Bone marrow Tfr2 deletion improves the therapeutic efficacy of the activin-receptor ligand trap RAP-536 in ß-thalassemic mice.

ß-thalassemia is a disorder characterized by anemia, ineffective erythropoiesis (IE), and iron overload, whose treatment still requires improvement. The activin receptor-ligand trap Luspatercept, a novel therapeutic option for ß-thalassemia, stimulates erythroid differentiation inhibiting the transforming growth factor ß pathway. However, its exact mechanism of action and the possible connection with erythropoietin (Epo), the erythropoiesis governing cytokine, remain to be clarified. Moreover, Luspatercept does not correct all the features of the disease, calling for the identification of strategies that enhance its efficacy. Transferrin receptor 2 (TFR2) regulates systemic iron homeostasis in the liver and modulates the response to Epo of erythroid cells, thus balancing red blood cells production with iron availability. Stimulating Epo signaling, hematopoietic Tfr2 deletion ameliorates anemia and IE in Hbbth3/+ thalassemic mice. To investigate whether hematopoietic Tfr2 inactivation improves the efficacy of Luspatercept, we treated Hbbth3/+ mice with or without hematopoietic Tfr2 (Tfr2BMKO/Hbbth3/+) with RAP-536, the murine analog of Luspatercept. As expected, both hematopoietic Tfr2 deletion and RAP-536 significantly ameliorate IE and anemia, and the combined approach has an additive effect. Since RAP-536 has comparable efficacy in both Hbbth3/+ and Tfr2BMKO/Hbbth3/+ animals, we propose that the drug promotes erythroid differentiation independently of TFR2 and EPO stimulation. Notably, the lack of Tfr2, but not RAP-536, can also attenuate iron-overload and related complications. Overall, our results shed further light on the mechanism of action of Luspatercept and suggest that strategies aimed at inhibiting hematopoietic TFR2 might improve the therapeutic efficacy of activin receptor-ligand traps.

A functional interplay between the two BMP-SMAD pathway inhibitors TMPRSS6 and FKBP12 regulates hepcidin expression in vivo.

The Activin A Receptor type I (ALK2) is a critical component of BMP-SMAD signaling that, in the presence of ligands, phosphorylates cytosolic SMAD1/5/8 and modulates important biological processes, including bone formation and iron metabolism. In hepatocytes, the BMP-SMAD pathway controls the expression of hepcidin, the liver peptide hormone that regulates body iron homeostasis via the BMP receptors ALK2 and ALK3, and the hemochromatosis proteins. The main negative regulator of the pathway in the liver is transmembrane serine protease 6 (TMPRSS6), which downregulates hepcidin by cleaving the BMP coreceptor hemojuvelin. ALK2 function is inhibited also by the immunophilin FKBP12, which maintains the receptor in an inactive conformation. FKBP12 sequestration by tacrolimus or its silencing upregulates hepcidin in primary hepatocytes and in vivo in acute but not chronic settings. Interestingly, gain-of-function mutations in ALK2 that impair FKBP12 binding to the receptor and activate the pathway cause a bone phenotype in patients affected by Fibrodysplasia Ossificans Progressiva but not hepcidin and iron metabolism dysfunction. This observation suggests that additional mechanisms are active in the liver to compensate for the increased BMP-SMAD signaling. Here we demonstrate that Fkbp12 downregulation in hepatocytes by antisense oligonucleotide treatment upregulates the expression of the main hepcidin inhibitor Tmprss6, thus counteracting the ALK2-mediated activation of the pathway. Combined downregulation of both Fkbp12 and Tmprss6 blocks this compensatory mechanism. Our findings reveal a previously unrecognized functional cross talk between FKBP12 and TMPRSS6, the main BMP-SMAD pathway inhibitors, in the control of hepcidin transcription.NEW & NOTEWORTHY This study uncovers a previously unrecognized mechanism of hepcidin and BMP-SMAD pathway regulation in hepatocytes mediated by the immunophilin FKBP12 and the transmembrane serine protease TMPRSS6.

On the Elusive Crystallography of Lithium-Rich Layered Oxides: Novel Structural Models.

