Retrospective comparison of a weight-based dose every 2 weeks with a fixed dose every month: a real-life analysis of nivolumab in the treatment of advanced melanoma.

Nivolumab was first authorized at a weight-based dose (WBD) of 3 mg/kg every two weeks (Q2W). Since 2017, a fixed dose (FD) regimen [first 240 mg Q2W and then 480 mg per month (Q4W)] was allowed. The objective of the study was to compare a WBD regimen and an FD regimen with regard to effectiveness and safety. We conducted a single-center, retrospective, real-life study of consecutive adult patients who had received a WBD of nivolumab or an FD of 480 mg Q4W. The primary endpoint was the occurrence of grade ≥3 immune-related adverse events (irAEs). The secondary endpoints were overall survival and cost of the treatment. In all, 342 patients were included: 71 in the WBD cohort and 271 in the FD cohort. Of these patients, 201 patients (59.6%) experienced an irAE, and 24 of these events were graded as ≥3. At 12 months, there was no significant difference in irAE occurrence between the two cohorts [hazard ratio (95% confidence interval): 0.54 (0.21-1.36), P  = 0.19]. The 12-month overall survival rate was significantly lower in the WBD cohort ( P  < 0.001). Switching from a fortnightly weight dose to a fixed monthly dose halves the cost of hospitalization. Our results did not show a significant difference between WBD and FD cohort in the occurrence of severe irAEs. However overall survival appeared to be significantly higher in FD group. Some clinical trials are investigating a hybrid dosing regimen in which a WBD is capped by an FD. The present results need to be confirmed in prospective studies.

Guidelines for clothing in the operating theatre, 2021.

OBJECTIVE: To provide guidelines for the choice of items of clothing (except sterile surgical gown) for staff working in the operating theatre. DESIGN: A committee of nine experts from SFAR and the SF2H learned societies was convened. A formal conflict-of-interest policy was developed at the beginning of the process and enforced throughout. Likewise, it did not benefit from any funding from a company marketing a health product (drug or medical device). The authors were required to follow the rules of the GRADE® method (Grading of Recommendations Assessment, Development and Evaluation) to assess the quality of the evidence on which the recommendations were based. METHODS: We aimed to formulate recommendations according to the GRADE® methodology for four different fields: operating theatre suits, operating theatre hats, masks, and shoes/over-shoes. Each question was formulated according to the PICO format (Patient, Intervention, Comparison, Outcome). The literature review and recommendations were formulated according to the GRADE® methodology. RESULTS: The experts' synthesis work and their application of the GRADE® method resulted in 13 recommendations. As the GRADE® method could not be integrally applied to all questions, some recommendations were formulated as expert opinions. CONCLUSION: Based on strong agreement between experts, we produced 13 recommendations to guide the choice of operating theatre attire.

Amikacin in emergency surgery: How to dose it optimally?

Amikacin is still a recommended option in emergency surgery. Current guidelines have suggested an amikacin dose of 15-20 mg/kg/24 h for intra-abdominal infections (IAI). Our objectives were to analyse amikacin pharmacokinetics (PK) and dosage requirements in patients who underwent emergency surgery, and to identify an optimal dosing approach. We performed a retrospective data analysis of patients who received amikacin for emergency surgery over 2.5 years, with measurement of both peak (Cmax) and trough (Cmin) concentration after the first dose. The BestDose software was used to analyse amikacin concentrations and simulate various alternative dosage regimens in each patient. We compared concentration estimates with target values: Cmax > 64 mg/L and Cmin < 2.5 mg/L at 24 h. Classification and regression tree analysis was used to identify determinants of Cmax target attainment (TA) and optimal dose. Data from 84 patients, including 62 with IAI, were analysed. Despite a median initial dose of 25 mg/kg, 32% of patients did not achieve the Cmax target. An amikacin dose ≤ 21.5 mg/kg was the primary predictor of failure to achieve the target. A dose of 30 mg kg of total or corrected body weight, as well as a fixed dose of 2500 mg would result in the highest TA. The primary determinants of the optimal dose were ideal body weight, age, and renal function. To conclude, recommended dosages of amikacin in emergency surgery are not optimal. A fixed initial dose of 2500 mg could simplify and optimise dosing in this setting.

ZrCuAg Thin-Film Metallic Glasses: Toward Biostatic Durable Advanced Surfaces.

