Integrated Approach of Life Cycle Assessment and Experimental Design in the Study of a Model Organic Reaction: New Perspectives in Renewable Vanillin-Derived Chemicals.

This work is focused on performing a quantitative assessment of the environmental impacts associated with an organic synthesis reaction, optimized using an experimental design approach. A nucleophilic substitution reaction was selected, employing vanillin as the substrate, a phenolic compound widely used in the food industry and of pharmaceutical interest, considering its antioxidant and antitumoral potential. To carry out the reaction, three different solvents have been chosen, namely acetonitrile (ACN), acetone (Ace), and dimethylformamide (DMF). The syntheses were planned with the aid of a multivariate experimental design to estimate the best reaction conditions, which simultaneously allow a high product yield and a reduced environmental impact as computed by Life Cycle Assessment (LCA) methodology. The experimental results highlighted that the reactions carried out in DMF resulted in higher yields with respect to ACN and Ace; these reactions were also the ones with lower environmental impacts. The multilinear regression models allowed us to identify the optimal experimental conditions able to guarantee the highest reaction yields and lowest environmental impacts for the studied reaction. The identified optimal experimental conditions were also validated by experimentally conducting the reaction in those conditions, which indeed led to the highest yield (i.e., 93%) and the lowest environmental impacts among the performed experiments. This work proposes, for the first time, an integrated approach of DoE and LCA applied to an organic reaction with the aim of considering both conventional metrics, such as reaction yield, and unconventional ones, such as environmental impacts, during its lab-scale optimization.

A computational study of the negative LiIn modified anode and its interaction with ß-Li3PS4 solid-electrolyte for battery applications.

All-solid-state lithium batteries (ASSLBs) have sparked interest due to their far superior energy density compared to current commercial material, but the heightened reactivity of the negative Li electrode can compromise the long-term cyclability of the cell, calling for the introduction of passivating layers or alloy anodes. In this article, we aim to explain the outstanding stability of LiIn alloy-based anodes over extended cycling by comparing its bulk and interface properties to Li-metal. Using density functional theory, we conducted an in-depth analysis of the LiIn surfaces' formation and subsequent structural stability in interfaces with the solid electrolyte ß-Li3PS4. Several LiIn facets are shown to possess sufficient structural stability, with the (110) surface being the most stable. The stable interfaces established with the ß-Li3PS4(100) surface featured favorable adhesion energy, low strain energy, and little reconstruction. By comparing these interface properties with the bulk properties of Li-metal and LiIn, we highlighted the influence of the cohesion energy, Fermi energy level, and band position of the two materials in the long-term stability of their anodes under battery conditions.

Structural brain abnormalities in Pallister-Killian syndrome: a neuroimaging study of 31 children.

BACKGROUND: Pallister-Killian syndrome (PKS) is a rare genetic disorder caused by mosaic tetrasomy of 12p with wide neurological involvement. Intellectual disability, developmental delay, behavioral problems, epilepsy, sleep disturbances, and brain malformations have been described in most individuals, with a broad phenotypic spectrum. This observational study, conducted through brain MRI scan analysis on a cohort of patients with genetically confirmed PKS, aims to systematically investigate the neuroradiological features of this syndrome and identify the possible existence of a typical pattern. Moreover, a literature review differentiating the different types of neuroimaging data was conducted for comparison with our population. RESULTS: Thirty-one individuals were enrolled (17 females/14 males; age range 0.1-17.5 years old at first MRI). An experienced pediatric neuroradiologist reviewed brain MRIs, blindly to clinical data. Brain abnormalities were observed in all but one individual (compared to the 34% frequency found in the literature review). Corpus callosum abnormalities were found in 20/30 (67%) patients: 6 had callosal hypoplasia; 8 had global hypoplasia with hypoplastic splenium; 4 had only hypoplastic splenium; and 2 had a thin corpus callosum. Cerebral hypoplasia/atrophy was found in 23/31 (74%) and ventriculomegaly in 20/31 (65%). Other frequent features were the enlargement of the cisterna magna in 15/30 (50%) and polymicrogyria in 14/29 (48%). Conversely, the frequency of the latter was found to be 4% from the literature review. Notably, in our population, polymicrogyria was in the perisylvian area in all 14 cases, and it was bilateral in 10/14. CONCLUSIONS: Brain abnormalities are very common in PKS and occur much more frequently than previously reported. Bilateral perisylvian polymicrogyria was a main aspect of our population. Our findings provide an additional tool for early diagnosis.Further studies to investigate the possible correlations with both genotype and phenotype may help to define the etiopathogenesis of the neurologic phenotype of this syndrome.