Lithium-rich layered oxides (LRLOs) are one of the most attractive families among future positive electrode materials for the so-called fourth generation of lithium-ion batteries (LIBs). Their electrochemical performance is enabled by the unique ambiguous crystal structure that is still not well understood despite decades of research. In the literature, a clear structural model able to describe their crystallographic features is missing thereby hindering a clear rationalization of the interplay between synthesis, structure, and functional properties. Here, the structure of a specific LRLO, Li1.28 Mn0.54 Ni0.13 Co0.02 Al0.03 O2 , using synchrotron X-ray diffraction (XRD), neutron diffraction (ND), and High-Resolution Transmission Electron Microscopy (HR-TEM), is analyzed. A systematic approach is applied to model diffraction patterns of Li1.28 Mn0.54 Ni0.13 Co0.02 Al0.03 O2 by using the Rietveld refinement method considering the R 3 ¯ $\bar{3}$ m and C2/m unit cells as the prototype structures. Here, the relative ability of a variety of structural models is compared to match the experimental diffraction pattern evaluating the impact of defects and supercells derived from the R 3 ¯ $\bar{3}$ m structure. To summarize, two possible models able to reconcile the description of experimental data are proposed here for the structure of Li1.28 Mn0.54 Ni0.13 Co0.02 Al0.03 O2 : namely a monoclinic C2/m defective lattice (prototype Li2 MnO3 ) and a monoclinic defective supercell derived from the rhombohedral R 3 ¯ $\bar{3}$ m unit cell (prototype LiCoO2 ).

Cellular and animal models for the investigation of ß-thalassemia.

ß-Thalassemia is a genetic form of anemia due to mutations in the ß-globin gene, that leads to ineffective and extramedullary erythropoiesis, abnormal red blood cells and secondary iron-overload. The severity of the disease ranges from mild to lethal anemia based on the residual levels of globins production. Despite being a monogenic disorder, the pathophysiology of ß-thalassemia is multifactorial, with different players contributing to the severity of anemia and secondary complications. As a result, the identification of effective therapeutic strategies is complex, and the treatment of patients is still suboptimal. For these reasons, several models have been developed in the last decades to provide experimental tools for the study of the disease, including erythroid cell lines, cultures of primary erythroid cells and transgenic animals. Years of research enabled the optimization of these models and led to decipher the mechanisms responsible for globins deregulation and ineffective erythropoiesis in thalassemia, to unravel the role of iron homeostasis in the disease and to identify and validate novel therapeutic targets and agents. Examples of successful outcomes of these analyses include iron restricting agents, currently tested in the clinics, several gene therapy vectors, one of which was recently approved for the treatment of most severe patients, and a promising gene editing strategy, that has been shown to be effective in a clinical trial. This review provides an overview of the available models, discusses pros and cons, and the key findings obtained from their study.

FK506 bypasses the effect of erythroferrone in cancer cachexia skeletal muscle atrophy.

Skeletal muscle atrophy is a hallmark of cachexia, a wasting condition typical of chronic pathologies, that still represents an unmet medical need. Bone morphogenetic protein (BMP)-Smad1/5/8 signaling alterations are emerging drivers of muscle catabolism, hence, characterizing these perturbations is pivotal to develop therapeutic approaches. We identified two promoters of "BMP resistance" in cancer cachexia, specifically the BMP scavenger erythroferrone (ERFE) and the intracellular inhibitor FKBP12. ERFE is upregulated in cachectic cancer patients' muscle biopsies and in murine cachexia models, where its expression is driven by STAT3. Moreover, the knock down of Erfe or Fkbp12 reduces muscle wasting in cachectic mice. To bypass the BMP resistance mediated by ERFE and release the brake on the signaling, we targeted FKBP12 with low-dose FK506. FK506 restores BMP-Smad1/5/8 signaling, rescuing myotube atrophy by inducing protein synthesis. In cachectic tumor-bearing mice, FK506 prevents muscle and body weight loss and protects from neuromuscular junction alteration, suggesting therapeutic potential for targeting the ERFE-FKBP12 axis.

How workplaces produce or reduce disability along the career paths of young people with cystic fibrosis.

