COVID-19 is associated with encephalopathy, but its diagnosis and prognostic value has yet to be fully characterized. We aimed to examine key neurobiomarkers of encephalopathy in patients with severe COVID-19 pneumonia, specifically serum neuron-specific enolase (NSE), serum S100-beta protein (S100B), and early electroencephalographic (EEG) abnormalities, and their association with short-term outcomes. We conducted a prospective, single-center cohort study including consecutive adult patients with COVID-19 admitted to the intensive care unit (ICU) for acute respiratory failure. NSE and S100B levels were measured on days 1, 2, and 3 post-admission, and standard EEG was performed as part of routine neuromonitoring. The primary outcome was mortality at 90 days. Among 134 included patients, 47 (35.1%) died within 90 days. NSE concentrations on days 1, 2, and 3 were significantly associated with mortality and intubation, whereas S100B concentrations were not. In multivariable analyses, maximal NSE concentration between day 1 and day 3 (adjusted odds ratio (aOR) 1.15, 95% CI 1.06-1.24), absence of EEG sleep figures (aOR 14.28, 95% CI 2.38-76.92), age (aOR per 1-point 1.10, 95% CI 1.04-1.17), and SOFA score (aOR per 1-point 1.28, 95% CI 1.01-1.62) were independently associated with mortality. NSE predicted mortality with an area under the Receiver Operating Characteristic curve of 0.72 (95% CI 0.61-0.82). A NSE threshold > 34/L predicted mortality with a specificity of 95% (95% CI 87-99%) and a sensitivity of 24% (95% CI 13-40%). Among patients with severe COVID-19 pneumonia, elevated serum NSE levels and absence of EEG sleep features, suggesting subclinical encephalopathy, were independently associated with increased mortality. These findings support the use of serum NSE and EEG as early prognostic biomarkers in critically ill patients without primary brain injury.

Maternal iron requirements increase during pregnancy. Placental transfer is unidirectional via transferrin receptor 1 and ferroportin, and most fetal iron accumulation occurs in the third trimester. Iron deficiency during pregnancy is associated with maternal fatigue, reduced work capacity, and increased risk of anemia, as well as adverse outcomes such as preterm birth, low birthweight, and impaired neonatal iron stores, which may affect early neurodevelopment. Oral iron supplementation reduces anemia and improves iron status. In women at risk of deficiency, lower prophylactic doses are commonly used. Intravenous iron is effective and generally safe from the second trimester in women who do not respond to or tolerate oral therapy. However, iron status shows a U-shaped association with outcomes: elevated maternal iron has been associated with preterm birth, low birthweight, and possible neurodevelopmental effects. Excess iron may induce oxidative stress and placental iron loading. Hepcidin suppression in the second and third trimesters enhances iron absorption. Important gaps remain regarding hepcidin regulation, placental transport mechanisms, safe upper supplementation limits, and optimal dosing strategies. While supplementation clearly benefits iron-deficient women, current evidence supports screening-based rather than universal supplementation in iron-replete populations. Herein, we discuss the need for iron during pregnancy, the impact of dysmetabolism, and the molecular actors at the cellular and systemic levels to build a translational bridge between clinical unmet needs and fundamental knowledge.

Emerging evidence suggests that iron-related cell death may contribute to placental dysfunction. During pregnancy, placenta-mediated iron supply is critical for fetal development. Iron demand rises substantially during gestation and must be tightly regulated: while insufficient iron compromises fetal growth, excessive iron accumulation can be highly toxic. In particular, iron overload can trigger ferroptosis, an iron-dependent, non-apoptotic form of programmed cell death characterized by redox imbalance and accumulation of lipid-reactive oxygen species. In this study, we investigated ferroptosis and iron toxicity in various trophoblast cell models (BeWo, differentiated BeWo, and JEG-3). Treatment with ferroptosis inducers (erastin and RSL3) or iron (ammonium ferric citrate and hemin arginate) caused a significant, specific concentration-dependent reduction in hCG secretion, increased cytotoxicity, and oxidative stress. Iron chelator or antioxidant effectively reversed only some of these iron-induced effects. Here, we report that, in BeWo and JEG-3 choriocarcinoma cell models, iron overload and ferroptosis impair hCG secretion without affecting other endocrine functions. Further studies in primary trophoblasts and in vivo models are needed to determine whether these observations extend to placental function during pregnancy.

