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Vitamin B9(folate)/B12 deficiency is known to induce brain structural and/or functional retardations. Besides neural tube defects in case of major consequences, several mild deregulations also lead to deleterious effect after birth, and folate supplementation recommended in some countries usually stop at the end of the first trimester. Various hormonal receptors were shown to be deregulated in brain tissue under this context. The glucocorticoid receptor (GR) is particularly sensitive to epigenetic regulation and post-traductional modifications. In a mother-offspring rat model of vitamin B9/B12 deficiency, we investigated whether a prolonged folate supplementation could restore the GR signalization in the hypothalamus. Our data showed that a deficiency in folate and vitamin B12 during the in-utero and the early postnatal periods was associated with reduced GR expression inn the hypothalamus. We also described for the first time a new post-traductional modification of GR that impaired ligand binding and GR activation, leading to decreased the expression of one of the GR targets in the hypothalamus, AgRP. Moreover, this brain-impaired GR pathway was associated with behavioral perturbations during offspring growth. Importantly, perinatal and postnatal supplementation with folic acid helped restore GR mRNA level and activity in hypothalamus cells and improved behavioral deficits.

International audience; BackgroundNeuromuscular blocking agents (NMBAs) are among the leading cause of perioperative anaphylaxis, and most of these reactions are IgE mediated. Allergic sensitisation induced by environmental exposure to other quaternary ammonium-containing compounds, such as pholcodine, has been suggested. The aim of this study was to assess the relationship between pholcodine exposure and NMBA-related anaphylaxis.MethodsALPHO was a multicentre case-control study, comparing pholcodine exposure within a year before anaesthesia between patients with NMBA-related perioperative anaphylaxis (cases) and control patients with uneventful anaesthesia in France. Each case was matched to two controls by age, sex, type of NMBA, geographic area, and season. Pholcodine exposure was assessed by a self-administered questionnaire and pharmaceutical history retrieved from pharmacy records. The diagnostic values of anti-pholcodine and anti-quaternary ammonium specific IgE (sIgE) were also evaluated.ResultsOverall, 167 cases were matched with 334 controls. NMBA-related anaphylaxis was significantly associated with pholcodine consumption (odds ratio 4.2; 95% confidence interval 2.3–7.0) and occupational exposure to quaternary ammonium compounds (odds ratio 6.1; 95% confidence interval 2.7–13.6), suggesting that apart from pholcodine, other environmental factors can also lead to sensitisation to NMBAs. Pholcodine and quaternary ammonium sIgEs had a high negative predictive value (99.9%) but a very low positive predictive value (

Epigenetic diseases can be produced by a stable alteration, called an epimutation, in DNA methylation, in which epigenome alterations are directly involved in the underlying molecular mechanisms of the disease. This review focuses on the epigenetics of two inherited metabolic diseases, epi-cblC, an inherited metabolic disorder of cobalamin (vitamin B

Aminoacyl-tRNA synthetases (aaRS) are ubiquitously expressed enzymes responsible for ligating amino acids to their cognate tRNA molecules through an aminoacylation reaction. The resulting aminoacyl-tRNA is delivered to ribosome elongation factors to participate in protein synthesis. Seryl-tRNA synthetase (SARS1) is one of the cytosolic aaRSs and catalyzes serine attachment to tRNASer . SARS1 deficiency has already been associated with moderate intellectual disability, ataxia, muscle weakness, and seizure in one family. We describe here a new clinical presentation including developmental delay, central deafness, cardiomyopathy, and metabolic decompensation during fever leading to death, in a consanguineous Turkish family, with biallelic variants (c.638G>T, p.(Arg213Leu)) in SARS1. This missense variant was shown to lead to protein instability, resulting in reduced protein level and enzymatic activity. Our results describe a new clinical entity and expand the clinical and mutational spectrum of SARS1 and aaRS deficiencies.

