COVID-19 in adult acute myeloid leukemia patients: a long-term follow-up study from the European Hematology Association survey (EPICOVIDEHA).

Patients with acute myeloid leukemia (AML) are at high risk of dying from coronavirus disease 2019 (COVID-19). The optimal management of AML patients with COVID-19 has not been established. Our multicenter study included 388 adult AML patients diagnosed with COVID-19 between February 2020 and October 2021. The vast majority were receiving or had received AML treatment in the preceding 3 months. COVID-19 was severe in 41.2% and critical in 21.1% of cases. The chemotherapeutic schedule was modified in 174 patients (44.8%), delayed in 68 and permanently discontinued in 106. After a median follow-up of 325 days, 180 patients (46.4%) had died; death was attributed to COVID-19 (43.3%), AML (26.1%) or to a combination of both (26.7%), whereas in 3.9% of cases the reason was unknown. Active disease, older age, and treatment discontinuation were associated with death, whereas AML treatment delay was protective. Seventy-nine patients had a simultaneous AML and COVID-19 diagnosis, with better survival when AML treatment could be delayed (80%; P<0.001). Overall survival in patients with a diagnosis of COVID-19 between January 2020 and August 2020 was significantly lower than that in patients diagnosed between September 2020 and February 2021 and between March 2021 and September 2021 (39.8% vs. 60% vs. 61.9%, respectively; P=0.006). COVID-19 in AML patients was associated with a high mortality rate and modifications of therapeutic algorithms. The best approach to improve survival was to delay AML treatment, whenever possible.

Development of a method for assessing the accumulation and metabolization of antidepressant drugs in zebrafish (Danio rerio) eleutheroembryos.

Antidepressant drugs are widely used for the treatment of common mental or other psychiatric disorders such as depression, which affect about 121 million people worldwide. This widespread use has contributed to the input of these pharmaceuticals and their metabolites into the environment. The aim of this work was to develop an analytical method to quantify the most widely used antidepressant drugs, selective serotonin reuptake inhibitors (SSRI), and their main metabolites in the environment. For this, a new and reliable miniaturized extraction method based on dispersive SPE cleanup procedure for extraction of SSRI followed by derivatization with n-heptafluorobutyrylimidazole, and detection by GC-MS was developed. The methodology, including a first-order one-compartment model, was then applied to a bioconcentration study in zebrafish (Danio rerio) eleutheroembryos. The results showed low bioaccumulation of these compounds; however, a biotransformation evidence of the parent compounds into their metabolites was observed after 6 h of exposure. These results indicate the need to integrate metabolic transformation rates to fully model and understand the bioaccumulation patterns of SSRI and their metabolites. Graphical abstract.

Gemin5 promotes IRES interaction and translation control through its C-terminal region.

Gene expression control largely depends on ribonucleoprotein complexes regulating mRNA translation. Initiation of translation in mRNAs that overcome cap-dependent translation inhibition is often driven by internal ribosome entry site (IRES) elements, whose activity is regulated by multifunctional RNA-binding factors. Here we show that Gemin5 interacts preferentially with a specific domain of a viral IRES consisting of a hairpin flanked by A/U/C-rich sequences. RNA-binding assays using purified proteins revealed that Gemin5-IRES interaction depends on the C-terminal region of the protein. Consistent with this novel finding, the C-terminal region of Gemin5, but not the N-terminal region, impaired translation. Furthermore, RNA selective 2'hydroxyl acylation analysed by primer extension (SHAPE) reactivity demonstrated that addition of purified Gemin5 to IRES mRNA induced the specific protection of residues around the hairpin of the IRES element. We further demonstrate that Gemin5 out-competed SHAPE reactivity variations induced by the IRES-binding factor PTB, leading to a local conformational change in the IRES structure. Together, our data unveil the inhibitory mechanism of Gemin5 on IRES-mediated translation.

Protein engineered variants of hepatocyte growth factor/scatter factor promote proliferation of primary human hepatocytes and in rodent liver.