Inflammatory bowel diseases cause chronic intestinal inflammation, including Crohn’s disease (CD) and ulcerative colitis (UC). Prostaglandin E-major urinary metabolite (PGE-MUM) is a urine biomarker for disease activity in IBD. This study evaluated PGE-MUM performance for predicting an active disease in patients with CD and UC. We also compared PGE-MUM performances to fecal calprotectin (FC) and blood C-reactive protein (CRP). A total of 214 patients were included from two University Hospitals in Italy and France. One hundred and twenty-one patients with CD and 86 with UC were included. We compared PGE-MUM, FC, and CRP in patients. In the CD group, PGE-MUM AUC for predicting an active disease was 0.659 with 46% sensitivity and 80% specificity. FC AUC was 0.957 with 98% sensitivity and 80% specificity. CRP AUC was 0.619, with 49% sensitivity and 76% specificity. In the UC group, PGE-MUM AUC was 0.693 with 37% sensitivity and 97% specificity. FC AUC was 0.916 with 78% sensitivity and 95% specificity. FC was superior to the PGE-MUM in CD (p < 0.0001) and UC (p = 0.003), indicating a higher performance in predicting an active disease. The Combination of both markers gave an AUC of 0.926 in UC and 0.952 in CD, comparable to that observed with FC alone. Cluster analysis revealed distinct inflammatory patterns with compact and homogenous character, with two endophenotypes based on biomarkers for UC and three for CD showing a between-class variance of 52% and 65%, respectively. PGE-MUM and FC are associated with clinical disease activity in UC and CD. PGE-MUM does not perform better than FC alone. These two markers’ combination showed three distinct patterns in CD and two in UC. Combining PGE-MUM and FC may improve the assessment of inflammation profiles in IBD and constitute a promising way for personalized approaches.

Congenital microcytic anemias are rare diseases associated with decreased hemoglobin synthesis and red blood cells of low corpuscular volume. DMT1/NRAMP2 is a highly conserved divalent cation transporter encoded by the SLC11A2 gene, expressed at the membrane of various cells. It ensures ferrous iron absorption from the apical membrane of enterocytes, iron recovery from urine by renal tubules, and acidified endosome uptake after transferrin internalization. Pathogenic DMT1 variants have been described in 10 individuals to date, associated with recessive hypochromic anemia and iron overload. Herein, we report a new variant of SLC11A2 (c.469A>G, p.Ile157Val) compound with known p.Arg416Cys associated with a frankly microcytic anemia and increased transferrin saturation. The clinical picture observed in the patient was exceptionally mild, extending the field of the DMT1 phenotypes to borderline anemias.

OBJECTIVES:. Neurologic outcomes of patients under venoarterial extracorporeal membrane oxygenation (VA-ECMO) may be worsened by secondary insults of systemic origin. We aimed to assess whether sepsis, commonly observed during ECMO support, is associated with brain injury and outcomes. DESIGN:. Single-center cohort study of the “exposed-non-exposed” type on consecutive adult patients treated by VA-ECMO. SETTING:. Medical ICU of a university hospital, France, 2013–2020. PATIENTS:. Patients with sepsis at the time of VA-ECMO cannulation (“sepsis” group) were compared with patients without sepsis (“no sepsis” group). The primary outcome measure was poor functional outcome at 90 days, defined by a score greater than or equal to 4 on the modified Rankin scale (mRS), indicating severe disability or death. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. A total of 196 patients were included (“sepsis,” n = 128; “no sepsis,” n = 68), of whom 87 (44.4%) had presented cardiac arrest before VA-ECMO cannulation. A poor functional outcome (mRS ≥ 4) was observed in 99 of 128 patients (77.3%) of the “sepsis” group and 46 of 68 patients (67.6%) of the “no sepsis” group (adjusted logistic regression odds ratio (OR) 1.21, 95% CI, 0.58–2.47; inverse probability of treatment weighting (IPTW) OR 1.24; 95% CI, 0.79–1.95). Subsequent analyses performed according to pre-ECMO cardiac arrest status suggested that sepsis was independently associated with poorer functional outcomes in the subgroup of patients who had experienced pre-ECMO cardiac arrest (adjusted logistic regression OR 3.44; 95% CI, 1.06–11.40; IPTW OR 3.52; 95% CI, 1.68–7.73), whereas no such association was observed in patients without pre-ECMO cardiac arrest (adjusted logistic regression OR 0.69; 95% CI, 0.27–1.69; IPTW OR 0.76; 95% CI, 0.42–1.35). Compared with the “no sepsis” group, “sepsis” patients presented a significant increase in S100 calcium-binding protein beta concentrations at day 1 (0.94 μg/L vs. 0.52 μg/L, p = 0.03), and more frequent EEG alterations (i.e., severe slowing, discontinuous background, and a lower prevalence of sleep patterns), suggesting brain injury. CONCLUSION:. We observed a detrimental role of sepsis on neurologic outcomes in the subgroup of patients who had experienced pre-ECMO cardiac arrest, but not in other patients.