BackgroundNeuromuscular blocking agents (NMBAs) are the leading cause of perioperative anaphylaxis (POA), most reactions being IgE mediated. Allergic sensitization induced by environmental exposure to other quaternary ammonium-containing compounds, such as pholcodine, has been suggested. The aim of this study was to assess the relationship between pholcodine exposure and NMBA-related POA.MethodsALPHO is a multicentre case-control study, comparing pholcodine exposure within a year before anaesthesia between patients with NMBA-related POA (cases) and control patients with uneventful anaesthesia. Each case was matched to two controls by age, sex, type of NMBA, geographic area, and season. Pholcodine exposure was assessed by a self-administered questionnaire and pharmaceutical history retrieved from pharmacy records. The diagnostic values of anti-pholcodine and anti-quaternary ammonium specific IgE (sIgE) were also evaluated.ResultsOverall, 167 cases were matched with 334 controls. NMBA-related POA was significantly associated with pholcodine consumption (OR =4.2; CI95% 2.3-7.0) and occupational exposure to quaternary ammoniums (OR = 6.1; CI95% 2.7-13.6). Anti-pholcodine and anti-quaternary ammonium sIgEs had a high negative predictive value (99.9%) but a very low positive predictive value (< 3%) for identifying NMBA-related POA.ConclusionPatients exposed to pholcodine 12 months prior to NMBA exposure have a significantly higher risk of a NMBA-related POA. The low positive predictive values of pholcodine and quaternary ammonium sIgEs precludes their use to identify a population with a high risk of NMBA-related POA. The strong association of NMBA-related POA with occupational exposure suggests that other environmental factors may also lead to sensitization to NMBAs.

Background: The genome-wide assessment of the DNA methylome has revolutionized our comprehension of epigenome alterations linked to complex human traits and diseases. The ability of epigenome-wide association studies (EWAS) to translate into biologically meaningful results relies on detecting epigenomic signatures with a high level of statistical certainty. However, the classical analyses of EWAS are prone to statistical inflation and bias, leading to spurious associations, particularly in case series with small sample sizes, such as those analyzing patients with rare inherited disorders. Methods: Based on the co-methylation pattern of CpG dinucleotides within the CpG islands, we propose the smoothing method at the genome-wide level through a sliding window approach to calculate and visualize data from EWAS to decipher the most informative epigenetic alterations of EWAS with a high degree of accuracy. Results: The smoothing method is a simple method that identifies epigenomic signatures with a high degree of certainty while controlling the risk of spurious findings outside the significant loci at a genome-wide level. We have systematically compared the smoothing method with a classical supervised approach in several EWAS settings, including two monogenic epigenetic diseases (epi-cblC and primary constitutional MLH1epimutation) and epigenetic predictors of aging. In the latter example, we showed that the smoothing method remained efficient even after applying an 80% reduction of the original sample size. Conclusions: The smoothing method for DNA methylation analyses is based on the biological correlate of the epigenome structure and identifies highly accurate epigenomic signatures in DNA methylation analyses. Its application to several settings of epigenome-wide analyses confirmed its usefulness for deciphering the most informative epigenomic signatures with a high degree of certainty while controlling the risk of spurious findings outside the significant loci at a genome-wide level. Our results suggest revisiting EWAS by applying the smoothing method to already available datasets to re-analyze and potentially identify highly accurate epigenomic signatures that could translate into biologically meaningful results.

Purpose To assess the association between plasma procalcitonin concentration at hospital admission and the risk of 50-day in-hospital mortality among patients with community-acquired bloodstream infections. Methods We carried out a retrospective, observational cohort study with all consecutive patients with bacteriologically confirmed community-acquired bloodstream infections hospitalized between 2006 and 2012. We aimed to assess the association between plasma procalcitonin at admission and 50-day in-hospital mortality. Patients were included in the analysis if they had undergone a blood culture test within 48 hours of hospitalization with a concomitant procalcitonin assay (time Results During the 7-year study period, 1593 patients were admitted to one of the healthcare facilities of the University Hospital of Nancy from home or through the emergency department and had positive blood cultures and concomitant procalcitonin assays. Among the patients, 452 met the selection criteria and were analyzed. In ROC analysis, procalcitonin at baseline was significantly associated with 50-day in-hospital mortality, with an optimal threshold > 4.24 ng/mL. A baseline procalcitonin > 4.24 ng/mL was independently associated with an increased risk of in-hospital mortality (multivariable logistic regression: odds ratio, 2.58; 95% CI, 1.57–4.25; P = 0.0002; Cox proportional hazard regression: hazard ratio, 2.01; 95% CI, 1.30–3.11; P = 0.002). In sensitivity analyses, baseline procalcitonin quartiles were independently associated with 50-day in-hospital mortality (multivariable logistic regression: odds ratio, 1.47; 95% CI, 1.17–1.85; P = 0.001; Cox proportional hazard regression: hazard ratio, 1.31; 95% CI, 1.07–1.60; P = 0.008). The independent associations between baseline procalcitonin and the risk of 50-day in-hospital mortality were maintained after adjusting for C-reactive protein and sepsis status at admission. Conclusion Our data provide the first evidence of the usefulness of plasma procalcitonin at admission as a risk-stratifying biomarker for predicting 50-day in-hospital mortality among patients with community-acquired bloodstream infections.