A combinatorial approach has served as a high-throughput strategy to identify compositional windows with optimized desired properties. Here, ZrCuAg thin-film metallic glasses were deposited by DC magnetron sputtering. For the purpose of using these coatings as biomedical surfaces, their durability in terms of mechanical and physicochemical properties as well as antibacterial properties were characterized. The effect of the chemical composition of thin films was studied. In particular, two key parameters were highlighted: the atomic ratio of Zr/Cu (with three values of 65/35, 50/50, and 35/65) and the silver content (from 1 to 16 at. %). All thin films are XRD amorphous and exhibit a typical veinlike pattern, which is characteristic of metallic glasses. They also show a dense and smooth surface and a hydrophobic behavior. Mechanical properties are found to be deeply influenced by the Zr/Cu ratio and the atomic structure. Although a low Zr/Cu ratio and/or a high silver content is detrimental to corrosion behavior, it favors the bactericidal effect of thin films. For all Zr/Cu ratios, ZrCuAg thin-film metallic glasses with silver contents higher than 12 at % are fully bactericidal. For lower silver contents, the bactericidal effect progressively decreases, which paves the way for a biostatic behavior of these surfaces.

Impact of Sucrose as Osmolyte on Molecular Dynamics of Mouse Acetylcholinesterase.

The enzyme model, mouse acetylcholinesterase, which exhibits its active site at the bottom of a narrow gorge, was investigated in the presence of different concentrations of sucrose to shed light on the protein and water dynamics in cholinesterases. The study was conducted by incoherent neutron scattering, giving access to molecular dynamics within the time scale of sub-nano to nanoseconds, in comparison with molecular dynamics simulations. With increasing sucrose concentration, we found non-linear effects, e.g., first a decrease in the dynamics at 5 wt% followed by a gain at 10 wt% sucrose. Direct comparisons with simulations permitted us to understand the following findings: at 5 wt%, sugar molecules interact with the protein surface through water molecules and damp the motions to reduce the overall protein mobility, although the motions inside the gorge are enhanced due to water depletion. When going to 10 wt% of sucrose, some water molecules at the protein surface are replaced by sugar molecules. By penetrating the protein surface, they disrupt some of the intra-protein contacts, and induce new ones, creating new pathways for correlated motions, and therefore, increasing the dynamics. This exhaustive study allowed for an explanation of the detail interactions leading to the observed non-linear behavior.

Comparison of the Binding of Reversible Inhibitors to Human Butyrylcholinesterase and Acetylcholinesterase: A Crystallographic, Kinetic and Calorimetric Study.

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) hydrolyze the neurotransmitter acetylcholine and, thereby, function as coregulators of cholinergic neurotransmission. Although closely related, these enzymes display very different substrate specificities that only partially overlap. This disparity is largely due to differences in the number of aromatic residues lining the active site gorge, which leads to large differences in the shape of the gorge and potentially to distinct interactions with an individual ligand. Considerable structural information is available for the binding of a wide diversity of ligands to AChE. In contrast, structural data on the binding of reversible ligands to BChE are lacking. In a recent effort, an inhibitor competition approach was used to probe the overlap of ligand binding sites in BChE. Here, we extend this study by solving the crystal structures of human BChE in complex with five reversible ligands, namely, decamethonium, thioflavin T, propidium, huprine, and ethopropazine. We compare these structures to equivalent AChE complexes when available in the protein data bank and supplement this comparison with kinetic data and observations from isothermal titration calorimetry. This new information now allows us to define the binding mode of various ligand families and will be of importance in designing specific reversible ligands of BChE that behave as inhibitors or reactivators.

[Fencing for promoting health after breast cancer]. / L'escrime pour promouvoir la santé après un cancer du sein.

Physical activity is recommended after breast cancer surgery. Fencing is a sport that is well suited to combatting fatigue, pain and reduced arm mobility. A healthcare executive, herself a fencer, puts the benefits of this sport into perspective, both physically and psychologically.

Performance of vegetated swales for improving road runoff quality in a moderate traffic urban area.

In recent years, due to their economic and ecological advantages, green infrastructures for stormwater management have been widely implemented. The present study focused on vegetated swales and compared two vegetated covers, grassed or planted with macrophytes in order to evaluate their performance in terms of water quality improvement. These swales collected runoff of a moderately busy road (<2500vehday(-1)) in a commercial area. Twelve storm events were analyzed over a two year period with measurement of total suspended solids (TSS), chemical oxygen demand (COD), biochemical oxygen demand (BOD), total hydrocarbons (THC), total phosphorous (TP), total Kjeldahl nitrogen (TKN), trace elements and 16 polycyclic aromatic hydrocarbons (PAHs). The grass cover led to poor results due to lower retention of soil particles on which trace elements and PAHs are bounded. The swales planted with macrophytes, with a deeper root system more capable of retaining soil particles, led to reductions of concentrations from 17 to 45% for trace elements such as lead, zinc and copper and 30% for the 16 PAHs in infiltrated waters. In addition, the macrophyte cover showed lower variability of pollutant concentrations in infiltrated waters compared to incoming waters. This buffering capacity is interesting to mitigate the impact of moderate peak pollution on surface water or ground water quality.