BACKGROUND & AIMS: Hepatocyte growth factor/scatter factor (HGF/SF) stimulates hepatocyte DNA synthesis and protects against apoptosis; in vivo it promotes liver regeneration and reduces fibrosis. However, its therapeutic value is limited by its complex domain structure, high cost of production, instability, and poor tissue penetration due to sequestration by heparin sulfate proteoglycans (HSPGs). METHODS: Using protein engineering techniques, we created a full-length form of HGF/SF (called HP21) and a form of the small, naturally occurring HGF/SF fragment, NK1 (called 1K1), which have reduced affinity for HSPG. We characterized the stability and proliferative and anti-apoptotic effects of these variants in primary human hepatocytes and in rodents. RESULTS: Analytical ultracentrifugation showed that 1K1 and NK1 were more stable than the native, full-length protein. All 4 forms of HGF/SF induced similar levels of DNA synthesis in human hepatocytes; 1K1 and NK1 required heparin, an HSPG analogue, for full agonistic activity. All the proteins reduced levels of Fas ligand-mediated apoptosis, reducing the activity of caspase-3/7 and cleavage of poly(adenosine diphosphate-ribose) polymerase. 1K1 was more active than NK1 in rodents; in healthy mice, 1K1 significantly increased hepatocyte DNA synthesis, and in mice receiving carbon tetrachloride, it reduced fibrosis. In rats, after 70% partial hepatectomy, daily administration of 1K1 for 5 days significantly increased liver mass and the bromodeoxyuridine labeling index compared with mice given NK1. CONCLUSIONS: 1K1, an engineered form of the small, naturally occurring HGF/SF fragment NK1, has reduced affinity for HSPG and exerts proliferative and antiapoptotic effects in cultured hepatocytes. In rodents, 1K1 has antifibrotic effects and promotes liver regeneration. The protein has better stability and is easier to produce than HGF/SF and might be developed as a therapeutic for acute and chronic liver disease.

Structural basis for the biological relevance of the invariant apical stem in IRES-mediated translation.

RNA structure plays a fundamental role in internal initiation of translation. Picornavirus internal ribosome entry site (IRES) are long, efficient cis-acting elements that recruit the ribosome to internal mRNA sites. However, little is known about long-range constraints determining the IRES RNA structure. Here, we sought to investigate the functional and structural relevance of the invariant apical stem of a picornavirus IRES. Mutation of this apical stem revealed better performance of G:C compared with C:G base pairs, demonstrating that the secondary structure solely is not sufficient for IRES function. In turn, mutations designed to disrupt the stem abolished IRES activity. Lack of tolerance to accept genetic variability in the apical stem was supported by the presence of coupled covariations within the adjacent stem-loops. SHAPE structural analysis, gel mobility-shift and microarrays-based RNA accessibility revealed that the apical stem contributes to maintain IRES RNA structure through the generation of distant interactions between two adjacent stem-loops. Our results demonstrate that a highly interactive structure constrained by distant interactions involving invariant G:C base pairs plays a key role in maintaining the RNA conformation necessary for IRES-mediated translation.

Nirmatrelvir/ritonavir in COVID-19 patients with haematological malignancies: a report from the EPICOVIDEHA registry.