Thromboembolic manifestations are relatively frequent in patients with intermediate/severe hyperhomocysteinemia (>30 µmol/L) related to inherited disorders and deficiencies in vitamin B12 and folate. In contrast, moderate hyperhomocysteinemia (15–30 µmol/L) is a modest predictor of cardiovascular risk. The recognition of homocysteine as a cardiovascular risk factor has been challenged by some but not all randomized clinical trials. We reviewed the main data of this controversy and formulated conclusions to be translated in clinical practice.Homocysteine-lowering trials have been performed in cardiovascular subjects with moderate but not intermediate/severe hyperhomocysteinemia despite the dose–effect risk association. The first meta-analyses found no benefit and led cardiology societies not recommending homocysteine in the assessment of cardiovascular risk. This guideline challenged the need to diagnose and treat the nutritional and genetic causes of intermediate/major hyperhomocysteinemia and was not revised when larger meta-analyses concluded to a reduced risk of stroke. In a recent observational study, 84% of consecutive cardiovascular patients assessed for homocysteine had intermediate or major hyperhomocysteinemia, which was properly assessed in only half of the cases and related to B12 and/or folate deficiency and Addison/Biermer disease in 55% of these cases.In conclusion, revisiting observational studies and clinical trials suggests that cardiovascular patients should be screened for hyperhomocysteinemia, when no other risk factor is found. Patients with intermediate/major hyperhomocysteinemia should be properly assessed and treated for B vitamin deficiencies and inherited disorders according to current guidelines. Further trials are needed to assess the effect of lowering homocysteine according to hyperhomocysteinemia categories at baseline.

The functional role of long noncoding RNAs (lncRNAs) in inherited metabolic disorders, including phenylketonuria (PKU), is unknown. We demonstrated that the mouse lncRNA Pair and human HULC associate with phenylalanine hydroxylase (PAH). Pair-knockout mice exhibited excessive blood phenylalanine, musty odor, hypopigmentation, growth retardation, and progressive neurological symptoms including seizures, which faithfully models human PKU. HULC depletion led to reduced PAH enzymatic activities in human induced pluripotent stem cell (hiPSC)-differentiated hepatocytes. Mechanistically, HULC modulated the enzymatic activities of PAH by facilitating PAH-substrate and PAH-cofactor interactions. To develop a therapeutic strategy for restoring liver lncRNAs, we designed GalNAc-tagged lncRNA mimics that exhibit liver enrichment. Treatment with GalNAc-HULC mimics reduced excessive phenylalanine in Pair(−/−) and Pah(R408W/R408W) mice and improved the phenylalanine tolerance of these mice.

Resume L’epigenetique est la discipline qui etudie les mecanismes permettant une modification du phenotype sans aucune modification de la sequence de l’ADN. Cette modification phenotypique est notamment induite par l’environnement. Elle peut etre reversible mais aussi transmissible de generation en generation. Les mecanismes impliques sont multiples et ne sont pas encore tous connus. La methylation de certaines cytosines de l’ADN ainsi que les methylations et les acetylations des histones jouent un role majeur. D’autres mecanismes moins bien connus, comme les modifications de la structure de la chromatine et l’intervention de divers ARN non codants courts, comme les miARN ou microARN, et long, comme les lncARN ou long ARN non codant, ou encore des evenements impliquant des phenomenes biochimiques ou de regulation jouent aussi un role important. Les modifications epigenetiques peuvent etre a l’origine de pathologies et pratiquement tous les domaines de la Medecine peuvent etre concernes, des maladies chroniques aux infections microbiennes. Les progres dans le domaine de l’epigenetique ont permis d’apporter une explication a des observations telles que certaines discordances du phenotype chez les jumeaux monozygotes, qui partagent pourtant le meme patrimoine genetique, ou la transmission a la descendance d’une obesite ou de maladies cardiovasculaires.