Using the theoretical perspective of "social participation" as considered in the Human Development-Disability Creation Process, this article examines certain obstacles and facilitators to sustainable access to work among young French adults with cystic fibrosis. Drawing from the analyses of 29 qualitative interviews, the results show how such obstacles do not depend solely on their health status or on the medical management of the illness, but also on the work environments that these young professionals have recently entered or are trying to access. In these contexts, managing information about the illness can represent a means of obtaining cooperation from colleagues and superiors to reduce material or organizational obstacles (e.g. adapted work schedules), as well as a means of preventing socially uncomfortable or disabling situations. In this light, the social participation model can complement Corbin and Strauss' illness trajectory model, by setting the multi-factorial disabling or participatory situations along illness or medical trajectories. This enables dynamic consideration of how workplaces contribute to producing or reducing disability, in interaction with the actions taken by young people with cystic fibrosis to manage their career paths but also the evolution of illness, symptoms, or medical requirements.

FKBP12 inhibits hepcidin expression by modulating BMP receptors interaction and ligand responsiveness in hepatocytes.

The expression of the iron regulatory hormone hepcidin in hepatocytes is regulated by the BMP-SMAD pathway through the type I receptors ALK2 and ALK3, the type II receptors ACVR2A and BMPR2, and the ligands BMP2 and BMP6. We previously identified the immunophilin FKBP12 as a new hepcidin inhibitor that acts by blocking ALK2. Both the physiologic ALK2 ligand BMP6 and the immunosuppressive drug Tacrolimus (TAC) displace FKBP12 from ALK2 and activate the signaling. However, the molecular mechanism whereby FKBP12 regulates BMP-SMAD pathway activity and thus hepcidin expression remains unclear. Here, we show that FKBP12 acts by modulating BMP receptor interactions and ligand responsiveness. We first demonstrate that in primary murine hepatocytes TAC regulates hepcidin expression exclusively via FKBP12. Downregulation of the BMP receptors reveals that ALK2, to a lesser extent ALK3, and ACVR2A are required for hepcidin upregulation in response to both BMP6 and TAC. Mechanistically, TAC and BMP6 increase ALK2 homo-oligomerization and ALK2-ALK3 hetero-oligomerization and the interaction between ALK2 and the type II receptors. By acting on the same receptors, TAC and BMP6 cooperate in BMP pathway activation and hepcidin expression both in vitro and in vivo. Interestingly, the activation state of ALK3 modulates its interaction with FKBP12, which may explain the cell-specific activity of FKBP12. Overall, our results identify the mechanism whereby FKBP12 regulates the BMP-SMAD pathway and hepcidin expression in hepatocytes, and suggest that FKBP12-ALK2 interaction is a potential pharmacologic target in disorders caused by defective BMP-SMAD signaling and characterized by low hepcidin and high BMP6 expression.

A single approach to targeting transferrin receptor 2 corrects iron and erythropoietic defects in murine models of anemia of inflammation and chronic kidney disease.

Anemia is a common complication of systemic inflammation. Proinflammatory cytokines both decrease erythroblast sensitivity to erythropoietin (EPO) and increase the levels of the hepatic hormone hepcidin, sequestering iron in stores and causing functional iron deficiency. Anemia of chronic kidney disease (CKD) is a peculiar form of anemia of inflammation, characterized by impaired EPO production paralleling progressive kidney damage. Traditional therapy based on increased EPO (often in combination with iron) may have off-target effects due to EPO interaction with its non-erythroid receptors. Transferrin Receptor 2 (Tfr2) is a mediator of the iron-erythropoiesis crosstalk. Its deletion in the liver hampers hepcidin production, increasing iron absorption, whereas its deletion in the hematopoietic compartment increases erythroid EPO sensitivity and red blood cell production. Here, we show that selective hematopoietic Tfr2 deletion ameliorates anemia in mice with sterile inflammation in the presence of normal kidney function, promoting EPO responsiveness and erythropoiesis without increasing serum EPO levels. In mice with CKD, characterized by absolute rather than functional iron deficiency, Tfr2 hematopoietic deletion had a similar effect on erythropoiesis but anemia improvement was transient because of limited iron availability. Also, increasing iron levels by downregulating only hepatic Tfr2 had a minor effect on anemia. However, simultaneous deletion of hematopoietic and hepatic Tfr2, stimulating erythropoiesis and increased iron supply, was sufficient to ameliorate anemia for the entire protocol. Thus, our results suggest that combined targeting of hematopoietic and hepatic Tfr2 may be a therapeutic option to balance erythropoiesis stimulation and iron increase, without affecting EPO levels.

Iron is a modifier of the phenotypes of JAK2-mutant myeloproliferative neoplasms.

