Past and Future of Phage Therapy and Phage-Derived Proteins in Patients with Bone and Joint Infection.

Phage-derived therapies comprise phage therapy and the use of phage-derived proteins as anti-bacterial therapy. Bacteriophages are natural viruses that target specific bacteria. They were proposed to be used to treat bacterial infections in the 1920s, before the discovery and widespread over-commercialized use of antibiotics. Phage therapy was totally abandoned in Western countries, whereas it is still used in Poland, Georgia and Russia. We review here the history of phage therapy by focusing on bone and joint infection, and on the development of phage therapy in France in this indication. We discuss the rationale of its use in bacterial infection and show the feasibility of phage therapy in the 2020s, based on several patients with complex bone and joint infection who recently received phages as compassionate therapy. Although the status of phage therapy remains to be clarified by health care authorities, obtaining pharmaceutical-grade therapeutic phages (i.e., following good manufacturing practice guidelines or being "GMP-like") targeting bacterial species of concern is essential. Moreover, multidisciplinary clinical expertise has to determine what could be the relevant indications to perform clinical trials. Finally "phage therapy 2.0" has to integrate the following steps: (i) follow the status of phage therapy, that is not settled and defined; (ii) develop in each country a close relationship with the national health care authority; (iii) develop industrial-academic partnerships; (iv) create academic reference centers; (v) identify relevant clinical indications; (vi) use GMP/GMP-like phages with guaranteed quality bioproduction; (vii) start as salvage therapy; (vii) combine with antibiotics and adequate surgery; and (viii) perform clinical trials, to finally (ix) demonstrate in which clinical settings phage therapy provides benefit. Phage-derived proteins such as peptidoglycan hydrolases, polysaccharide depolymerases or lysins are enzymes that also have anti-biofilm activity. In contrast to phages, their development has to follow the classical process of medicinal products. Phage therapy and phage-derived products also have a huge potential to treat biofilm-associated bacterial diseases, and this is of crucial importance in the worldwide spread of antimicrobial resistance.

[A historical view of breast implants: Controversy on silicones and breast implant associated -anaplastic large cell lymphoma]. / Seins à dessein. Une histoire d' implants mammaires : controverses autour de la silicone et du lymphome anaplasique a grandes cellules-associe implants mammaires.

Since the dawn of breast implantation back in the sixties, five generations of breast implants have tried to provide the most natural-looking results while striving to eliminate the risk of unpleasant ruptures or capsular contractures. National Health regulators (i.e. the FDA in USA and ANSM in France) have had an "after the facts" reaction, which led to a so-called "dirty war" among producers in the form of a 1992 Silicone's Moratorium (after suspicions of associated cancer or immune-related disorders) all this under the rigid oversight of a FDA director, who seemed more sensible to media scandal than scientific data. After more than a decade of consistent scientific evidence, the interdiction was finally ended in France in 2001 and in the USA in 2006, however the scandals resurfaced again in 2011 after a proven fraud on the "PIP - affair" and most recently with "breast implant associated - anaplastic large cell lymphoma", an extremely serious and rare pathology, treated only by surgical means, until further research. We describe also a chronology on the way the FDA finally recognized this dramatic complication.

Effect of Ratio in Ammonium Nitrate on the Structural, Microstructural, Magnetic, and AC Conductivity Properties of BaFe12O19.

This paper investigates the effect of the ratio of ammonium nitrate (AN) on the structural, microstructural, magnetic, and alternating current (AC) conductivity properties of barium hexaferrite (BaFe12O19). The BaFe12O19 were prepared by using the salt melt method. The samples were synthesized using different powder-to-salt weight ratio variations (1:3, 1:4, 1:5, 1:6 and 1:7) of BaCO3 + Fe2O3 and ammonium nitrate salt. The NH4NO3 was melted on a hot plate at 170 °C. A mixture of BaCO3 and Fe2O3 were added into the NH4NO3 melt solution and stirred for several hours using a magnetic stirrer under a controlled temperature of 170 °C. The heating temperature was then increased up to 260 °C for 24 hr to produce an ash powder. The x-ray diffraction (XRD) results show the intense peak of BaFe12O19 for all the samples and the presence of a small amount of the impurity Fe2O3 in the samples, at a ratio of 1:5 and 1:6. From the Fourier transform infra-red (FTIR) spectra, the band appears at 542.71 cm - 1 and 432.48 cm - 1 , which corresponding to metal⁻oxygen bending and the vibration of the octahedral sites of BaFe12O19. The field emission scanning electron microscope (FESEM) images show that the grains of the samples appear to stick each other and agglomerate at different masses throughout the image with the grain size 5.26, 5.88, 6.14, 6.22, and 6.18 µm for the ratios 1:3, 1:4, 1:5, 1:6, and 1:7 respectively. From the vibrating sample magnetometer (VSM) analysis, the magnetic properties of the sample ratio at 1:3 show the highest value of coercivity Hc of 1317 Oe, a saturation magnetization Ms of 91 emu/g, and a remnant Mr of 44 emu/g, respectively. As the temperature rises, the AC conductivity is increases with an increase in frequency.

