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Daniel Bacqueville,1,* Anne Maret,2,* Maïté Noizet,1 Laure Duprat,1 Christine Coutanceau,3 Victor Georgescu,3 Sandrine Bessou-Touya,1 Hélène Duplan1 1Department of Pharmacology, Pierre Fabre Dermo-Cosmétique, Toulouse, France; 2Clinical Skin Research Center, Pierre Fabre Dermo-Cosmétique, Toulouse, France; 3Laboratoires Dermatologiques Avène, Lavaur, France*These authors contributed equally to this workCorrespondence: Daniel BacquevilleDepartment of Pharmacology, Pierre Fabre Dermo-Cosmétique, Avenue Hubert Curien, BP 13562, 31035 Toulouse Cedex 1, FranceTel +33 5 34 50 64 27Fax +33 5 34 50 34 24Email daniel.bacqueville@pierre-fabre.comBackground: Skin aging is characterized by slacking and loss of density, especially under ultraviolet (UV) radiation exposure.Objective: To investigate the beneficial effects of a combination containing bakuchiol (BK) and vanilla tahitensis extract (VTE) to prevent skin photoaging in vitro and to improve clinical outcomes for naturally aged skin.Materials and Methods: Human dermal fibroblasts were treated with active compounds, exposed to an acute dose of UVA and analyzed by confocal microscopy: actin network for morphology, interleukin-8 (IL-8) for inflammation and p16 for senescence. Human skin was used to evaluate chronic UVA-induced glycosaminoglycan (GAG) loss and to assess the benefit of topical application of a BK+VTE serum (Alcian blue staining). An open-label clinical trial was conducted in women applying the serum twice daily for 56 days (n=43). Skin remodeling was assessed by FaceScan®. Firmness was evaluated through Dynaskin® and clinical scoring. Skin radiance was also rated on standardized full-face photographs.Results: UVA induced a significant increase in IL-8 and p16 expression and marked morphological changes in fibroblasts. Treatment with BK or VTE alone prevented both actin network alteration and IL-8 upregulation. Interestingly, BK+VTE demonstrated synergistic protection against IL-8 and p16 overexpression. Serum application prevented GAG loss at the dermo-epidermal junction and increased dermal GAG in UVA-exposed skin explants. In the clinical trial, face ptosis was reduced by 11% on average for 26 responsive subjects and up to 23%. Depth of skin deformation was also reduced by 24% on average for 30 responsive subjects and up to 30%. This firming effect was confirmed by clinical scoring. Radiance was significantly improved by 29% on average for 33 responsive subjects. The serum demonstrated good tolerance/safety.Conclusion: BK+VTE combination demonstrated anti-aging efficacy and might provide a substantial benefit in the daily care of naturally aged skin in women, through their synergistic effect on inflammaging and senescence.Keywords: anti-aging therapy, clinical trial, inflammaging, senescence, skin model

Intrinsic and extrinsic factors, including lifestyle and sun exposure, can contribute to cell senescence, which impairs skin homeostasis, that may in turn lead to skin aging. Senescent cells have a specific secretome, called the senescence-associated secretory phenotype (SASP) that includes MMPs, CXCLs and S100A8/9. Reducing the SASP with senotherapeutics is a promising strategy to reduce skin aging. Here we evaluated the effect of a formula containing niacinamide and hyaluronic acid, which are known to limit senescence and skin aging. We conducted three different studies. (1) Ex vivo explants treated with the formula had more collagen and glycosaminoglycan. (2) In a clinical trial with forty-four women, two months of treatment improved fine lines, wrinkles, luminosity, smoothness, homogeneity, and plumpness. (3) In a third study on thirty women, we treated one arm for two months and took skin biopsies to study gene expression. 101 mRNAs and 13 miRNAs were differentially expressed. We observed a likely senomorphic effect, as there was a decrease in many SASP genes including MMP12 and CXCL9 and a significant downregulation of autocrine signaling genes: S100A8 and S100A9. These pharmaco-clinical results are the first to demonstrate the senomorphic properties of an effective anti-aging formula in skin., (© 2024. The Author(s).)