Background: Nirmatrelvir/ritonavir treatment decreases the hospitalisation rate in immunocompetent patients with COVID-19, but data on efficacy in patients with haematological malignancy are scarce. Here, we describe the outcome of nirmatrelvir/ritonavir treatment in a large cohort of the latter patients. Methods: This is a retrospective cohort study from the multicentre EPICOVIDEHA registry (NCT04733729) on patients with haematological malignancy, who were diagnosed with COVID-19 between January and September 2022. Patients receiving nirmatrelvir/ritonavir were compared to those who did not. A logistic regression was run to determine factors associated with nirmatrelvir/ritonavir administration in our sample. Mortality between treatment groups was assessed with Kaplan-Meier survival plots after matching all the patients with a propensity score. Additionally, a Cox regression was modelled to detect factors associated with mortality in patients receiving nirmatrelvir/ritonavir. Findings: A total of 1859 patients were analysed, 117 (6%) were treated with nirmatrelvir/ritonavir, 1742 (94%) were treated otherwise. Of 117 patients receiving nirmatrelvir/ritonavir, 80% had received ≥1 anti-SARS-CoV-2 vaccine dose before COVID-19 onset, 13% of which received a 2nd vaccine booster. 5% were admitted to ICU. Nirmatrelvir/ritonavir treatment was associated with the presence of extrapulmonary symptoms at COVID-19 onset, for example anosmia, fever, rhinitis, or sinusitis (aOR 2.509, 95%CI 1.448-4.347) and 2nd vaccine booster (aOR 3.624, 95%CI 1.619-8.109). Chronic pulmonary disease (aOR 0.261, 95%CI 0.093-0.732) and obesity (aOR 0.105, 95%CI 0.014-0.776) were not associated with nirmatrelvir/ritonavir use. After propensity score matching, day-30 mortality rate in patients treated with nirmatrelvir/ritonavir was 2%, significantly lower than in patients with SARS-CoV-2 directed treatment other than nirmatrelvir/ritonavir (11%, p = 0.036). No factor was observed explaining the mortality difference in patients after nirmatrelvir/ritonavir administration. Interpretation: Haematological malignancy patients were more likely to receive nirmatrelvir/ritonavir when reporting extrapulmonary symptoms or 2nd vaccine booster at COVID-19 onset, as opposed to chronic pulmonary disease and obesity. The mortality rate in patients treated with nirmatrelvir/ritonavir was lower than in patients with targeted drugs other than nirmatrelvir/ritonavir. Funding: EPICOVIDEHA has received funds from Optics COMMIT (COVID-19 Unmet Medical Needs and Associated Research Extension) COVID-19 RFP program by GILEAD Science, United States (Project 2020-8223).

Impact of SARS-CoV-2 vaccination and monoclonal antibodies on outcome post-CD19-directed CAR T-cell therapy: an EPICOVIDEHA survey.

Patients with previous CD19-directed chimeric antigen receptor (CAR) T-cell therapy have a prolonged vulnerability to viral infections. Coronavirus disease 2019 (COVID-19) has a great impact and has previously been shown to cause high mortality in this population. Until now, real-world data on the impact of vaccination and treatment on patients with COVID-19 after CD19-directed CAR T-cell therapy are lacking. Therefore, this multicenter, retrospective study was conducted with data from the EPICOVIDEHA survey. Sixty-four patients were identified. The overall mortality caused by COVID-19 was 31%. Patients infected with the Omicron variant had a significantly lower risk of death due to COVID-19 compared with patients infected with previous variants (7% vs 58% [P = .012]). Twenty-six patients were vaccinated at the time of the COVID-19 diagnosis. Two vaccinations showed a marked but unsignificant reduction in the risk of COVID-19-caused mortality (33.3% vs 14.2% [P = .379]). In addition, the course of the disease appears milder with less frequent intensive care unit admissions (39% vs 14% [P = .054]) and a shorter duration of hospitalization (7 vs 27.5 days [P = .022]). Of the available treatment options, only monoclonal antibodies seemed to be effective at reducing mortality from 32% to 0% (P = .036). We conclude that survival rates of CAR T-cell recipients with COVID-19 improved over time and that the combination of prior vaccination and monoclonal antibody treatment significantly reduces their risk of death. This trial was registered at www.clinicaltrials.gov as #NCT04733729.

Age, successive waves, immunization, and mortality in elderly COVID-19 hematological patients: EPICOVIDEHA findings.