In a recent phase 3 trial, givosiran, an siRNA inhibitor of the ALAS1 expression, drastically reduced the number of neurovisceral attacks in patients with severe acute intermittent porphyria (AIP). We conducted a retrospective study on 25 patients with severe AIP treated with givosiran in France. We have developed a personalized approach by monitoring precursor levels to adapt the frequency of injections. The effectiveness (96% fewer attacks) was identical to the classic regimen of monthly injections measured during phase 3. Our data suggest that givosiran is more effective when administered early in the course of the disease. We confirmed the high prevalence of adverse effects, sometimes severe, with almost systematic hyperhomocysteinemia, a thromboembolic risk, acute cytolysis, a case of acute pancreatitis, and a worsening of renal failure.

Inflammatory bowel diseases (IBD) etiology is multifactorial. Luminal microRNAs (miRNAs) have been suspected to play a role in the promotion of chronic inflammation, but the extent to which fecal miRNAs are interacting with the intestinal ecosystem in a way that contribute to diseases, including IBD, remains unknown. Here, fecal let-7b and miR-21 were found elevated, associated with inflammation, and correlating with multiple bacteria in IBD patients and IL-10-/- mice, model of spontaneous colitis. Using an in vitro microbiota modeling system, we revealed that these two miRNAs can directly modify the composition and function of complex human microbiota, increasing their proinflammatory potential. In vivo investigations revealed that luminal increase of let-7b drastically alters the intestinal microbiota and enhances macrophages' associated proinflammatory cytokines (TNF, IL-6, and IL-1 beta). Such proinflammatory effects are resilient and dependent on the bacterial presence. Moreover, we identified that besides impairing the intestinal barrier function, miR-21 increases myeloperoxidase and antimicrobial peptides secretion, causing intestinal dysbiosis. More importantly, in vivo inhibition of let-7b and miR-21 with anti-miRNAs significantly improved the intestinal mucosal barrier function and promoted a healthier host-microbiota interaction in the intestinal lining, which altogether conferred protection against colitis. In summary, we provide evidence of the functional significance of fecal miRNAs in host-microbiota communication, highlighting their therapeutic potential in intestinal inflammation and dysbiosis-related conditions, such as IBD.

Cerebral malaria (CM), the most lethal complication of Plasmodium falciparum severe malaria (SM), remains fatal for 15-25% of affected children despite the availability of treatment. P. falciparum infects and multiplies in erythrocytes, contributing to anemia, parasite sequestration, and inflammation. An unbiased proteomic assessment of infected erythrocytes and plasma samples from 24 Beninese children was performed to study the complex mechanisms underlying CM. A significant down-regulation of proteins from the ubiquitin-proteasome pathway and an up-regulation of the erythroid precursor marker transferrin receptor protein 1 (TFRC) were associated with infected erythrocytes from CM patients. At the plasma level, the samples clustered according to clinical presentation. Significantly, increased levels of the 20S proteasome components were associated with SM. Targeted quantification assays confirmed these findings on a larger cohort (n = 340). These findings suggest that parasites causing CM preferentially infect reticulocytes or erythroblasts and alter their maturation. Importantly, the host plasma proteome serves as a specific signature of SM and presents a remarkable opportunity for developing innovative diagnostic and prognostic biomarkers.

Herein, we report the case of a 42-year-old woman, hospitalized in a French tertiary hospital for a relapse of a chronic enteropathy, who was found on admission to have no detectable serum transferrin. Surprisingly, she only exhibited mild anaemia. This atransferrinemia persisted for two months throughout her hospitalization, during which her haemoglobin concentration remained broadly stable. Based on her clinical history and evolution, we concluded to an acquired atransferrinemia secondary to chronic undernutrition, inflammation and liver failure. We discuss the investigations performed in this patient, and hypotheses regarding the relative stability of her haemoglobin concentration despite the absence of detectable transferrin.

Background: Iron metabolism dysregulation may play a role in organ failure observed in Coronavirus disease 2019 (COVID-19). This study aimed to explore the whole iron metabolism in hospitalized COVID-19 patients and evaluate the impact of tocilizumab.Methods: We performed an observational multicentric cohort study, including patients with PCR-proven COVID19 from the intensive care unit (ICU) (n = 66) and medical ward (n = 38). We measured serum interleukin-6 (IL6), ferritin, glycosylated ferritin (GF), transferrin, iron, and hepcidin. The primary outcome was death.Results: Among the 104 patients, we observed decreased median GF percentage (35 %; IQ 23-51.5), low iron concentration (7.5 & mu;mol/L; IQ 4-14), normal but low transferrin saturation (TSAT; 21%; IQ 11-33) and increased median hepcidin concentration (58.7 ng/mL; IQ 20.1-92.1). IL-6, ferritin, and GF were independently and significantly associated with death (p = 0.026, p = 0.023, and p = 0.009, respectively). Surprisingly, we observed a decorrelation between hepcidin and IL-6 concentrations in some patients. These findings were amplified in tocilizumab-treated patients.Conclusion: Iron metabolism is profoundly modified in COVID-19. The pattern we observed presents differences with a typical inflammation profile. We observed uncoupled IL-6/hepcidin levels in some patients. The benefit of additive iron chelation therapy should be questionable in this setting.