Importance: Patients in the emergency department (ED) who are waiting for hospital admission on a wheeled cot may be subject to harm. However, mortality and morbidity among older patients who spend the night in the ED while waiting for a bed in a medical ward are unknown., Objective: To assess whether older adults who spend a night in the ED waiting for admission to a hospital ward are at increased risk of in-hospital mortality., Design, Settings, and Participants: This was a prospective cohort study of older patients (≥75 years) who visited the ED and were admitted to the hospital on December 12 to 14, 2022, at 97 EDs across France. Two groups were defined and compared: those who stayed in the ED from midnight until 8:00 am (ED group) and those who were admitted to a ward before midnight (ward group)., Main Outcomes and Measures: The primary end point was in-hospital mortality, truncated at 30 days. Secondary outcomes included in-hospital adverse events (ie, falls, infection, bleeding, myocardial infarction, stroke, thrombosis, bedsores, and dysnatremia) and hospital length of stay. A generalized linear-regression mixed model was used to compare end points between groups., Results: The total sample comprised 1598 patients (median [IQR] age, 86 [80-90] years; 880 [55%] female and 718 [45%] male), with 707 (44%) in the ED group and 891 (56%) in the ward group. Patients who spent the night in the ED had a higher in-hospital mortality rate of 15.7% vs 11.1% (adjusted risk ratio [aRR], 1.39; 95% CI, 1.07-1.81). They also had a higher risk of adverse events compared with the ward group (aRR, 1.24; 95% CI, 1.04-1.49) and increased median length of stay (9 vs 8 days; rate ratio, 1.20; 95% CI, 1.11-1.31). In a prespecified subgroup analysis of patients who required assistance with the activities of daily living, spending the night in the ED was associated with a higher in-hospital mortality rate (aRR, 1.81; 95% CI, 1.25-2.61)., Conclusions and Relevance: The findings of this prospective cohort study indicate that for older patients, waiting overnight in the ED for admission to a ward was associated with increased in-hospital mortality and morbidity, particularly in patients with limited autonomy. Older adults should be prioritized for admission to a ward.

Introduction: Understanding hypoxemia, with and without the clinical signs of acute respiratory failure (ARF) in COVID-19, is key for management. Hence, from a population of critical patients admitted to the emergency department (ED), we aimed to study silent hypoxemia (Phenotype I) in comparison to symptomatic hypoxemia with clinical signs of ARF (Phenotype II). Methods: This multicenter study was conducted between 1 March and 30 April 2020. Adult patients who were presented to the EDs of nine Great-Eastern French hospitals for confirmed severe or critical COVID-19, who were then directly admitted to the intensive care unit (ICU), were retrospectively included. Results: A total of 423 critical COVID-19 patients were included, out of whom 56.1% presented symptomatic hypoxemia with clinical signs of ARF, whereas 43.9% presented silent hypoxemia. Patients with clinical phenotype II were primarily intubated, initially, in the ED (46%, p < 0.001), whereas those with silent hypoxemia (56.5%, p < 0.001) were primarily intubated in the ICU. Initial univariate analysis revealed higher ICU mortality (29.2% versus 18.8%, p < 0.014) and in-hospital mortality (32.5% versus 18.8%, p < 0.002) in phenotype II. However, multivariate analysis showed no significant differences between the two phenotypes regarding mortality and hospital or ICU length of stay. Conclusions: Silent hypoxemia is explained by various mechanisms, most physiological and unspecific to COVID-19. Survival was found to be comparable in both phenotypes, with decreased survival in favor of Phenotype II. However, the spectrum of silent to symptomatic hypoxemia appears to include a continuum of disease progression, which can brutally evolve into fatal ARF.

Introduction: For the past two years, healthcare systems worldwide have been battling the ongoing COVID-19 pandemic. Several studies tried to find predictive factors of mortality in COVID-19 patients. We aimed to research age as a predictive factor associated with in-hospital mortality in severe and critical SARS-CoV-2 infection. Methods: Between 1 March and 20 April 2020, we conducted a multicenter and retrospective study on a cohort of severe COVID-19 patients who were all hospitalized in the Intensive Care Unit (ICU). We led our study in nine hospitals of northeast France, one of the pandemic’s epicenters in Europe. Results: The median age of our study population was 66 years (58−72 years). Mortality was 24.6% (CI 95%: 20.6−29%) in the ICU and 26.5% (CI 95%: 22.3−31%) in the hospital. Non-survivors were significantly older (69 versus 64 years, p < 0.001) than the survivors. Although a history of cardio-vascular diseases was more frequent in the non-survivor group (p = 0.015), other underlying conditions and prior level of autonomy did not differ between the two groups. On multivariable analysis, age appeared to be an interesting predictive factor of in-hospital mortality. Thus, age ranges of 65 to 74 years (OR = 2.962, CI 95%: 1.231−7.132, p = 0.015) were predictive of mortality, whereas the group of patients aged over 75 years was not (OR = 3.084, CI 95%: 0.952−9.992, p = 0.06). Similarly, all comorbidities except for immunodeficiency (OR = 4.207, CI 95%: 1.006−17.586, p = 0.049) were not predictive of mortality. Finally, survival follow-up was obtained for the study population. Conclusion: Age appears to be a relevant predictive factor of in-hospital mortality in cases of severe or critical SARS-CoV-2 infection.