Using infrared and Raman microspectroscopies to compare ex vivo involved psoriatic skin with normal human skin.

Psoriasis is a chronic dermatosis that affects around 3% of the world's population. The etiology of this autoimmune pathology is not completely understood. The barrier function of psoriatic skin is known to be strongly altered, but the structural modifications at the origin of this dysfunction are not clear. To develop strategies to reduce symptoms of psoriasis or adequate substitutes for modeling, a deep understanding of the organization of psoriatic skin at a molecular level is required. Infrared and Raman microspectroscopies have been used to obtain direct molecular-level information on psoriatic and healthy human skin biopsies. From the intensities and positions of specific vibrational bands, the lipid and protein distribution and the lipid order have been mapped in the different layers of the skin. Results showed a similar distribution of lipids and collagen for normal and psoriatic human skin. However, psoriatic skin is characterized by heterogeneity in lipid/protein composition at the micrometer scale, a reduction in the definition of skin layer boundaries and a decrease in lipid chain order in the stratum corneum as compared to normal skin. A global decrease of the structural organization is exhibited in psoriatic skin that is compatible with an alteration of its barrier properties.

Macrophage activation syndrome with acute hepatitis E during tocilizumab treatment for rheumatoid arthritis.

Tocilizumab is a humanized antibody against the membrane and soluble receptors for interleukin-6. Tocilizumab is among the disease-modifying antirheumatic drugs (DMARDs) used to treat moderate-to-severe active rheumatoid arthritis (RA) refractory to conventional DMARDs. We report a case of macrophage activation syndrome that complicated acute hepatitis E and started within 24hours after the fourth tocilizumab infusion in a patient with RA.

Characterization of a psoriatic skin model produced with involved or uninvolved cells.

Current knowledge suggests that uninvolved psoriatic skin could demonstrate characteristics associated with both normal and involved psoriatic skins. However, the triggering factor allowing the conversion of uninvolved skin into a psoriatic plaque is not fully understood. To counter this lack of information, we decided to develop pathological skin substitutes produced with uninvolved psoriatic cells, in order to better characterize the uninvolved psoriatic skin. Substitutes were produced using the self-assembly approach. Macroscopic, immunohistochemical, permeability and physicochemical results showed that involved substitutes had a thicker epidermis, higher cell proliferation, abnormal cell differentiation and a more permeable and disorganized stratum corneum compared with normal substitutes. Various results were observed using uninvolved cells, leading to two proposed profiles: profile 1 was suggested for uninvolved skin substitutes mimicking the results obtained with normal skin substitutes; and profile 2 was dedicated to those mimicking involved skin substitutes in all aspects that were analysed. In summary, uninvolved substitutes of profile 1 had a thin, well-organized epidermis with normal cell proliferation and differentiation, such as observed with normal substitutes, while uninvolved substitutes of profile 2 showed an inverse trend, i.e. a thicker epidermis, higher cell proliferation, abnormal cell differentiation and a more disorganized and more permeable stratum corneum, such as seen with involved substitutes. The results suggest that uninvolved substitutes could demonstrate characteristics associated with both normal or involved psoriatic skins.

A comparative study between human skin substitutes and normal human skin using Raman microspectroscopy.

Research in the field of bioengineered skin substitutes is motivated by the need to find new dressings for people affected by skin injuries (burns, diabetic ulcers), and to develop adequate skin models to test new formulations developed in vitro. Thanks to advances in tissue engineering, it is now possible to produce human skin substitutes without any exogenous material, using the self-assembly method developed by the Laboratoire d'Organogénèse Expérimentale. These human skin substitutes consist of a dermis and a stratified epidermis (stratum corneum and living epidermis). Raman microspectroscopy has been used to characterize and compare the molecular organization of skin substitutes with normal human skin. Our results confirm that the stratum corneum is a layer rich in lipids which are well ordered (trans conformers) in both substitutes and normal human skin. The amount of lipids decreases and more gauche conformers appear in the living epidermis in both cases. However, the results also show that there are fewer lipids in the substitutes and that the lipids are more organized in the normal human skin. Concerning the secondary structure of proteins and protein content, the data show that they are similar in the substitutes and in the normal human skin. In fact, the epidermis is rich in α-keratin, whereas the dermis contains mainly type I collagen.