Comparative Assessment of Off-label and Unlicensed Drug Prescriptions in Children: FDA Versus ANSM Guidelines.

PURPOSE: The main objectives of this study were to assess the incidence of off-label (OL) and/or unlicensed (UL) prescriptions in a sample of pediatric Lebanese patients by using US Food and Drug Administration (FDA) and the French Medical Regulatory Authority (ANSM) regulations. The goal was to analyze the divergences between regulations and to identify those drugs most commonly involved in OL-UL utilization. METHODS: This study was a retrospective analysis (500 pediatric files) conducted in a Lebanese University hospital in 3 pediatric wards (chronic diseases, acute diseases, and the pediatric intensive care unit). FINDINGS: The frequency of OL-UL drug use was significantly different between pediatric wards (P < 0.001), with the highest incidence occurring in the intensive care unit. The most frequent OL-UL prescriptions occurred with cancer (oncology) admissions. Age was significantly related to OL-UL frequency (highest incidence in children aged between 0 and 1 year). The number of drugs prescribed per patient ranged between 1 and 20 (mean [SD], 4.13 [2.6]). The incidence of OL-UL prescriptions was significantly higher in patients treated with a greater number of medicines (P < 0.001). Overall, 58.9% of drug prescriptions were authorized according to ANSM and 50.7% according to FDA regulations; 11.1% (ANSM) and 15.8% (FDA) were UL, and 30.2% (ANSM) and 33.5% (FDA), respectively, were OL use (where OL for the indication were the most common). The highest percentage of OL-UL prescriptions was seen with the following groups: blood and blood-forming organs, genitourinary system, and sex hormones. Divergence between FDA and ANSM was mainly observed for OL medicines. UL prescriptions assessed according to both regulations showed similar results. IMPLICATIONS: This study highlights the need for prescribers to continuously examine updates to official regulations to avoid using an OL-UL drug whenever possible. It also calls for better harmonization between worldwide official guidelines concerning drugs used in children to reduce risk factors for adverse drug reactions.

Liquid chromatography-tandem mass spectrometry assay for therapeutic drug monitoring of the tyrosine kinase inhibitor, midostaurin, in plasma from patients with advanced systemic mastocytosis.

We developed and validated quantitative bioanalytical liquid chromatography-tandem mass spectrometry assay for the protein kinase inhibitor, midostaurin. Plasma samples were pre-treated using a protein precipitation with methanol containing midostaurin-d5 as an internal standard. After centrifugation, 5µL of the supernatant was injected into the chromatographic system. The system consisted of a 3.5µm particle bonded octadecyl silica column, with gradient elution using a mixture of 0.1% (v/v) formic acid in acetonitrile and 10mM ammonium formate in water with 0.1% formic acid. The analyte was quantified using the selected reaction-monitoring mode of a triple quadrupole mass spectrometer equipped with a heated electrospray interface. The assay was validated in a 75-2500ng/mL calibration range. For quality control, within-day and between-day precisions were 1.2-2.8%, and 1.2-6.9%, respectively. The ß-expectation tolerance limit (accuracy) met the limits of acceptance ±15% (±20% for the LLQ). The drug was sufficiently stable under all relevant analytical conditions. The assay has successfully been used to assess drug levels for therapeutic drug monitoring in patients presenting advanced systemic mastocytosis and treated with the promising midostaurin.

In vitro efficacy of Myxococcus fulvus ANSM068 to biotransform aflatoxin B1.

Aflatoxin B(1) (AFB(1)) is commonly found in cereals and animal feeds and causes a significant threat to the food industry and animal production. Several microbial isolates with high AFB(1) transformation ability have been identified in our previous studies. The aim of this research was to characterize one of those isolates, Myxococcus fulvus ANSM068, and to explore its biotransformation mechanism. The bacterial isolate of M. fulvus ANSM068, isolated from deer feces, was able to transform AFB(1) by 80.7% in liquid VY/2 medium after incubation at 30 °C for 72 h. The supernatant of the bacterial culture was more effective in transforming AFB(1) as compared to the cells alone and the cell extract. The transformation activity was significantly reduced and eradicated after the culture supernatant was treated with proteinase K, proteinase K plus SDS and heating. Culture conditions, including nitrogen source, initial pH and incubation temperature were evaluated for an optimal AFB(1) transformation. Liquid chromatography mass spectrometry (LCMS) analyses showed that AFB(1) was transformed to a structurally different compound. Infrared analysis (IR) indicated that the lactone ring on the AFB(1) molecule was modified by the culture supernatant. Chromatographies on DEAE-Ion exchange and Sephadex-Molecular sieve and SDS-PAGE electrophoresis were used to determine active components from the culture supernatant, indicating that enzyme(s) were responsible for the AFB(1) biotransformation. This is the first report on AFB(1) transformation by a strain of myxobacteria through enzymatic reaction(s).