Objective: We investigated the dermal bioavailability and antioxidative properties of a sunscreen formulation containing two antioxidants, oxothiazolidine (OTZ) and δ-tocopheryl glucoside (DTG). OTZ reacts directly with reactive oxygen species to form taurine, while DTG is metabolized in δ-tocopherol to achieve antioxidative activities., Methods: After topical application to a hair follicle-derived reconstructed human epidermis (RHE) model, followed by solar-simulated radiation, kinetics of bioavailability and antioxidative responses were measured over 24 h. Markers for oxidative stress were malondialdehyde (MDA), superoxide dismutase (SOD) and catalase activities., Results: The two antioxidants had different bioavailability profiles: OTZ was rapidly and extensively absorbed, whereas DTG was slowly absorbed and converted to δ-tocopherol. Compared to OTZ alone, the protection against effects on MDA levels and SOD and catalase activities was higher when DTG was used alone or in combination with OTZ. When used in combination, the degree of protection increased over time and remained constant over 24 h with maximal protection 2 h post-irradiation. DTG slowly penetrated into the skin and was present in the skin at all post-irradiation timepoints, thus allowing a slow but constant supply of δ-tocopherol over at least 24 h. By contrast, the oxidative protection by OTZ was immediate but short-lived due to its rapid penetration through the RHE and into the receptor fluid., Conclusion: These results indicate a complementary sunlight protective action of OTZ and DTG with an immediate delivery of OTZ just after topical application of the formulation, and a prolonged skin delivery of δ-tocopherol from the slower penetration and metabolism of DTG., (© 2021 Society of Cosmetic Scientists and the Société Française de Cosmétologie.)

Introduction: The COVID-19 outbreak had a major impact on healthcare systems worldwide. Our study aims to describe the characteristics and therapeutic emergency mobile service (EMS) management of patients with vital distress due to COVID-19, their in-hospital care pathway and their in-hospital outcome., Methods: This retrospective and multicentric study was conducted in the six main centers of the French Greater East region, an area heavily impacted by the pandemic. All patients requiring EMS dispatch and who were admitted straight to the intensive care unit (ICU) were included. Clinical data from their pre-hospital and hospital management were retrieved., Results: We included a total of 103 patients (78.6% male, median age 68). In the initial stage, patients were in a critical condition (median oxygen saturation was 72% (60-80%)). In the field, 77.7% (CI 95%: 71.8-88.3%) were intubated. Almost half of our population (45.6%, CI 95%: 37.1-56.9%) had clinical Phenotype 1 (silent hypoxemia), while the remaining half presented Phenotype 2 (acute respiratory failure). In the ICU, a great number had ARDS (77.7%, CI 95% 71.8-88.3% with a PaO 2 /FiO 2 < 200). In-hospital mortality was 33% (CI 95%: 24.6-43.3%). The two phenotypes showed clinical and radiological differences (respiratory rate, OR = 0.98, p = 0.02; CT scan lesion extension >50%, OR = 0.76, p < 0.03). However, no difference was found in terms of overall in-hospital mortality (OR = 1.07, p = 0.74)., Conclusion: The clinical phenotypes appear to be very distinguishable in the pre-hospital field, yet no difference was found in terms of mortality. This leads us to recommend an identical management in the initial phase, despite the two distinct presentations.

Triple-negative breast cancers (TNBCs) account for a large proportion of breast cancer deaths, due to the high rate of recurrence from residual, resistant tumor cells. New treatments are needed, to bypass chemoresistance and improve survival. The WNT pathway, which is activated in TNBCs, has been identified as an attractive pathway for treatment targeting. We analyzed expression of the WNT coreceptors LRP5 and LRP6 in human breast cancer samples. As previously described, LRP6 was overexpressed in TNBCs. However, we also showed, for the first time, that LRP5 was overexpressed in TNBCs too. The knockdown of LRP5 or LRP6 decreased tumorigenesis in vitro and in vivo , identifying both receptors as potential treatment targets in TNBC. The apoptotic effect of LRP5 knockdown was more robust than that of LRP6 depletion. We analyzed and compared the transcriptomes of cells depleted of LRP5 or LRP6, to identify genes specifically deregulated by LRP5 potentially implicated in cell death. We identified serine/threonine kinase 40 (STK40) as one of two genes specifically downregulated soon after LRP5 depletion. STK40 was found to be overexpressed in TNBCs, relative to other breast cancer subtypes, and in various other tumor types. STK40 depletion decreased cell viability and colony formation, and induced the apoptosis of TNBC cells. In addition, STK40 knockdown impaired growth in an anchorage-independent manner in vitro and slowed tumor growth in vivo . These findings identify the largely uncharacterized putative protein kinase STK40 as a novel candidate treatment target for TNBC., Competing Interests: CONFLICTS OF INTEREST The authors have no conflicts of interest to declare.