Phase 1, Single-blind, randomized, controlled, single-ascending dose Given to healthy volunteers (Part 1) & to participants with cHBV infection (Part 2) Current management of chronic hepatitis B virus (cHBV) infection requires lifelong treatment with oral antivirals.ALN-HBV and VIR-2218 are investigational RNAi therapeutics that target all major HBV transcripts.The objectives of these studies were to evaluate the safety and tolerability of a single dose of ALN-HBV and VIR-2218 in healthy adult volunteers and to evaluate the antiviral activity of VIR-2218 in adult participants with cHBV infection.

Background The quantification of delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) in urine are the first-line tests for diagnosis and monitoring of acute hepatic porphyrias (AHP). Ion-exchange chromatography (IEC), which is time- and staff-consuming and limited to urine, is still the preferred method in many specialized laboratories, despite the development of mass spectrometry-based methods. Methods We describe a new LC-MS method that allows for rapid and simple quantification of ALA and PBG in urine and plasma with an affordable instrument that was used to analyze 2260 urine samples and 309 blood samples collected in 2 years of routine activity. The results were compared to those obtained with IEC, and urine reference ranges and concentrations in asymptomatic carriers were determined. Plasma concentrations were measured in healthy subjects and subgroups of symptomatic and asymptomatic AHP carriers. Results In urine, the clinical decision limits were not impacted by the change of method despite discrepancies in low absolute concentrations, leading to lower normal values. Two-thirds of asymptomatic AHP carriers (with the exception of coproporphyria carriers) showed an increased urine PBG concentration. Urine and plasma levels showed a good correlation except in patients with kidney disease in whom the urine/plasma ratio was relatively low. Conclusion We described an LC-MS based method for the routine diagnosis and monitoring of AHP that allows for the detection of more asymptomatic carriers than the historical method. Blood analysis appears to be particularly relevant for patients with kidney disease, where urine measurement underestimates the increase in ALA and PBG levels.

Herein, we report the case of a 42-year-old woman, hospitalized in a French tertiary hospital for a relapse of a chronic enteropathy, who was found on admission to have no detectable serum transferrin. Surprisingly, she only exhibited mild anaemia. This atransferrinemia persisted for two months throughout her hospitalization, during which her haemoglobin concentration remained broadly stable. Based on her clinical history and evolution, we concluded to an acquired atransferrinemia secondary to chronic undernutrition, inflammation and liver failure. We discuss the investigations performed in this patient, and hypotheses regarding the relative stability of her haemoglobin concentration despite the absence of detectable transferrin.

Background: In patients with acute intermittent porphyria (AIP), induction of delta aminolevulinic acid synthase 1 (ALAS1) leads to haem precursor accumulation that may cause recurring acute attacks. In a recent phase III trial, givosiran significantly reduced the attack rate in severe AIP patients. Frequent adverse events were injection-site reaction, fatigue, nausea, chronic kidney disease and increased alanine aminotransferase. Objectives: To describe the efficacy and safety of givosiran based on a personalized medical approach. Methods: We conducted a retrospective patient file study in 25 severe AIP patients treated with givosiran in France. We collected data on clinical and biochemical efficacy along with reports of adverse events. Results: Givosiran drastically reduced the attack rate in our cohort, as 96% were attack-free at the time of the study. The sustained efficacy of givosiran in most patients allowed us to personalize dosing frequency. In 42%, givosiran was only given when haem precursor levels were increasing. Our data suggest that givosiran is most effective when given early in the disease course. We confirmed a high prevalence of adverse events. One patient discontinued treatment due to acute pancreatitis. All patients had hyperhomocysteinemia, and all patients with initial homocysteine levels available showed an increase under treatment. In this context, one patient was diagnosed with pulmonary embolism. Conclusion: The sustained effect of givosiran allowed a decrease in dosing frequency without compromising treatment efficacy. The high prevalence of adverse events emphasizes the importance of restricting the treatment to severe AIP and administering the minimum effective dose for each patient. (c) 2022 Elsevier Inc. All rights reserved.