Characterization of the structure of human skin substitutes by infrared microspectroscopy.

The skin acts mainly as a protective barrier from the external environment, thanks to the stratum corneum which is the outermost layer of the skin. As in vitro tests on skin are essential to elaborate new drugs, the development of skin models closer to reality becomes essential. It is now possible to produce in vitro human skin substitutes through tissue engineering by using the self-assembly method developed by the Laboratoire d'Organogénèse Expérimentale. In the present work, infrared microspectroscopy imaging analyses were performed to get in-depth morpho-spectral characterization of the three characteristic layers of human skin substitutes and normal human skin, namely the stratum corneum, living epidermis, and dermis. An infrared spectral analysis of the skin is a powerful tool to gain information on the order and conformation of the lipid chains and the secondary structure of proteins. On one hand, the symmetric stretching mode of the lipid methylene groups (2,850 cm(-1)) is sensitive to the acyl chain conformational order. The evolution profile of the frequency of this vibrational mode throughout the epidermis suggests that lipids in the stratum corneum are more ordered than those in the living epidermis. On the other hand, the frequencies of the infrared components underneath the envelop of the amide I band provide information about the overall protein conformation. The analysis of this mode establishes that the proteins essentially adopt an α-helix conformation in the epidermis, probably associated with the presence of keratin, while modifications of the protein content are observed in the dermis (extracellular matrix made of collagen). Finally, the lipid organization, as well as the protein composition in the different layers, is similar for human skin substitutes and normal human skin, confirming that the substitutes reproduce essential features of real skin and are appropriate biomimetics.

Organophosphate hydrolases as catalytic bioscavengers of organophosphorus nerve agents.

Bioscavengers are molecules able to neutralize neurotoxic organophosphorus compounds (OP) before they can reach their biological target. Human butyrylcholinesterase (hBChE) is a natural bioscavenger each molecule of enzyme neutralizing one molecule of OP. The amount of natural enzyme is insufficient to achieve good protection. Thus, different strategies have been envisioned. The most straightforward consists in injecting a large dose of highly purified natural hBChE to increase the amount of bioscavenger in the bloodstream. This proved to be successful for protection against lethal doses of soman and VX but remains expensive. An improved strategy is to regenerate prophylactic cholinesterases (ChE) by administration of reactivators after exposure. But broad-spectrum efficient reactivators are still lacking, especially for inhibited hBChE. Cholinesterase mutants capable of reactivating spontaneously are another option. The G117H hBChE mutant has been a prototype. We present here the Y124H/Y72D mutant of human acetylcholinesterase; its spontaneous reactivation rate after V-agent inhibition is increased up to 110 fold. Catalytic bioscavengers, enzymes capable of hydrolyzing OP, present the best alternative. Mesophilic bacterial phosphotriesterase (PTE) is a candidate with good catalytic efficiency. Its enantioselectivity has been enhanced against the most potent OP isomers by rational design. We show that PEGylation of this enzyme improves its mean residence time in the rat blood stream 24-fold and its bioavailability 120-fold. Immunogenic issues remain to be solved. Human paraoxonase 1 (hPON1) is another promising candidate. However, its main drawback is that its phosphotriesterase activity is highly dependent on its environment. Recent progress has been made using a mammalian chimera of PON1, but we provide here additional data showing that this chimera is biochemically different from hPON1. Besides, the chimera is expected to suffer from immunogenic issues. Thus, we stress that interest for hPON1 must not fade away, and in particular, the 3D structure of the hPON1 eventually in complex with OP has to be solved.

Magnetic resonance imaging evaluation of cerebral cavernous malformations with susceptibility-weighted imaging.

BACKGROUND: Cerebral cavernous malformations (CCMs) can be sporadic or inherited, the latter characterized by multiple lesions. Novel imaging sequences have increased the sensitivity of detecting multiple CCMs. OBJECTIVE: To compare T2-weighted gradient echo (T2*GRE) and susceptibility-weighted imaging (SWI) sequences in familial and sporadic CCM to assess their respective sensitivity. METHODS: This prospective study included 23 consecutive cases grouped as multifocal/familial CCMs (n=14), solitary/clustered sporadic CCMs with developmental venous anomaly (n=8), and postirradiation CCMs (n=1). Brain magnetic resonance imaging included T2*GRE and SWI sequences. Two radiologists independently counted the number of lesions on each sequence. The difference in the number of lesions on both sequences was compared, and interobserver agreement was evaluated. RESULTS: In multifocal/familial cases, a mean of 34.7 lesions were detected on T2*GRE and 66.9 on SWI (P=.001). The difference of lesion prevalence with the 2 techniques was significant (P=.006), with strong interobserver correlation for the T2*GRE sequence (P<.001) and SWI sequence (P<.001). Patients with solitary/clustered sporadic CCMs, including those associated with venous anomaly, had no difference in lesion prevalence in the 2 sequences. CONCLUSION: SWI is more sensitive than T2*GRE in detecting CCM in multifocal/familial CCMs. Among cases classified as solitary/clustered with conventional imaging, including those associated with venous anomaly, the SWI did not impart additional sensitivity or reveal occult lesions not evident on T2*GRE sequence. No case was changed from the solitary/clustered to the multifocal clinical category because of SWI.

