stakeholders to review the scientific status of T cell-based assays, foster a mutual scientific understanding and conceive new options to assess T cell activation. Participants agreed that current T cell assays have come a long way in predicting immunogenicity, but that further investment and collaboration is required to simplify assays, optimize their sensitivity, better define human donor-to-donor variability and evaluate their value to predict sensitizer potency. Furthermore, the potential role of T cell assays in AOP-based testing strategies and subsequent safety assessment concepts for cosmetic ingredients was discussed. It was agreed that it is currently difficult to anticipate uses of T cell assay data for safety assessment and concluded that experience from case studies on real-life risk assessment scenarios is needed to further consider the usefulness of assessing the fourth AOP key event.

Allergic contact dermatitis is a primarily T-cell-mediated inflammatory skin disease induced by exposure to small molecular-weight haptens, which covalently bind to proteins. The abundance of cutaneous T cells that recognize CD1a antigen-presenting molecules raises the possibility that MHC-independent antigen presentation may be relevant in some hapten-driven immune responses. Here we examine the ability of contact sensitizers to influence CD1-restricted immunity. Exposure of human antigen-presenting cells such as monocyte-derived dendritic cells and THP-1 cells to the prototypical contact sensitizer dinitrochlorobenzene potentiated the response of CD1a- and CD1d-autoreactive T cells, which released a vast array of cytokines in a CD1- and TCR-dependent manner. The potentiating effects of dinitrochlorobenzene depended upon newly synthesized CD1 molecules and the presence of endogenous stimulatory lipids. Further examination of a broad panel of contact sensitizers revealed 1,4-benzoquinone, resorcinol, isoeugenol, and cinnamaldehyde to activate the same type of CD1-restricted responses. These findings provide a basis for the antigen-specific activation of skin-associated CD1-restricted T cells by small molecules and may have implications for contact sensitizer-induced inflammatory skin diseases., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The U-SENS™ assay, formerly known as MUSST (Myeloid U937 Skin Sensitization Test), is an in vitro method to assess skin sensitization. Dendritic cell activation following exposure to sensitizers was modelled in the U937 human myeloid cell line by measuring the induction of the expression of CD86 by flow cytometry. The predictive performance of U-SENS™ was assessed via a comprehensive comparison analysis with the available human and LLNA data of 175 substances. U-SENS™ showed 79% specificity, 90% sensitivity and 88% accuracy. A four laboratory ring study demonstrated the transferability, reliability and reproducibility of U-SENS™, with a reproducibility of 95% within laboratories and 79% between-laboratories, showing that the U-SENS™ assay is a promising tool in a skin sensitization risk assessment testing strategy., (Copyright © 2015. Published by Elsevier Ltd.)

The need for non-animal data to assess skin sensitisation properties of substances, especially cosmetics ingredients, has spawned the development of many in vitro methods. As it is widely believed that no single method can provide a solution, the Cosmetics Europe Skin Tolerance Task Force has defined a three-phase framework for the development of a non-animal testing strategy for skin sensitization potency prediction. The results of the first phase – systematic evaluation of 16 test methods – are presented here. This evaluation involved generation of data on a common set of ten substances in all methods and systematic collation of information including the level of standardisation, existing test data,potential for throughput, transferability and accessibility in cooperation with the test method developers.A workshop was held with the test method developers to review the outcome of this evaluation and to discuss the results. The evaluation informed the prioritisation of test methods for the next phase of the non-animal testing strategy development framework. Ultimately, the testing strategy – combined with bioavailability and skin metabolism data and exposure consideration – is envisaged to allow establishment of a data integration approach for skin sensitisation safety assessment of cosmetic ingredients.

The Human Papillomavirus (HPV) E2 protein, which inhibits the E6 and E7 viral oncogenes, is believed to have anti-oncogenic properties. Here, we challenge this view and show that HPV-18 E2 over-activates the Spindle Assembly Checkpoint (SAC) and induces DNA breaks in mitosis followed by aneuploidy. This phenotype is associated with interaction of E2 with the Mitotic Checkpoint Complex (MCC) proteins Cdc20, MAD2 and BUBR1. While BUBR1 silencing rescues the mitotic phenotype induced by E2, p53 silencing or presence of E6/E7 (inactivating p53 and increasing BUBR1 levels respectively) both amplify it. This work pinpoints E2 as a key protein in the initiation of HPV-induced cervical cancer and identifies the SAC as a target for oncogenic pathogens. Moreover, our results suggest a role of p53 in regulating the mitotic process itself and highlight SAC over-activation in a p53-negative context as a highly pathogenic event.

The E2 protein is expressed in the early stage of human papillomavirus (HPV) infection that is associated with cervical lesions. This protein plays important roles in regulation of viral replication and transcription. To characterize the role of E2 protein in modulation of cellular gene expression in HPV infected cells, genome-wide expression profiling of human primary keratinocytes (HPK) harboring HPV16 E2 and HPV18 E2 was investigated using microarray. The Principle Components Analysis (PCA) revealed that the expression data of HPV16 E2 and HPV18 E2-transduced HPKs were rather closely clustered. The Venn diagram of modulated genes showed an overlap of 10 common genes in HPV16 E2 expressing HPK and HPV18 E2 expressing HPK. These genes were expressed with significant difference by comparison with control cells. In addition, the distinct sets of modulated genes were detected 14 and 34 genes in HPV16 E2 and HPV18 E2 expressing HPKs, respectively.

In the early stages of human papillomavirus (HPV) infection, the viral proteins elicit specific immune responses that can participate to regression of ano-genital lesions. HPV E6 protein for instance can reduce type I interferon (IFN) including IFN-κ that is involved in immune evasion and HPV persistence. To evaluate the role of E2 protein in innate immunity in HPV16-associated cervical lesions, genome-wide expression profiling of human primary keratinocytes (HPK) transduced by HPV16 E2 was investigated using microarrays and innate immunity associated genes were specifically analyzed. The analyses showed that the expression of 779 genes was modulated by HPV16E2 and 92 of them were genes associated with innate immunity. Notably IFN-κ and STING were suppressed in HPK expressing the E2 proteins of HPV16 or HPV18 and the trans-activation amino-terminal domain of E2 was involved in the suppressive effect. The relationship between STING, IFN-κ and interferon stimulated genes (ISGs) in HPK was confirmed by gene silencing and real time PCR. The expression of STING and IFN-κ were further determined in clinical specimens by real time PCR. STING and IFN-κ were down-modulated in HPV positive low grade squamous intraepithelial lesions compared with HPV negative controls. This study demonstrates that E2 proteins of high risk HPV reduce STING and IFN-κ transcription and its downstream target genes that might be an immune evasion mechanism involved in HPV persistence and cervical cancer development.