Development and validation of a prediction score for failure to casirivimab/imdevimab in hospitalized patients with COVID-19 pneumonia.

Introduction: Casirivimab and imdevimab (CAS/IMV) are two non-competing, high-affinity human IgG1 anti-SARS-CoV-2 monoclonal antibodies, that showed a survival benefit in seronegative hospitalized patients with COVID-19. This study aimed to estimate the day-28 risk of mechanical ventilation (MV) and death in individuals hospitalized for severe COVID-19 pneumonia and receiving CAS/IMV. Additionally, it aimed to identify variables measured at the time of hospital admission that could predict these outcomes and derive a prediction algorithm. Methods: This is a retrospective, observational cohort study conducted in 12 hospitals in Italy. Adult patients who were consecutively hospitalized from November 2021 to February 2022 receiving CAS/IMV were included. A multivariable logistic regression model was used to identify predictors of MV or death by day 28 from treatment initiation, and ß-coefficients from the model were used to develop a risk score that was derived by means of leave-one-out internal cross-validation (CV), external CV, and calibration. Secondary outcome was mortality. Results: A total of 480 hospitalized patients in the training set and 157 patients in the test set were included. By day 28, 36 participants (8%) underwent MV and 28 died (6%) for a total of 58 participants (12%) experiencing the composite primary endpoint. In multivariable analysis, four factors [age, PaO2/FiO2 ratio, lactate dehydrogenase (LDH), and platelets] were independently associated with the risk of MV/death and were used to generate the proposed risk score. The accuracy of the score in the area under the curve (AUC) was 0.80 and 0.77 in internal validation and test for the composite endpoint and 0.87 and 0.86 for death, respectively. The model also appeared to be well calibrated with the raw data. Conclusion: The mortality risk reported in our study was lower than that previously reported. Although CAS/IMV is no longer used, our score might help in identifying which patients are not likely to benefit from monoclonal antibodies and may require alternative interventions.

Midline non-ictal rhythmic waveforms as possible electroencephalographic biomarkers of Smith-Klingsmore syndrome in children.

Introduction: Pathogenic variants of the MTOR gene result in the Smith-Kingsmore syndrome, whose phenotypical spectrum includes facial dysmorphisms and neurological features. Expressivity is variable, patients exhibit a combination of intellectual disability, macrocephaly and epilepsy. The diagnosis can be missed, failing to detect the causative pathogenic mutation in patients with somatic mosaicism or even skipping to analyze MTOR when the phenotype is not completely expressed. Case study: Herein, we report two children harboring the same MTOR recurring mutation (c.5395G>A/p.Glu1799Lys) whose EEG displayed a peculiar combination of midline rhythmic waveforms and asynchronous spike-and-wave discharges with anterior fast activity in sleep and wake. Conclusion: We suggest these features might be considered as possible hallmarks of the syndrome and could aid to expedite the diagnosis when the phenotype is incomplete.

CCL18, CHI3L1, ANG2, IL-6 systemic levels are associated with the extent of lung damage and radiomic features in SARS-CoV-2 infection.

OBJECTIVE AND DESIGN: We aimed to identify cytokines whose concentrations are related to lung damage, radiomic features, and clinical outcomes in COVID-19 patients. MATERIAL OR SUBJECTS: Two hundred twenty-six patients with SARS-CoV-2 infection and chest computed tomography (CT) images were enrolled. METHODS: CCL18, CHI3L1/YKL-40, GAL3, ANG2, IP-10, IL-10, TNFα, IL-6, soluble gp130, soluble IL-6R were quantified in plasma samples using Luminex assays. The Mann-Whitney U test, the Kruskal-Wallis test, correlation and regression analyses were performed. Mediation analyses were used to investigate the possible causal relationships between cytokines, lung damage, and outcomes. AVIEW lung cancer screening software, pyradiomics, and XGBoost classifier were used for radiomic feature analyses. RESULTS: CCL18, CHI3L1, and ANG2 systemic levels mainly reflected the extent of lung injury. Increased levels of every cytokine, but particularly of IL-6, were associated with the three outcomes: hospitalization, mechanical ventilation, and death. Soluble IL-6R showed a slight protective effect on death. The effect of age on COVID-19 outcomes was partially mediated by cytokine levels, while CT scores considerably mediated the effect of cytokine levels on outcomes. Radiomic-feature-based models confirmed the association between lung imaging characteristics and CCL18 and CHI3L1. CONCLUSION: Data suggest a causal link between cytokines (risk factor), lung damage (mediator), and COVID-19 outcomes.