JAK 2-V617F mutation causes myeloproliferative neoplasms (MPNs) that can manifest as polycythemia vera (PV), essential thrombocythemia (ET), or primary myelofibrosis. At diagnosis, patients with PV already exhibited iron deficiency, whereas patients with ET had normal iron stores. We examined the influence of iron availability on MPN phenotype in mice expressing JAK2-V617F and in mice expressing JAK2 with an N542-E543del mutation in exon 12 (E12). At baseline, on a control diet, all JAK2-mutant mouse models with a PV-like phenotype displayed iron deficiency, although E12 mice maintained more iron for augmented erythropoiesis than JAK2-V617F mutant mice. In contrast, JAK2-V617F mutant mice with an ET-like phenotype had normal iron stores comparable with that of wild-type (WT) mice. On a low-iron diet, JAK2-mutant mice and WT controls increased platelet production at the expense of erythrocytes. Mice with a PV phenotype responded to parenteral iron injections by decreasing platelet counts and further increasing hemoglobin and hematocrit, whereas no changes were observed in WT controls. Alterations of iron availability primarily affected the premegakaryocyte-erythrocyte progenitors, which constitute the iron-responsive stage of hematopoiesis in JAK2-mutant mice. The orally administered ferroportin inhibitor vamifeport and the minihepcidin PR73 normalized hematocrit and hemoglobin levels in JAK2-V617F and E12 mutant mouse models of PV, suggesting that ferroportin inhibitors and minihepcidins could be used in the treatment for patients with PV.

Consensus Statement on the definition and classification of metabolic hyperferritinaemia.

Hyperferritinaemia is a common laboratory finding that is often associated with metabolic dysfunction and fatty liver. Metabolic hyperferritinaemia reflects alterations in iron metabolism that facilitate iron accumulation in the body and is associated with an increased risk of cardiometabolic and liver diseases. Genetic variants that modulate iron homeostasis and tissue levels of iron are the main determinants of serum levels of ferritin in individuals with metabolic dysfunction, raising the hypothesis that iron accumulation might be implicated in the pathogenesis of insulin resistance and the related organ damage. However, validated criteria for the non-invasive diagnosis of metabolic hyperferritinaemia and the staging of iron overload are still lacking, and there is no clear evidence of a benefit for iron depletion therapy. Here, we provide an overview of the literature on the relationship between hyperferritinaemia and iron accumulation in individuals with metabolic dysfunction, and on the associated clinical outcomes. We propose an updated definition and a provisional staging system for metabolic hyperferritinaemia, which has been agreed on by a multidisciplinary global panel of expert researchers. The goal is to foster studies into the epidemiology, genetics, pathophysiology, clinical relevance and treatment of metabolic hyperferritinaemia, for which we provide suggestions on the main unmet needs, optimal design and clinically relevant outcomes.

Managing the Dual Nature of Iron to Preserve Health.

Because of its peculiar redox properties, iron is an essential element in living organisms, being involved in crucial biochemical processes such as oxygen transport, energy production, DNA metabolism, and many others. However, its propensity to accept or donate electrons makes it potentially highly toxic when present in excess and inadequately buffered, as it can generate reactive oxygen species. For this reason, several mechanisms evolved to prevent both iron overload and iron deficiency. At the cellular level, iron regulatory proteins, sensors of intracellular iron levels, and post-transcriptional modifications regulate the expression and translation of genes encoding proteins that modulate the uptake, storage, utilization, and export of iron. At the systemic level, the liver controls body iron levels by producing hepcidin, a peptide hormone that reduces the amount of iron entering the bloodstream by blocking the function of ferroportin, the sole iron exporter in mammals. The regulation of hepcidin occurs through the integration of multiple signals, primarily iron, inflammation and infection, and erythropoiesis. These signals modulate hepcidin levels by accessory proteins such as the hemochromatosis proteins hemojuvelin, HFE, and transferrin receptor 2, the serine protease TMPRSS6, the proinflammatory cytokine IL6, and the erythroid regulator Erythroferrone. The deregulation of the hepcidin/ferroportin axis is the central pathogenic mechanism of diseases characterized by iron overload, such as hemochromatosis and iron-loading anemias, or by iron deficiency, such as IRIDA and anemia of inflammation. Understanding the basic mechanisms involved in the regulation of hepcidin will help in identifying new therapeutic targets to treat these disorders.