OBJECTIVES: Elderly patients with hematologic malignancies face the highest risk of severe COVID-19 outcomes. The infection's impact on different age groups remains unstudied in detail. METHODS: We analyzed elderly patients (age groups: 65-70, 71-75, 76-80, and >80 years old) with hematologic malignancies included in the EPICOVIDEHA registry between January 2020 and July 2022. Univariable and multivariable Cox regression models were conducted to identify factors influencing death in COVID-19 patients with hematological malignancy. RESULTS: The study included data from 3,603 elderly patients (aged 65 or older) with hematological malignancy, with a majority being male (58.1%) and a significant proportion having comorbidities. The patients were divided into four age groups, and the analysis assessed COVID-19 outcomes, vaccination status, and other variables in relation to age and pandemic waves. The 90-day survival rate for patients with COVID-19 was 71.2%, with significant differences between groups. The pandemic waves had varying impacts, with the first wave affecting patients over 80 years old, the second being more severe in 65-70, and the third being the least severe in all age groups. Factors contributing to 90-day mortality included age, comorbidities, lymphopenia, active malignancy, acute leukemia, less than three vaccine doses, severe COVID-19, and using only corticosteroids as treatment. CONCLUSION: These data underscore the heterogeneity of elderly hematological patients, highlight the different impacts of COVID-19 waves and the pivotal importance of vaccination, and may help in planning future healthcare efforts.

Tailoring the switch from IRES-dependent to 5'-end-dependent translation with the RNase P ribozyme.

Translation initiation driven by internal ribosome entry site (IRES) elements is dependent on the structural organization of the IRES region. We have previously shown that a structural motif within the foot-and-mouth-disease virus IRES is recognized in vitro as substrate for the Synechocystis sp. RNase P ribozyme. Here we show that this structure-dependent endonuclease recognizes the IRES element in cultured cells, leading to inhibition of translation. Inhibition of IRES activity was dependent on the expression of the active ribozyme RNA subunit. Moreover, expression of the antisense sequence of the ribozyme did not inhibit IRES activity, demonstrating that stable RNA structures located upstream of the IRES element do not interfere with internal initiation. RNAs carrying defective IRES mutants that were substrates of the ribozyme in vivo revealed an increased translation of the reporter in response to the expression of the active ribozyme. In support of RNA cleavage, subsequent analysis of the translation initiation manner indicated a switch from IRES-dependent to 5'-end-dependent translation of RNase P target RNAs. We conclude that the IRES element is inactivated by expression in cis of RNase P in the cytoplasm of cultured cells, providing a promising antiviral tool to combat picornavirus infections. Furthermore, our results reinforce the essential role of the structural motif that serves as RNase P recognition motif for IRES activity.

Alternative Mechanisms to Initiate Translation in Eukaryotic mRNAs.

The composition of the cellular proteome is under the control of multiple processes, one of the most important being translation initiation. The majority of eukaryotic cellular mRNAs initiates translation by the cap-dependent or scanning mode of translation initiation, a mechanism that depends on the recognition of the m(7)G(5')ppp(5')N, known as the cap. However, mRNAs encoding proteins required for cell survival under stress bypass conditions inhibitory to cap-dependent translation; these mRNAs often harbor internal ribosome entry site (IRES) elements in their 5'UTRs that mediate internal initiation of translation. This mechanism is also exploited by mRNAs expressed from the genome of viruses infecting eukaryotic cells. In this paper we discuss recent advances in understanding alternative ways to initiate translation across eukaryotic organisms.

Structural equation modelling of mercury intra-skeletal variability on archaeological human remains.

Archaeological burial environments are useful archives to investigate the long-term trends and the behaviour of mercury. In order to understand the relationship between mercury, skeletons and soil, we applied Partial Least Squares - Structural Equation Modelling (PLS-SEM) to a detailed, multisampling (n = 73 bone samples +37 soil samples) design of two archaeological graves dating to the 6th to 7th centuries CE (A Lanzada site, NW Spain). Mercury content was assessed using a DMA-80, and data about bone structure and the grave soil/sediments were obtained using FTIR-ATR spectroscopy. The theoretical model is supported by proxies of bone structure, grave soil/sediments, and location of the bone within the skeleton. The general model explained 61 % of mercury variance. Additionally, Partial Least Square - Prediction Oriented Segmentation (PLS-POS) was also used to check for segmentation in the dataset. POS revealed two group of samples depending on the bone phase (hydroxyapatite or collagen) controlling the Hg content, and the corresponding models explained 86 % and 76 % of Hg variance, respectively. The results suggest that mercury behaviour in the graves is complex, and that mercury concentrations were influenced by i) the ante-mortem status of the bone matrix, related to the weight of each bone phase; ii) post-mortem evolution of bone crystallinity, where bone loses mercury with increasing alteration; and iii) the proximity of the skeletal pieces to mercury target organs, as decomposition and collapse of the thoracic and abdominal soft tissues causes a secondary mercury enrichment in bones from the body trunk during early post-mortem. Skeletons provide a source of mercury to the soil whereas soil/sediments contribute little to skeletal mercury content.

