Background The efficacy and safety of tofacitinib, a Janus kinase inhibitor, in patients who are hospitalized with coronavirus disease 2019 (Covid-19) pneumonia are unclear. Methods We randomly assigned, in a 1:1 ratio, hospitalized adults with Covid-19 pneumonia to receive either tofacitinib at a dose of 10 mg or placebo twice daily for up to 14 days or until hospital discharge. The primary outcome was the occurrence of death or respiratory failure through day 28 as assessed with the use of an eight-level ordinal scale (with scores ranging from 1 to 8 and higher scores indicating a worse condition). All-cause mortality and safety were also assessed. Results A total of 289 patients underwent randomization at 15 sites in Brazil. Overall, 89.3% of the patients received glucocorticoids during hospitalization. The cumulative incidence of death or respiratory failure through day 28 was 18.1% in the tofacitinib group and 29.0% in the placebo group (risk ratio, 0.63; 95% confidence interval [CI], 0.41 to 0.97; P=0.04). Death from any cause through day 28 occurred in 2.8% of the patients in the tofacitinib group and in 5.5% of those in the placebo group (hazard ratio, 0.49; 95% CI, 0.15 to 1.63). The proportional odds of having a worse score on the eight-level ordinal scale with tofacitinib, as compared with placebo, was 0.60 (95% CI, 0.36 to 1.00) at day 14 and 0.54 (95% CI, 0.27 to 1.06) at day 28. Serious adverse events occurred in 20 patients (14.1%) in the tofacitinib group and in 17 (12.0%) in the placebo group. Conclusions Among patients hospitalized with Covid-19 pneumonia, tofacitinib led to a lower risk of death or respiratory failure through day 28 than placebo. (Funded by Pfizer; STOP-COVID ClinicalTrials.gov number, NCT04469114 .)

To cite this version:Marie Vagner, Ester Santigosa. Characterization and modulation of gene expression and enzymatic activity of delta-6 desaturase in teleosts: A review.This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues.Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited.In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier's archiving and manuscript policies are encouraged to visit:There is currently considerable interest in understanding how the biosynthetic pathways of highly unsaturated fatty acids (HUFA) are regulated in fish. The aim is to know if it is possible to replace fish oils (FO), rich in HUFA, by vegetable oils (VO), poor in HUFA and rich in their 18 carbon fatty acid precursors, in the feed of cultured fish species of commercial importance. Thus many studies have focussed on delta-6 desaturase (Δ6D) since it is the rate-limiting enzyme involved in HUFA biosynthesis from precursors. The aims of this paper were (i) to review and compare the structure, function, and tissue distribution of the Δ6D gene in teleosts and (ii) to review the effect of nutrition and environment on the modulation of Δ6D gene expression and on the activity of this enzyme in teleosts. Most existing studies have clearly shown that Δ6D is modulated by nutrition and environment in freshwater fish. This modulation allows the control of lipid metabolism and the maintenance of cell membrane functionality. Δ6D gene expression and enzymatic activity were higher in fish fed VO diets than in those fed FO diets, irrespective of their life cycle in seawater or freshwater; this concurs with expectations regarding the compensation for HUFA deficiency in VO. However, the magnitude of these increases was not great enough to maintain HUFA tissue content. Such a decrease in tissue content may result either from competition between substrates for Δ6D or from the inhibition of subsequent steps in HUFA biosynthesis, such as elongation or delta-5 desaturation activity. Other studies showed that Δ6D enzyme activity is stimulated at low temperatures and low salinities, which keep cell membranes fluid. In salmonids, Δ6D would then play an important role in the adaptation to salinity changes at parr-smolt transformation. In marine fish, similar nutritional and environmental modulations may occur, although conflicting data exist. A low expression of the Δ6D gene or the involvement of genetic, environmental, or hormonal factors could explain why Δ6D appears to be barely functional in marine fish. This review shows that, despite the large number of studies investigating the regulation of Δ6D, little is kno...