Transferrin receptor 2 (Tfr2) genetic deletion makes transfusion-independent a murine model of transfusion-dependent ß-thalassemia.

ß-thalassemia is a genetic disorder caused by mutations in the ß-globin gene, and characterized by anemia, ineffective erythropoiesis and iron overload. Patients affected by the most severe transfusion-dependent form of the disease (TDT) require lifelong blood transfusions and iron chelation therapy, a symptomatic treatment associated with several complications. Other therapeutic opportunities are available, but none is fully effective and/or applicable to all patients, calling for the identification of novel strategies. Transferrin receptor 2 (TFR2) balances red blood cells production according to iron availability, being an activator of the iron-regulatory hormone hepcidin in the liver and a modulator of erythropoietin signaling in erythroid cells. Selective Tfr2 deletion in the BM improves anemia and iron-overload in non-TDT mice, both as a monotherapy and, even more strikingly, in combination with iron-restricting approaches. However, whether Tfr2 targeting might represent a therapeutic option for TDT has never been investigated so far. Here, we prove that BM Tfr2 deletion improves anemia, erythrocytes morphology and ineffective erythropoiesis in the Hbbth1/th2 murine model of TDT. This effect is associated with a decrease in the expression of α-globin, which partially corrects the unbalance with ß-globin chains and limits the precipitation of misfolded hemoglobin, and with a decrease in the activation of unfolded protein response. Remarkably, BM Tfr2 deletion is also sufficient to avoid long-term blood transfusions required for survival of Hbbth1/th2 animals, preventing mortality due to chronic anemia and reducing transfusion-associated complications, such as progressive iron-loading. Altogether, TFR2 targeting might represent a promising therapeutic option also for TDT.

Du modèle médical vers un modèle social de l'autonomie des personnes atteintes de mucoviscidose. Une étude sociologique du point de vue des acteurs professionnels et associatifs.

Patient autonomy is an equivocal notion that refers to several intertwined figures. What is expected of young cystic fibrosis patients when speaking to actors (professionals and associations) involved with them ? In this sociological contribution, we show the limits of a medical model of autonomy that does not allow us to think about a whole series of micro-adjustments to the practices of people with cystic fibrosis. The analysis is based on publications by national associations fighting against cystic fibrosis, and on semi-structured interviews with professionals working with people living with this disease. It shows that autonomy is not only thought of by the professionals who support them in terms of an individual management model centered on the patient's medical skills and personal resources, but also as the result of environmental factors. It reveals an innovative characteristic of autonomy in the field of health care, largely supported by the specialized and reinforced medical support of coordinating nurses. This support allows the development of a detailed clinical knowledge of the situations experienced by their patients.

The mutual crosstalk between iron and erythropoiesis.

Iron homeostasis and erythropoiesis are strongly interconnected. On one side iron is essential to terminal erythropoiesis for hemoglobin production, on the other erythropoiesis may increase iron absorption through the production of erythroferrone, the erythroid hormone that suppresses hepcidin expression Also erythropoietin production is modulated by iron through the iron regulatory proteins-iron responsive elements that control the hypoxia inducible factor 2-α. The second transferrin receptor, an iron sensor both in the liver and in erythroid cells modulates erythropoietin sensitivity and is a further link between hepcidin and erythropoiesis. When erythropoietin is decreased in iron deficiency the erythropoietin sensitivity is increased because the second transferrin receptor is removed from cell surface. A deranged balance between erythropoiesis and iron/hepcidin may lead to anemia, as in the case of iron deficiency, defective iron uptake and erythroid utilization or subnormal recycling. Defective control of hepcidin production may cause iron deficiency, as in the recessive disorder iron refractory iron deficiency anemia or in anemia of inflammation, or in iron loading anemias, which are characterized by excessive but ineffective erythropoiesis. The elucidation of the mechanisms that regulates iron homeostasis and erythropoiesis is leading to the development of drugs for the benefit of both iron and erythropoiesis disorders.

Pushing Stoichiometries of Lithium-Rich Layered Oxides Beyond Their Limits.