Differential expression of the enzymatic system controlling synthesis, metabolism, and transport of PGF2 alpha in human fetal membranes.

The present study investigated the expression of genes and proteins associated with PGF2alpha biosynthesis, catabolism, and transport in matched amnion and choriodecidua of human term placenta. The concentration of PGF2alpha within fetal membranes depends on the balance between complex enzymatic systems responsible for, respectively, its synthesis-by prostaglandin-endoperoxide synthase 2 (PTGS2) and members of the aldo-keto reductase (AKR) family, AKR1C3 and AKR1B1-and its catabolic inactivation-through hydroxy-prostaglandin-dehydrogenase (HPGD). We observed that AKR1C3 shows equal basal expression (mRNA and protein) in choriodecidua and amnion but that AKR1B1 exhibits preferential expression in the choriodecidua. Expression of HPGD and solute carrier organic anion transporter family member 2A1 (SLCO2A1) was found primarily in the choriodecidua. We also evaluated whether an inflammatory environment induced by the gram-negative bacterial endotoxin lipopolysaccharide (LPS) affects expression of each candidate enzymes. The amnion responded to LPS with a small but significant decrease of AKR1B1 mRNA expression. In contrast, we found a significant increase in PTGS2 and AKR1C3 mRNA expression in choriodecidua after LPS challenge, but such regulation was confirmed only at protein levels for PTGS2 and not for AKR1C3. Our results suggest that the choriodecidua appears to be the main tissue, which expresses maximally all the components (synthesis, degradation, and transport) controlling PGF2alpha levels.

Application of laccase-mediator system (LMS) for the degradation of organophosphorus compounds.

Degradation of organophosphorus compounds was achieved in the presence of purified fungal laccase from Trametes versicolor and a small molecular weight redox mediator (ABTS). This laccase-mediator system (LMS) catalyzed degradation of VX, PhX and VR while had no apparent effect on CVX, ecothiophate or demeton. Inhibition of ABTS oxidation was shown with VX, PhX, VR and CVX. Results with CVX suggest either no degradation subsequent to interaction with the laccase active site or the formation of a new toxic compound. PhX degradation was also monitored by mass spectroscopy, a method that allowed us to identify certain intermediates formed during OP degradation. Altogether, results underline the importance of the OP nitrogen atom at beta-position and of its substituents, even though the intimate mechanism of laccase-catalyzed degradation is not yet known.

The PDE4 inhibitor rolipram prevents NF-kappaB binding activity and proinflammatory cytokine release in human chorionic cells.

Spontaneous preterm delivery is linked to intrauterine inflammation. Fetal membranes are involved in the inflammatory process as an important source of mediators, and the chorion leave produces high levels of the proinflammatory cytokine TNF-alpha when stimulated by LPS. The transcription factor NF-kappaB is the main regulator of this inflammatory process and controls the production of cytokines by the chorion leave. Phosphodiesterase 4 inhibitors are recognized for their anti-inflammatory and myorelaxant effects. The purpose of this study was to investigate whether PDE4 inhibition affects the LPS signaling in human cultured chorionic cells. We showed that these cells express TLR4, the main LPS receptor, and exhibit a predominant PDE4 activity. Upon LPS challenge, PDE4 activity increases concomitantly to the induction of the specific isoform PDE4B2 and chorionic cells secrete TNF-alpha. LPS induces the nuclear translocation of the NF-kappaB p65 subunit and the activation of three different NF-kappaB complexes in chorionic cells. The presence of the PDE4 inhibitor rolipram reduces the TNF-alpha production and the activation of the three NF-kappaB complexes. These data indicate that the PDE4 family interacts with the LPS signaling pathway during the inflammatory response of chorionic cells. PDE4 selective inhibitors may thus represent a new therapeutic approach in the management of inflammation-induced preterm delivery.