A linkage map of 40 linkage groups (LGs) was developed for brook charr, Salvelinus fontinalis, using an F2 interstrain hybrid progeny (n = 171) and 256 coding gene SNP developed specifically for brook charr and validated from a large (>1000) subset of putative SNP, as well as 81 microsatellite markers. To identify quantitative trait loci (QTL) related to reproduction functions, these fish were also phenotyped at six physiological traits, including spermatozoid head diameter, sperm concentration, plasma testosterone, plasma 11-keto-testosterone, egg diameter, and plasma 17β-estradiol. Five significant QTL were detected over four LGs for egg diameter and plasma 17β-estradiol concentration in females, and sperm concentration as well as spermatozoid head diameter in males. In females, two different QTLs located on LG 11 and LG 34 were associated with the egg number, whereas one QTL was associated with plasma 17β-estradiol concentration (LG 8). Their total percent variance explained (PVE) was 26.7% and 27.6%, respectively. In males, two QTL were also detected for the sperm concentration, and their PVE were estimated at 18.58% and 14.95%, respectively. The low QTL number, associated with the high PVE, suggests that the variance in these reproductive physiological traits was either under the control of one major gene or a small number of genes. The QTL associated with sperm concentration, plasma 17β-estradiol, and egg diameter appeared to be under a dominance effect, whereas the two others were under a negative additive effect. These results show that genes underlying the phenotypic variance of these traits are under different modes of action (additive vs. dominance) and may be used to predict an increase or a decrease in their phenotypic values in subsequent generations of selective breeding. Moreover, this newly developed panel of mapped SNP located in coding gene regions will be useful for screening wild populations, especially in the context of investigating the genetic impact of massive stocking of domestic brook charr to support the angling industry throughout eastern North America.

The purpose of this study was to check if it is possible to influence sea bass juvenile metabolism by a conditioning of larvae from day 6 post hatching to day 45 to a low or a high HUFA compound diet (LH, 0.8% EPA + DHA and HH, 2.2% EPA + DHA) when reared at 16 or 22 °C. Following a 3-month intermediate period (at 19 °C using a commercial diet), the adaptability of the 4 initial larval groups to a HUFA experimental deprived diet (0.5% EPA + DHA) were tested at 19 °C in a 60 day-experiment (d-151-211). The four experimental duplicated conditions were ex-LH16 and ex-HH16 for the 2 groups previously reared at 16 °C (initial weight, 7.3 ± 0.5 g) and ex-LH22 and ex-HH22 for the 2 groups previously reared at 22 °C (initial weight, 11.1 ± 0.5 g). Survival was maximal and there was a 1.6-2 fold increase in mass during the experiment. Growth was similar in the 4 experimental groups: NS difference in growth curve slopes (P = 0.7). At the end of the experiment (d-211), whole body fat levels were in the same range in all groups (13-15% WW). The fatty acid (FA) composition in polar lipids (PL) and total lipids (TL) were significantly affected by initial weight related to larvae conditioning, which can be mainly attributed to a dilution effect (impact of initial FA content on final FA content versus relative mass increase during the course of the experiment). Conversely to this trend, DHA content in PL was higher in the ex-LH groups than in the ex-HH groups whatever thermal conditioning of larvae was. This indicated that ex-LH groups had a better capacity to adapt to a deficient HUFA diet than ex-HH fish. The relative expression of the delta-6 desaturase (Δ6D) was significantly higher in ex-LH than in ex-HH groups (P < 0.001) between d-151 and d-181, which suggested that Δ6D transcription in ex-LH groups was positively modulated by the HUFA-deprived diet. This stimulation of the first step of the desaturation/elongation pathway could allow synthesizing FA needed to compensate low dietary HUFA supply. This study shows for the first time that it seems possible to influence juvenile fish metabolism by a nutritional conditioning during the larval stage.