International audience; ABSTRACT Background The association of moderate hyperhomocysteinemia (HHcy) (15–30 μmol/L) with cardiovascular diseases (CVD) has been challenged by the lack of benefit of vitamin supplementation to lowering homocysteine. Consequently, the results of interventional studies have confused the debate regarding the management of patients with intermediate/severe HHcy. Objective We sought to evaluate the association of intermediate (30–100 μmol/L) and severe (>100 μmol/L) HHcy related to vitamin deficiencies and/or inherited disorders with CVD outcomes. Methods We performed a retrospective cross-sectional study on consecutive patients who underwent a homocysteine assay in a French University Regional Hospital Center. Patients with CVD outcomes were assessed for vitamin B12, folate, Hcy, methylmalonic acid, and next-generation clinical exome sequencing. Results We evaluated 165 patients hospitalized for thromboembolic and other cardiovascular (CV) manifestations among 1006 patients consecutively recruited. Among them, 84% (138/165) had Hcy >30 μmol/L, 27% Hcy >50 μmol/L (44/165) and 3% Hcy >100 μmol/L (5/165). HHcy was related to vitamin B12 and/or folate deficiency in 55% (87/165), mutations in one or more genes of one-carbon and/or vitamin B12 metabolisms in 11% (19/165), and severe renal failure in 15% (21/141) of the studied patients. HHcy was the single vascular risk retrieved in almost 9% (15/165) of patients. Sixty % (101/165) of patients received a supplementation to treat HHcy, with a significant decrease in median Hcy from 41 to 17 µmol/L (IQR: 33.6–60.4 compared with 12.1–28). No recurrence of thromboembolic manifestations was observed after supplementation and antithrombotic treatment of patients who had HHcy as a single risk, after ∼4 y of follow-up. Conclusion The high frequency of intermediate/severe HHcy differs from the frequent moderate HHcy reported in previous observational studies of patients with pre-existing CVD. Our study points out the importance of diagnosing and treating nutritional deficiencies and inherited disorders to reverse intermediate/severe HHcy associated with CVD outcomes.

Summary Background Patients with morbid obesity have a high risk of deficits in micronutrients, after bariatric surgery. The reasons why systematic use of multivitamin and trace element supplements cannot prevent all deficits are complex and should deserve more attention. Little is known about the influence of micronutrient deficits at surgery. Aim This present study aimed to explore the deficit in vitamin B12 vs other micronutrients during the follow-up of a French cohort of cases with bariatric surgery under systematic multivitamin/trace elements supplementation and to determine whether it was influenced by clinical, metabolic characteristics at surgery. Methods We prospectively enrolled obese patients with bariatric surgery (laparoscopic gastric bypass or laparoscopic sleeve gastrectomy) between 2013 and 2018 (OBESEPI/ALDEPI Cohort, NCT02663388). They received a daily multivitamin/micronutrients supplement. Follow-up data at 4 visits, 2, 12, 18 and 24 months after surgery, were collected. Results The highest rate of deficits was observed at visit 1 for vitamin D (35.7%), iron (21.9%) and folate (10.2%). Except B12, the deficits of all micronutrients decreased in later visits. In contrast, cases with vitamin B12 deficit decreased from 13.5% at surgery to 2.0% at visit 1, and increased in later visits, with a maximum of 12.0% at visit 3. Vitamin B12 concentration at surgery was the single predictor of B12 deficit at visit 3. It was also associated with age, and APRI score, an index of nonalcoholic fatty liver disease (NAFLD), in multivariate analysis. Conclusions The failure of systematic supplementation with multivitamin/trace elements tablets to prevent specific deficits illustrates the need for adapted specific supplementations, in some cases. The worsening of B12 deficit rate in the 18–24 months follow-up depends in part to low B12 at time of surgery. A special consideration should be devoted to this subset of patients. The cohort study was registered at clinicaltrials.gov as NCT02663388.

