VP30.01: Cell‐free DNA screening for 22q11.2DS by targeted method based on microarray quantitation in the average risk population: results from a single European laboratory

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Catalytic ozonation by metal ions for municipal wastewater disinfection and simulataneous micropollutants removal

This work evaluated the effects of Fe2+, Co2+ and Al3+ in municipal wastewater disinfection through E.coli and Pseudomonas spp inactivation along with cellular adenosine triphosphate (ATP) depletion. Simultaneously, the effect of catalytic ozonation of secondary effluent on the removal of selected micropollutants with different ozone kinetics (acetamiprid, dichlorvos and atrazine) was evaluated. E.coli and Pseudomonas spp inactivation increased almost 20% with 1 mgL-1 Fe2+, Co2+, Al3+ and 40% with 10 mgL-1 Fe2+ compared with single ozonation. The bacteria reactivation after the treatments showed that Fe2+ was the most effective metal ion on inhibiting regrowth. The cellular ATP followed the same trend as the indicators microorganisms inactivation, with significant reduction of ATP over the treatment compared to single ozonation. Finally, the HO¿ exposure per consumed ozone ratio was applied for single ozonation, Fe2+/O3, Co2+/O3 and Al3+/O3 processes to evaluate and compare the contribution of radical pathway on micropollutants abatement

Definition of Healthy Ranges for Alanine Aminotransferase Levels: A 2021 Update

The changing epidemiology of liver disease, and modifications in the recommended analytical methodology call for a re-evaluation of the upper reference limits (URLs) of alanine aminotransferase (ALT) levels. Using the same ap- proach consolidated 20 years ago to define the healthy population, we defined the URL for the newly recommended International Federation of Clinical Chemistry (IFCC) standardized test. In a cross-sectional study, we examined 21,296 apparently healthy blood donors (age 18-65 years) and calculated the sex-specific URL by the 95th percentile in indi- viduals without risk factors for liver disease. These were tested for the ability to predict liver damage in a subset of 745 participants with dysmetabolism, in an independent cohort of 977 unselected donors, and in 899 patients with chronic liver disease. ALT levels were measured by the IFCC test. Male sex, body mass index, glucose, lipids, ferritin, hyper- tension, and younger age were independent ALT predictors (P < 0.001). Updated URLs were identified at 42/30 U/L in males/females, approximately 30% lower than those currently recommended by the IFCC. Due to improved sensitiv- ity, they conferred the ability to detect steatosis and significant fibrosis in individuals with dysmetabolism (odds ratio [OR] = 2.31, range 1.40-3.80, P = 0.001; and OR = 3.35, range 1.19-9.42, P = 0.021; respectively), although with a limited accuracy, and significant fibrosis in unselected donors (OR = 2.32, 1.02-5.31, P = 0.045). Updated URLs had a moderate to high accuracy to discriminate liver conditions (area under the receiver operating characteristic curve = 0.81, range 0.78-0.91). Conclusion: Updated URLs by the IFCC method were lower than those calculated in initial studies, but higher than those in use with the recommended old, nonstandardized method, and were able to better predict liver disease. The limited awareness that different techniques are still in use should be regarded as a possible source of medical errors

Exome-Wide Association Study on Alanine Aminotransferase Identifies Sequence Variants in the GPAM and APOE Associated With Fatty Liver Disease

Background &amp; Aims: Fatty liver disease (FLD) is a growing epidemic that is expected to be the leading cause of end-stage liver disease within the next decade. Both environmental and genetic factors contribute to the susceptibility of FLD. Several genetic variants contributing to FLD have been identified in exome-wide association studies. However, there is still a missing hereditability indicating that other genetic variants are yet to be discovered. Methods: To find genes involved in FLD, we first examined the association of missense and nonsense variants with alanine aminotransferase at an exome-wide level in 425,671 participants from the UK Biobank. We then validated genetic variants with liver fat content in 8930 participants in whom liver fat measurement was available, and replicated 2 genetic variants in 3 independent cohorts comprising 2621 individuals with available liver biopsy. Results: We identified 190 genetic variants independently associated with alanine aminotransferase after correcting for multiple testing with Bonferroni method. The majority of these variants were not previously associated with this trait. Among those associated, there was a striking enrichment of genetic variants influencing lipid metabolism. We identified the variants rs2792751 in GPAM/GPAT1, the gene encoding glycerol-3-phosphate acyltransferase, mitochondrial, and rs429358 in APOE, the gene encoding apolipoprotein E, as robustly associated with liver fat content and liver disease after adjusting for multiple testing. Both genes affect lipid metabolism in the liver. Conclusions: We identified 2 novel genetic variants in GPAM and APOE that are robustly associated with steatosis and liver damage. These findings may help to better elucidate the genetic susceptibility to FLD onset and progression

