ABSTRACT
Background: Several recently completed clinical trials in NASH patients have included fibrosis stage reductions in 20-30% of the patients in placebo cohorts(a,b,c). The mechanisms driving these reductions have not yet been identified. Reductions of alcohol intake could be influential, as moderate alcohol intake has been shown to enhance hepatic de novo lipogenesis (d). Moreover, alcohol consumption is common in populations worldwide and has increased in some populations during the COVID-19 pandemic (e,f). NASH clinical trial protocols do not exclude moderate alcohol consumers (20-30 g/d, equivalent to 1.5-2 standard drinks/d). A quantitative systems pharmacology (QSP) model, NAFLDsym (g), was employed to test the hypothesis that reductions in daily moderate alcohol intake could reduce liver lipid burden, lipotoxicity, and fibrosis stage in NASH patients. Method(s): NASH SimCohorts (n=50;liver fat = 22+/-7%, ALT = 48+/-10 U/L, fibrosis stage 3) regularly consuming 30 g/d alcohol were used to simulate reductions in daily alcohol intake. Baseline alcohol administration was simulated as two 15 g drinks over one hour, coincident with the dinner meal. GastroPlus was used to simulate the rate of hepatic metabolism. Consistent with previous reports, 20% of the metabolized alcohol was able to contribute to hepatic de novo lipogenesis in the simulations (d,h). Reductions of alcohol intake to 15 g/d or 0 g/d were simulated for 52weeks in the SimCohorts, with changes in liver fat, plasma ALT, and fibrosis stage predicted. Result(s): Decreased alcohol intake elicited fibrosis stage reductions, with a greater frequency of patients with an improved fibrosis stage in the 0 g/d vs. 15 g/d simulations. Twentyfour-hour average de novo lipogenesis was predicted to decline 56+/-8% and 30+/-5% in the 0 g/d or 15 g/d simulations. Liver fat was predicted to decrease 5+/-3% and 1+/-1% and ALT decreased 10 +/-7 % and 1+/-1% when alcohol intake was reduced to 0 or 15 g/d, respectively. Conclusion(s): Reductions in moderate alcohol intake for NASH patients who are regular consumers may lead to improvements in fibrosis stage due to decreased de novo lipogenesis. This behavioral adjustment may influence the frequency of observed fibrosis stage reductions in clinical trials whether on placebo or treatment, particularly in studies conducted in regions with a higher prevalence of moderate alcohol consumption. a Newsome 2021 b Francque 2022 c Harrison 2022 d Siler 1999 e Holmes 2017 f Pelham 2022 g Siler 2022 h Lundquist 1962.
ABSTRACT
Background/Case Studies: The National Standard of Canada on Blood and Blood Components, CSA-Z902:20, was published in March 2020 with the addition of clause 10.7.4. which states that "females, 45 years and under, with child bearing potential, should be transfused with K negative red cell (RBC) units unless known to be K positive". In order to absorb the anticipated increase demand for K (Kell) phenotyped units in a cost-effective manner, routine testing of K phenotype on the commercial PK7300 platform was implemented in our blood donor center. Moreover, since requests for CEce phenotyped units had increased significantly in recent years, these phenotypes were tested along with the K unless the donor's K phenotype had been previously tested. Thus, the number of distributed units of all ABO groups labeled with these phenotypes, positive or negative, increased very significantly. The objective of this study was to measure the impact of the implementation of CEce and K automated phenotyping on phenotyping activities in Quebec hospital transfusion medicine laboratories (TML). Study Design/Methods: The rate of CEce and K phenotype assays performed on RBC units in hospitals was compared between pre (January-December 2019) and postimplementation period (January-December 2021). Year 2019 was chosen as the pre period since year 2020 was impacted by COVID-19. Data was extracted from Trace- Line (MAK-SYSTEM International Group) used in all Quebec hospital TML. The estimated savings seen in hospital TML post-implementation was calculated based on the cost of reagent, labor time and supplies for each assay using a manual method. Pre and post-implementation difference in proportion was estimated using two-sided Z test. Results/Findings: The rate of CEce or K testing on donations performed in hospitals significantly decreased when comparing 2019 to 2021 (40% vs. 11.2% respectively;p value = <0.00001). Those significative decreases were also observed for all phenotypes tested independently, as shown in Table 1. Based on these data, the availability of those phenotypes on the RBC units represents an approximate recurrent saving of $270,000 CAD per year. Conclusion(s): In summary, this study shows a substantial reduction in the number of all phenotype testing performed by hospital TML when comparing pre and postimplementation of CEce and K routine automated phenotype. Furthermore, this measure is cost-effective and decreases labor in hospital TML. (Table Presented).