Resume Les regimes vegetariens ont ete proposes comme approche nutritionnelle pouvant potentiellement reduire le risque de maladies chroniques non transmissible. De plus, il existe une pression societale forte pour diminuer les aliments d’origine animale de la consommation alimentaire des pays occidentaux. Comparer les effets sur la sante des regimes vegetariens et du regime omnivore est donc une question d’actualite importante, a laquelle nous tentons d’apporter une reponse basee sur les meta-analyses publiees sur ce theme. Les regimes vegetariens sont associes a une concentration plus faible de cholesterol sanguin total, LDL-cholesterol et HDL-cholesterol, et sont sans effet sur le taux de triglycerides. Ils augmentent le risque de carence en vitamine B12, principalement chez les nourrissons de meres vegetariennes, chez les femmes enceintes et les personnes âgees et diminuent les reserves en fer evaluees par la ferritine. En revanche, il existe un effet protecteur des regimes vegetariens sur le risque d’obesite pathologique, des autres composantes du syndrome metabolique dont le diabete et l’hypertension et sur le risque de maladies cardio-vasculaires. L’etude des effets sur le risque de cancer ont produit des resultats contradictoires. La revue exhaustive de la litterature montre qu’il existe des donnees tres parcellaires sur les effets des regimes vegetariens pour les acides gras omega-3, l’iode, le calcium, la vitamine B12 et la vitamine D et la comparaison avec le regime mediterraneen. L’effet des regimes vegetariens sur les tranches d’âge necessite egalement une attention particuliere.

Le pronostic de la phénylcétonurie (PCU) a été transformé par le dépistage néonatal et la prise en charge diététique via un apport contrôlé en phénylalanine. Ce traitement doit être suivi toute la vie durant, ce qui pose des problèmes de compliances importants. Un traitement médicamenteux par saproptérine (ou BH4) est venu apporter une aide à un pourcentage réduit de patients qui répondent à ce médicament. Une enzymothérapie par voie sous-cutanée est disponible aux États-Unis et a obtenue une AMM européenne, mais génère des effets secondaires importants, ce qui en limite l’efficacité. De nouvelles options thérapeutiques de la PCU sont actuellement en développement, en particulier par thérapie génique. Le but de cet article est de faire le point sur la physiopathologie et sur les différentes nouvelles modalités thérapeutiques actuellement en développement.

International audience; Autism spectrum disorders (ASD) are influenced by interacting maternal and environmental risk factors. High-dose folinic acid has shown improvement in verbal communication in ASD children. The EFFET randomized placebo-controlled trial (NCT02551380) aimed to evaluate the efficacy of folinic acid (FOLINORAL®) at a lower dose of 5 mg twice daily.Nineteen children were included in the EFFET trial. The primary efficacy outcome was improvement of Autism Diagnostic Observation Schedule (ADOS) score. The secondary outcomes were the improvement in ADOS sub scores communication, social interactions, Social Responsiveness Score (SRS) and treatment safety.The global ADOS score and social interaction and communication sub scores were significantly improved at week 12 compared to baseline in the folinic acid group (P = 0.003, P = 0.004 and P = 0.022, respectively), but not in the placebo group (P = 0.574, P = 0.780, P = 0.269, respectively). We observed a greater change of ADOS global score (−2.78 vs. −0.4 points) and (−1.78 vs. 0.20 points) in the folinic acid group, compared to the placebo group. No serious adverse events were observed.This pilot study showed significant efficacy of folinic acid with an oral formulation that is readily available. It opens a perspective of therapeutic intervention with folinic acid but needs to be confirmed by a multi-center trial on a larger number of children.

The diagnosis of iron deficiency is based on ferritin and transferrin saturation (TfS) in inflammatory bowel disease (IBD) patients, yet guideline thresholds are not evidence-based. Soluble transferrin receptor (sTfR) is one of the best noninvasive tests in patients with inflammation.To evaluate the accuracy of ferritin and/or TfS for diagnosing iron deficiency in IBD and identify the optimal thresholds of these parameters using sTfR as reference.Two hundred and two patients (2072 samples) receiving at least one infusion of biologic (vedolizumab or infliximab) were included.In ulcerative colitis patients with C-reactive protein (CRP)10 mg/L, optimal iron deficiency diagnostic performances were observed with ferritin and TfS thresholds of 65 µg/L (sensitivity of 0.78 and specificity of 0.76) and 16% (sensitivity of 0.79 and specificity of 0.90), respectively. For ulcerative colitis patients with CRP 10 mg/L, the thresholds with the best diagnostic performance were 80 µg/L (sensitivity of 0.75 and a specificity of 0.82) for ferritin and 11% for TfS (sensitivity of 0.75 and a specificity of 0.82). There was no added value for combined ferritin and TfS. No ferritin or TfS threshold had good diagnostic performance in Crohn's disease patients (AUC for ferritin was 0.65 (95% CI 0.55-0.75) and the AUC for TfS was 0.70 (95% CI 0.61-0.78).Ferritin and TfS are reliable parameters for iron deficiency diagnosis only in ulcerative colitis patients, at thresholds different from current guidelines. In Crohn's disease patients, sTfR should be used given the poor diagnostic performance of ferritin and TfS.