Understanding Necrosol pedogenetical processes in post-Roman burials developed on dunes sands.

In Archaeology much emphasis is dedicated to bone preservation, but less attention is paid to the burial soil (i.e., Necrosol), despite its crucial role in governing the geochemical environment. The interaction between human remains and sediments starts after inhumation, leading to bidirectional physico-chemical changes. To approach these complex, bidirectional processes, we sampled at high resolution (n = 46) two post-Roman wooden coffin burials (one single and another double), and the coeval paleosol (n = 20; nearby pedo-sedimentary sequence). The samples were analysed for physical (grain size, colour) and chemical (pH; LOI; elemental composition: FTIR-ATR, XRF, C, N) properties. Principal component analysis enabled to identify five main pedogenetical processes: decalcification, melanization, acidification, neoformation of secondary minerals (i.e., clays) and enrichment in phosphorus. Melanization, acidification and phosphorous enrichment seem to be convergent processes in Necrosols-irrespective of the parent material. Decalcification may be restricted to carbonate containing soil/sediments. Despite not mentioned in previous research, clay formation might also be an overall process. Compared to the local, coeval paleosol, pedogenesis in the studied burial soils was low (double burial) to moderate (single burial). Our results also emphasize the need to study the finer soil fractions, as they provide clues both on soil formation and bone diagenesis.

A novel role for Gemin5 in mRNA translation.

In eukaryotic cells translation initiation occurs through two alternative mechanisms, a cap-dependent operating in the majority of mRNAs, and a 5'-end-independent driven by internal ribosome entry site (IRES) elements, specific for a subset of mRNAs. IRES elements recruit the translation machinery to an internal position in the mRNA through a mechanism involving the IRES structure and several trans-acting factors. Here, we identified Gemin5 protein bound to the foot-and-mouth disease virus (FMDV) and hepatitis C virus (HCV) IRES using two independent approaches, riboproteomic analysis and immunoprecipitation of photocrosslinked factors. Functional analysis performed in Gemin5 shRNA-depleted cells, or in in vitro translation reactions, revealed an unanticipated role of Gemin5 in translation control as a down-regulator of cap-dependent and IRES-driven translation initiation. Consistent with this, pull-down assays showed that Gemin5 forms part of two distinct complexes, a specific IRES-ribonucleoprotein complex and an IRES-independent protein complex containing eIF4E. Thus, beyond its role in snRNPs biogenesis, Gemin5 also functions as a modulator of translation activity.

Approaching mercury distribution in burial environment using PLS-R modelling.

Mercury environmental cycle and toxicology have been widely researched. Given the long history of mercury pollution, researching mercury trends in the past can help to understand its behaviour in the present. Archaeological skeletons have been found to be useful sources of information regarding mercury loads in the past. In our study we applied a soil multi-sampling approach in two burials dated to the 5th to 6th centuries AD. PLRS modelling was used to elucidate the factors controlling mercury distribution. The model explains 72% of mercury variance and suggests that mercury accumulation in the burial soils is the result of complex interactions. The decomposition of the bodies not only was the primary source of mercury to the soil but also responsible for the pedogenetic transformation of the sediments and the formation of soil components with the ability to retain mercury. The amount of soft tissues and bone mass also resulted in differences between burials, indicating that the skeletons were a primary/secondary source of mercury to the soil (i.e. temporary sink). Within burial variability seems to depend on the proximity of the soil to the thoracic area, where the main mercury target organs were located. We also conclude that, in coarse textured soils, as the ones studied in this investigation, the finer fraction (i.e. silt + clay) should be analysed, as it is the most reactive and the one with the higher potential to provide information on metal cycling and incipient soil processes. Finally, our study stresses the need to characterise the burial soil environment in order to fully understand the role of the interactions between soil and skeleton in mercury cycling in burial contexts.