Fibroblasts are important players in regulating tissue homeostasis. In the dermis, they are involved in wound healing where they differentiate into contractile myofibroblasts leading to wound closure. In nonhealing chronic wounds, fibroblasts fail to undertake differentiation. We established and used a human ex vivo model of chronic wounds where fibroblasts can undergo normal myofibroblast differentiation, or take on a nondifferentiable pathological state. At the whole genome scale, we identified the genes that are differentially regulated in these two cell fates. By coupling the search of evolutionary conserved regulatory elements with global gene network expression changes, we identified transcription factors (TF) potentially involved in myofibroblast differentiation, and constructed a network of relationship between these key factors. Among these, we found that TCF4, SOX9, EGR2, and FOXS1 are major regulators of fibroblast to myofibroblast differentiation. Conversely, down-regulation of MEOX2, SIX2, and MAF causes reprogramming of fibroblasts to myofibroblasts even in absence of TGF-β, the natural inducer of myofibroblast differentiation. These results provide insight into the fibroblast differentiation program and reveal a TF network essential for cellular reprogramming. They could lead to the development of new therapeutics to treat fibroblast-related human pathologies., (© 2015 by the Wound Healing Society.)

The management of a healthcare institution generates risks through the very hazards of the management process. The management of these risks is integrated into the global safety management process and into the strategic thinking of geriatric hospitals.

Virus-induced gene silencing (VIGS) is an important tool for the analysis of gene function in plants. This technique exploits recombinant viral vectors harbouring fragments of plant genes in their genome to generate double-stranded RNAs that initiate homology-dependent silencing of the target gene. Several viral VIGS vectors have already been successfully used in reverse-genetics studies of a variety of processes occurring in plants. Here, we show that a viral vector derived from Turnip yellow mosaic virus (TYMV) has the ability to induce VIGS in Arabidopsis thaliana, accession Col-0, provided that it carries an inverted-repeat fragment of the target gene. Robust and reliable gene silencing was observed when plants were inoculated simply by abrasion with intact plasmid DNA harbouring a cDNA copy of the viral genome, thus precluding the need for in vitro transcription, biolistic or agroinoculation procedures. Our results indicate that a 76 bp fragment is sufficient to cause gene silencing in leaves, stems and flowers, and that the TYMV-derived vector also has the ability to target genes expressed in meristematic tissues. The VIGS vector described here may thus represent an ideal tool for improving high-throughput functional genomics in Arabidopsis.

The expression of a fusion protein formed between the avian infectious bronchitis virus M protein and the bacterial enzyme beta-glucuronidase (GUS) in plants promotes the formation of new organization of the endoplasmic reticulum in tobacco plants. This unusual organization of the membranes, never present in nontransformed plants, has been explained by the oligomerization of the GUS domains of the IBVM-GUS fusion proteins. These specific organized membranes could have broad implications for biotechnology since their formation could be used as a mechanism for retaining and accumulating resident proteins in specific and discrete membrane compartments. In this study, we have shown that the unusual organization of native membranes due to overexpression of the IBVM-GUS fusion gene in tobacco transgenic plants and calli is present at higher levels in plant cell suspensions than in plant tissues. In these cell suspensions, IBVM-GUS protein was continuously synthesized and accumulated throughout the cell culture. An enrichment of the chimeric IBVM-GUS protein corresponding to a five-fold increase in the microsomal fractions was achieved and the GUS enzyme did not show any modification on enzyme kinetics. However, the GUS activity could be differentially distributed in the fractions eluted at different pH suggesting differences in the surface topography of histidine residues for this recombinant GUS.

Turnip yellow mosaic virus (TYMV) is a positive-strand RNA virus able to infect Arabidopsis thaliana. To establish a TYMV infection system in Arabidopsis cell culture, TYMV replicons with the capsid protein gene replaced by a reporter gene expressing the Sh ble protein conferring zeocin resistance were used to transfect Arabidopsis cells. Zeocin-resistant Arabidopsis calli were used to generate a suspension cell culture. Detection of viral proteins and RNAs after 18 months in culture demonstrated persistent replication of the replicon. The Arabidopsis cell culture yielded soluble, active replication complexes, providing a useful tool to study host factors involved in TYMV replication.