Background epi-cblC is a recently discovered inherited disorder of intracellular vitamin B12 metabolism associating hematological, neurological, and cardiometabolic outcomes. It is produced by an epimutation at the promoter common to CCDC163P and MMACHC, which results from an aberrant antisense transcription due to splicing mutations in the antisense PRDX1 gene neighboring MMACHC. We studied whether the aberrant transcription produced a second epimutation by encompassing the CpG island of the TESK2 gene neighboring CCDC163P. Methods We unraveled the methylome architecture of the CCDC163P–MMACHC CpG island (CpG:33) and the TESK2 CpG island (CpG:51) of 17 epi-cblC cases. We performed an integrative analysis of the DNA methylome profiling, transcriptome reconstruction of RNA-sequencing (RNA-seq), chromatin immunoprecipitation sequencing (ChIP-Seq) of histone H3, and transcription expression of MMACHC and TESK2. Results The PRDX1 splice mutations and activation of numerous cryptic splice sites produced antisense readthrough transcripts encompassing the bidirectional MMACHC/CCDC163P promoter and the TESK2 promoter, resulting in the silencing of both the MMACHC and TESK2 genes through the deposition of SETD2-dependent H3K36me3 marks and the generation of epimutations in the CpG islands of the two promoters. Conclusions The antisense readthrough transcription of the mutated PRDX1 produces an epigenetic silencing of MMACHC and TESK2. We propose using the term 'epi-digenism' to define this epigenetic disorder that affects two genes. Epi-cblC is an entity that differs from cblC. Indeed, the PRDX1 and TESK2 altered expressions are observed in epi-cblC but not in cblC, suggesting further evaluating the potential consequences on cancer risk and spermatogenesis.

Vitamin B12 is assimilated and transported by complex mechanisms that involve three transport proteins, intrinsic factor (IF), haptocorrin (HC) and transcobalamin (TC) and their respective membrane receptors. Vitamin deficiency is mainly due to inadequate dietary intake in vegans, and B12 malabsorption is related to digestive diseases. This review explores the physiology of vitamin B12 absorption and the mechanisms and diseases that produce malabsorption. In the stomach, B12 is released from food carrier proteins and binds to HC. The degradation of HC by pancreatic proteases and the pH change trigger the transfer of B12 to IF in the duodenum. Cubilin and amnionless are the two components of the receptor that mediates the uptake of B12 in the distal ileum. Part of liver B12 is excreted in bile, and undergoes an enterohepatic circulation. The main causes of B12 malabsorption include inherited disorders (Intrinsic factor deficiency, Imerslund-Gräsbeck disease, Addison's pernicious anemia, obesity, bariatric surgery and gastrectomies. Other causes include pancreatic insufficiency, obstructive Jaundice, tropical sprue and celiac disease, bacterial overgrowth, parasitic infestations, Zollinger-Ellison syndrome, inflammatory bowel diseases, chronic radiation enteritis of the distal ileum and short bowel. The assessment of B12 deficit is recommended in the follow-up of subjects with bariatric surgery. The genetic causes of B12 malabsorption are probably underestimated in adult cases with B12 deficit. Despite its high prevalence in the general population and in the elderly, B12 malabsorption cannot be anymore assessed by the Schilling test, pointing out the urgent need for an equivalent reliable test.

Our understanding of brain biology and function is one of the least characterized and therefore, there are no effective treatments for most of neurological disorders. The influence of vitamins, and particularly vitamin B

Background & aims Nutritional predisposition to severe coronavirus disease 2019 (COVID-19) remains unclear. Zinc deficiency could be critical since it is associated with a higher susceptibility to infections. We evaluated the prevalence of hypozincemia in the early stage of COVID-19, its association with risk factors for severe COVID-19 and its prognostic value for hospitalization for respiratory complications within 10 days. Methods For 152 COVID-19 patients and 88 non-COVID-19 patients admitted to COVID-19 screening centers, national early warning score for COVID-19 (NEWS) and laboratory analyses were performed to identify the risk for severe COVID-19. Multivariable logistic regression analysis assessed whether hypozincemia was an independent predictor of hospitalization for respiratory complications within 10 days (primary judgment criterion). The secondary judgment criteria were high NEWS score (≥7), comorbidities and biomarkers associated with severe COVID-19. Results Hypozincemia was more frequent in COVID-19 patients compared to non-COVID-19 patients (27.6% vs 11.4%; p = 0.003). Older patients (≥65 years) and medically assisted nursing home residents were at higher risk of hypozincemia (p