Obstetric complications in bipolar disorder: Psychiatric factors and the risk of caesarean section.

Bipolar Disorder (BD) is a chronic psychiatric condition with somatic morbidity that requires continuous mood stabilizing treatment to prevent relapses. Pregnant women with BD have shown an increased rate of caesarean section (C-Section) in comparison with women without BD. Because specific differentiated profiles between mothers with BD that require C-Section and those that do not require C-Section have not been largely discussed, we aim to explore the risk factors associated with the type of delivery in pregnant women with BD. A prospective cohort study was conducted at the Perinatal Mental Health Unit. 100 pregnant women with BD were followed throughout their pregnancy by obstetric and psychiatric services at the same hospital. The cohort was developed in order to compare psychiatric and obstetric outcomes between women with BD that required C-Section (N = 40) versus women that did not require C-Section (N = 60). Final regression models showed an increased risk for obstetric complications during labour (OR 4,52, 95% CI 1,66-12,29), higher rates of hypothyroidism (OR 3,73, 95% CI 1,04-13,73) and treatment with lithium + antidepressant (OR 4,24, 95% CI 1,34-13,40) amongst the C-Section group when compared to the non-C-Section group. In our sample, women with BD treated with lithium plus antidepressant, with hypothyroidism and without obstetric complications have a 70,5% probability of C-Section. In conclusion, psychopharmacology and thyroid function might help understanding which women with BD will have more probability of C-Section. The implementation of more targeted interventions in selected patients might be useful to avoid complications during delivery.

Human bones tell the story of atmospheric mercury and lead exposure at the edge of Roman World.

Atmospheric metal pollution is a major health concern whose roots pre-date industrialization. This study pertains the analyses of ancient human skeletons and compares them with natural archives to trace historical environmental exposure at the edge of the Roman Empire in NW Iberia. The novelty of our approach relies on the combination of mercury, lead and lead isotopes. We found over a 700-year period that rural Romans incorporated two times more mercury and lead into their bones than post-Romans inhabiting the same site, independent of sex or age. Atmospheric pollution sources contributed on average 57% (peaking at 85%) of the total lead incorporated into the bones in Roman times, which decreased to 24% after the decline of Rome. These values and accompanying changes in lead isotopic composition mirror changes in atmospheric Pb deposition recorded in local peatlands. Thus, skeletons are a time-transgressive archive reflecting contaminant exposure.

Mobile Intensive Care Unit versus Hospital walk-in patients, in the treatment of first episode ST- elevation myocardial infarction.

OBJECTIVE: To determine the impact of the attention given by emergency medical services teams working in mobile intensive care units (MICU) versus patients arriving at the hospital under their own means with ST-elevation myocardial infarction (STEMI) event in terms of time to reperfusion (TR), mortality at 30 days and six months. METHODS: We retrospectively studied 634 consecutive patients with STEMI who underwent primary a percutaneous coronary intervention from January 1st 2015 to December 31st 2018 in a single centre. Depending on the first medical contact patients were classified into two groups, MICU versus walk-in patients. We extracted data on patients' characteristics, symptoms, treatments, times to reperfusion and mortality. RESULTS: In our study 634 patients were included, of whom 59.0% were initially attended by the MICU. Differences were seen between the two groups in time delays to the first medical contact (120.0 vs 63.0 min; p < 0.001) and TR (208.0 Vs 150.0 min; p < 0.001). Patients attended by the MICUs presented a shorter ICU and hospital stay. The lowest 30-day mortality rate was observed in MICU group: 9.0% in contrast with 4.5%, p = 0.03; remaining after 6 months. The multivariable analysis showed that the initial attention given by MICU to STEMI patients was a protective agent against mortality [OR: 0.32 (0.11-0.90); p = 0.03]. CONCLUSION: Initial attention of the patients with STEMI by doctor-on-board-MICU and available 24 h a day 7 days a week as part of a regional network (CORECAM), was associated with a decrease in the ischemia time, hospital stay and mortality of these patients in our environment.