Rare ATG7 genetic variants predispose patients to severe fatty liver disease

Background &amp; Aims: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver disorders and has a strong heritable component. The aim of this study was to identify new loci that contribute to severe NAFLD by examining rare variants. Methods: We performed whole-exome sequencing in individuals with NAFLD and advanced fibrosis or hepatocellular carcinoma (n = 301) and examined the enrichment of likely pathogenic rare variants vs. the general population. This was followed by validation at the gene level. Results: In patients with severe NAFLD, we observed an enrichment of the p.P426L variant (rs143545741 C&gt;T; OR 5.26, 95% CI 2.1-12.6; p = 0.003) of autophagy-related 7 (ATG7), which we characterized as a loss-of-function, vs. the general population, and an enrichment in rare variants affecting the catalytic domain (OR 13.9; 95% CI 1.9-612; p = 0.002). In the UK Biobank cohort, loss-of-function ATG7 variants increased the risk of cirrhosis and hepatocellular carcinoma (OR 3.30; 95% CI 1.1-7.5 and OR 12.30, 95% CI 2.6-36, respectively; p &lt;0.001 for both). The low-frequency loss-of-function p.V471A variant (rs36117895 T&gt;C) was also associated with severe NAFLD in the clinical cohort (OR 1.7; 95% CI 1.2-2.5; p = 0.003), predisposed to hepatocellular ballooning (p = 0.007) evolving to fibrosis in a Liver biopsy cohort (n = 2,268), and was associated with liver injury in the UK Biobank (aspartate aminotransferase levels, p &lt;0.001), with a larger effect in severely obese individuals in whom it was linked to hepatocellular carcinoma (p = 0.009). ATG7 protein localized to periportal hepatocytes, particularly in the presence of ballooning. In the Liver Transcriptomic cohort (n = 125), ATG7 expression correlated with suppression of the TNFα pathway, which was conversely upregulated in p.V471A carriers. Conclusions: We identified rare and low-frequency ATG7 loss-of-function variants that promote NAFLD progression by impairing autophagy and facilitating ballooning and inflammation. Lay summary: We found that rare mutations in a gene called autophagy-related 7 (ATG7) increase the risk of developing severe liver disease in individuals with dysmetabolism. These mutations cause an alteration in protein function and impairment of self-renewal of cellular content, leading to liver damage and inflammation

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Multichannel challenges. La risposta degli e-tailer in Italia

Obiettivi. La ricerca indaga le strategie multicanale degli e-tailer in termini di motivazioni, ruolo attribuito ai differenti canali ed eventuali sinergie cross-channel. Metodologia. Mediante il software Nvivo11 è stata realizzata una content analysis delle trascrizioni letterali di 25 interviste in profondità ai principali e-tailer operanti in Italia. Risultati. Gli e-tailer sono guidati principalmente da motivazioni connesse alla soddisfazione del cliente al fine di personalizzare l’offerta e incrementare la fedeltà. Inoltre, le imprese adottano un mix specifico di canali assegnandogli ruoli differenti. L’e-commerce è attualmente utilizzato anche per favorire l’acquisizione, il coinvolgimento e il mantenimento del cliente. Il mobile e i social per informare e, nei casi più avanzati, per creare community di utenti. Infine, si rilevano sinergie derivanti dall’uso congiunto di molteplici canali, sia fra canali online, sia fra canali online e offline. In qualche caso è possibile riscontrare effetti competitivi fra canali, a volte creati appositamente dall’impresa stessa. Limiti della ricerca. La contenuta numerosità del campione rispondente non consente di estendere i risultati a tutti gli e-tailer. Inoltre, non è riscontrabile l’impatto sulla performance della strategia multicanale adottata. Implicazioni pratiche. La ricerca offre suggerimenti per le imprese che intendono adottare oppure rafforzare strategie multicanale, in un ambiente in cui oggi il consumatore ha a disposizione una molteplicità di touchpoint con l’impresa. Originalità del lavoro. Sono ancora limitate le ricerche empiriche con una prospettiva aziendale sulla multicanalità. Questo lavoro accresce la conoscenza della tematica relativa al multichannel customer managemen

Optimization of UV/H2O2 and ozone wastewater treatment by the experimental design methodology

The objective of this study was to optimize UV/H2O2 and ozonation systems by means of an experimental design using as a response the efficiency of the operational conditions to remove the methylene blue (MB) dye. Two classes of experimental planning were used: the Doehlert matrix (DM) and the central composite design (CCD). The most important variables for each process were hydrogen peroxide concentration, the ratio of illuminated volume/total volume of the reactor and recirculation flow rate for UV/H2O2, and ozone flow rate, consumed ozone and MB concentration for the ozonation. The DM was more efficient in optimizing the systems, since it used a smaller number of experiments and achieved similar results when compared to the CCD. After optimization, the disinfection efficiency of the systems was tested with secondary effluent evaluating the inactivation of microbiological indicators, Escherichia coli and total coliforms, using the optimized and the worst condition previously obtained with MB removal as response. The inactivation efficiencies in the optimum conditions were about 99%, allowing an efficient disinfection as well as the production of an effluent with quality to be reused according to specific legislations, while at the worse conditions, the inactivation did not reach standards for reuse40151910CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP306218/2014-32014/17774-1; 2016/07911-

Fluorescence in situ hybridization dissection of a chronic myeloid leukemia case bearing the apparently balanced translocations (9;22)(q34;q11.2) and (11;11)(p15;q13)

We report on a patient with chronic myeloid leukemia (CML), which was detected by conventional cytogenetic analysis, to carry two different acquired and apparently balanced translocations, (9;22)(q34;q11.2) and (11;11)(p15;q13). By fluorescence in situ hybridization characterization, we were able to finely map the genomic regions involved in the translocation breakpoints and to disclose concomitant deletions adjacent to the breakpoints on the two derivative chromosomes 11 and the derivative chromosome 22, and the insertion of a segment from chromosome band 11q12.2 into the derivative chromosome 9. We discuss the putative mechanism that could have led to the formation of this complex rearrangement and speculate on the role in leukemogenesis played by the genes mapping at the breakpoints and within the deleted regions