International audience; Background: Hepatocellular carcinoma is a frequent consequence of alcohol-related liver disease, with variable incidence among heavy drinkers. We did a genome-wide association study (GWAS) to identify common genetic variants for alcohol-related hepatocellular carcinoma. Methods: We conducted a two-stage case-control GWAS in a discovery cohort of 2107 unrelated European patients with alcohol-related liver disease aged 20–92 years recruited between Oct 22, 1993, and March 12, 2017. Cases were patients with alcohol-related hepatocellular carcinoma diagnosed by imaging or histology. Controls were patients with alcohol-related liver disease without hepatocellular carcinoma. We used an additive logistic regression model adjusted for the first ten principal components to assess genetic variants associated with alcohol-related hepatocellular carcinoma. We did another analysis with adjustment for age, sex, and liver fibrosis. New candidate associations (pandlt;1 × 10−6) and variants previously associated with alcohol-related hepatocellular carcinoma were evaluated in a validation cohort of 1933 patients with alcohol-related liver disease aged 29–92 years recruited between July 21, 1995, and May 2, 2019. We did a meta-analysis of the two case–control cohorts. Findings: The discovery cohort included 775 cases and 1332 controls. Of 7 962 325 variants assessed, we identified WNT3A-WNT9A (rs708113; p=1·11 × 10−8) and found support for previously reported regions associated with alcohol-related hepatocellular carcinoma risk at TM6SF2 (rs58542926; p=6·02 × 10−10), PNPLA3 (rs738409; p=9·29 × 10−7), and HSD17B13 (rs72613567; p=2·49 × 10−4). The validation cohort included 874 cases and 1059 controls and three variants were replicated: WNT3A-WNT9A (rs708113; p=1·17 × 10−3), TM6SF2 (rs58542926; p=4·06 × 10−5), and PNPLA3 (rs738409; p=1·17 × 10−4). All three variants reached GWAS significance in the meta-analysis: WNT3A-WNT9A (odds ratio 0·73, 95% CI 0·66–0·81; p=3·93 × 10−10), TM6SF2 (1·77, 1·52–2·07; p=3·84×10−13), PNPLA3 (1·34, 1·22–1·47; p=7·30 × 10−10). Adjustment for clinical covariates yielded similar results. We observed an additive effect of at-risk alleles on alcohol-related hepatocellular carcinoma. WNT3A-WNT9A rs708113 was not associated with liver fibrosis. Interpretation: WNT3A-WNT9A is a susceptibility locus for alcohol-related hepatocellular carcinoma, suggesting an early role of the Wnt–β-catenin pathway in alcohol-related hepatocellular carcinoma carcinogenesis.

epi-cblC is a recently discovered inherited disorder of intracellular vitamin BWe unraveled the methylome architecture of the CCDC163P-MMACHC CpG island (CpG:33) and the TESK2 CpG island (CpG:51) of 17 epi-cblC cases. We performed an integrative analysis of the DNA methylome profiling, transcriptome reconstruction of RNA-sequencing (RNA-seq), chromatin immunoprecipitation sequencing (ChIP-Seq) of histone H3, and transcription expression of MMACHC and TESK2.The PRDX1 splice mutations and activation of numerous cryptic splice sites produced antisense readthrough transcripts encompassing the bidirectional MMACHC/CCDC163P promoter and the TESK2 promoter, resulting in the silencing of both the MMACHC and TESK2 genes through the deposition of SETD2-dependent H3K36me3 marks and the generation of epimutations in the CpG islands of the two promoters.The antisense readthrough transcription of the mutated PRDX1 produces an epigenetic silencing of MMACHC and TESK2. We propose using the term 'epi-digenism' to define this epigenetic disorder that affects two genes. Epi-cblC is an entity that differs from cblC. Indeed, the PRDX1 and TESK2 altered expressions are observed in epi-cblC but not in cblC, suggesting further evaluating the potential consequences on cancer risk and spermatogenesis.