Lithium-rich layered oxides (LRLOs) are opening unexplored frontiers for high-capacity/high-voltage positive electrodes in Li-ion batteries (LIBs) to meet the challenges of green and safe transportation as well as cheap and sustainable stationary energy storage from renewable sources. LRLOs exploit the extra lithiation provided by the Li1.2TM0.8O2 stoichiometries (TM = a blend of transition metals with a moderate cobalt content) achievable by a layered structure to disclose specific capacities beyond 200-250 mA h g-1 and working potentials in the 3.4-3.8 V range versus Li. Here, we demonstrate an innovative paradigm to extend the LRLO concept. We have balanced the substitution of cobalt in the transition-metal layer of the lattice with aluminum and lithium, pushing the composition of LRLO to unexplored stoichiometries, that is, Li1.2+x (Mn,Ni,Co,Al)0.8-x O2-δ. The fine tuning of the composition of the metal blend results in an optimized layered material, that is, Li1.28Mn0.54Ni0.13Co0.02Al0.03O2-δ, with outstanding electrochemical performance in full LIBs, improved environmental benignity, and reduced manufacturing costs compared to the state-of-the-art.

[Delicate transition: Building-up an adult life for young people with developmental chromosomal anomalies]. / Délicates transitions - Construction d'une place d'adulte pour des jeunes vivant avec une anomalie chromosomique du développement.

A qualitative study was performed in the South of France among young people (16-25 years) affected by chromosomal anomalies: Down, velo-cardio-facial, or Williams-Beuren syndromes. We conducted interviews with them and with their parents to understand the obstacles to social participation that they most frequently face when becoming adults. Once their education comes to an end, young adults with developmental anomalies face several difficulties to develop and keep diversified social ties and to find their place in society, be it with a stable job - either in the ordinary working environment or in sheltered employment - or by attending occupational workshops. While parents are mostly concerned with finding a professional place for their children, the latter seem to especially value opportunities for satisfactory relational dynamics outside of the protective frame of the family. Nevertheless, a wish for familial protection keeps coexisting with their wish for independence.

TITLE: Délicates transitions - Construction d'une place d'adulte pour des jeunes vivant avec une anomalie chromosomique du développement. ABSTRACT: Nous avons mené une étude qualitative par entretiens individuels et collectifs (focus groups) auprès de jeunes (de 16 à 25 ans) touchés par une anomalie chromosomique (trisomie 21, microdélétion 22q11.2 associée au syndrome vélo-cardio-facial, ou microdélétion 7q11.23 associée au syndrome de Williams-Beuren) et de leurs familles, afin de comprendre les obstacles à la participation sociale qu'ils rencontrent lors du passage à l'âge adulte. Confrontés à de nombreuses contraintes pour développer des liens sociaux diversifiés et pour trouver une place sociale, professionnelle ou non, après la scolarité, ces jeunes semblent attribuer la plus grande importance à une dynamique relationnelle positive en dehors de l'espace familial, dont ils continuent toutefois de souhaiter la protection.

CXCL10 levels at hospital admission predict COVID-19 outcome: hierarchical assessment of 53 putative inflammatory biomarkers in an observational study.

BACKGROUND: Host inflammation contributes to determine whether SARS-CoV-2 infection causes mild or life-threatening disease. Tools are needed for early risk assessment. METHODS: We studied in 111 COVID-19 patients prospectively followed at a single reference Hospital fifty-three potential biomarkers including alarmins, cytokines, adipocytokines and growth factors, humoral innate immune and neuroendocrine molecules and regulators of iron metabolism. Biomarkers at hospital admission together with age, degree of hypoxia, neutrophil to lymphocyte ratio (NLR), lactate dehydrogenase (LDH), C-reactive protein (CRP) and creatinine were analysed within a data-driven approach to classify patients with respect to survival and ICU outcomes. Classification and regression tree (CART) models were used to identify prognostic biomarkers. RESULTS: Among the fifty-three potential biomarkers, the classification tree analysis selected CXCL10 at hospital admission, in combination with NLR and time from onset, as the best predictor of ICU transfer (AUC [95% CI] = 0.8374 [0.6233-0.8435]), while it was selected alone to predict death (AUC [95% CI] = 0.7334 [0.7547-0.9201]). CXCL10 concentration abated in COVID-19 survivors after healing and discharge from the hospital. CONCLUSIONS: CXCL10 results from a data-driven analysis, that accounts for presence of confounding factors, as the most robust predictive biomarker of patient outcome in COVID-19.