Children with Autism Spectrum Disorder and Abnormalities of Clinical EEG: A Qualitative Review.

Over the last decade, the comorbidity between Autism Spectrum Disorder (ASD) and epilepsy has been widely demonstrated, and many hypotheses regarding the common neurobiological bases of these disorders have been put forward. A variable, but significant, prevalence of abnormalities on electroencephalogram (EEG) has been documented in non-epileptic children with ASD; therefore, several scientific studies have recently tried to demonstrate the role of these abnormalities as a possible biomarker of altered neural connectivity in ASD individuals. This narrative review intends to summarize the main findings of the recent scientific literature regarding abnormalities detected with standard EEG in children/adolescents with idiopathic ASD. Research using three different databases (PubMed, Scopus and Google Scholar) was conducted, resulting in the selection of 10 original articles. Despite an important lack of studies on preschoolers and a deep heterogeneity in results, some authors speculated on a possible association between EEG abnormalities and ASD characteristics, in particular, the severity of symptoms. Although this correlation needs to be more strongly elucidated, these findings may encourage future studies aimed at demonstrating the role of electrical brain abnormalities as an early biomarker of neural circuit alterations in ASD, highlighting the potential diagnostic, prognostic and therapeutic value of EEG in this field.

Circulating haematopoietic stem cells and long-term outcomes of COVID-19.

BACKGROUND AND AIMS: An acute depletion of circulating haematopoietic stem/progenitor cells (HSPCs) occurs during COVID-19, especially among patients with a poorer disease course. We herein examined whether HSPCs levels at hospital admission for COVID-19 predict 1-year mortality and the long-COVID syndrome. MATERIALS AND METHODS: Patients hospitalized for COVID-19 in an infectious disease ward were consecutively enrolled. Circulating HSPC levels were assessed by flow cytometry as cells expressing CD34 and/or CD133. Follow-up was performed for 12 months after hospitalization through the review of electronic medical records and demographic local registers. RESULTS: The study included 100 patients, 36 of whom reported symptoms of long-COVID and 20 died during follow-up. The reduction of 1-SD of HSPCs was associated with a 3- to 5-fold increase in the risk of 1-year mortality. Age, admission hyperglycaemia, C-reactive protein peak, liver enzymes, the need of high-flow oxygen and/or invasive ventilation were predictors of mortality at univariate analysis. Among pre-existing comorbidities, coronary heart disease and chronic kidney disease, but not diabetes, were associated with 1-year mortality. In multivariate analyses, HSPCs remained significantly associated with 1-year mortality independently of confounders. The development of pneumonia an in-hospital treatment with glucocorticoids and convalescent plasma were associated with long-COVID symptoms at follow-up. HSPCs, diabetes and other comorbidities were not predictors of long-COVID. CONCLUSIONS: In a cohort of patients hospitalized for COVID-19, lower HSPC levels at the time of admission were independent predictors of 1-year mortality. However, COVID-19 severity, but not HSPC level, was significantly associated with the development of long-COVID symptoms.

Bilateral temporal lobe dysplasia and seizure onset associated with biallelic CNTNAP2 variants.

Biallelic CNTNAP2 variants have been associated with Pitt-Hopkins-like syndrome. We describe six novel and one previously reported patients from six independent families and review the literature including 64 patients carrying biallelic CNTNAP2 variants. Initial reports highlighted intractable focal seizures and the failure of epilepsy surgery in children, but subsequent reports did not expand on this aspect. In all our patients (n = 7), brain MRI showed bilateral temporal gray/white matter blurring with white matter high signal intensity, more obvious on the T2-FLAIR sequences, consistent with bilateral temporal lobe dysplasia. All patients had focal seizures with temporal lobe onset and semiology, which were recorded on EEG in five, showing bilateral independent temporal onset in four. Epilepsy was responsive to anti-seizure medications in two patients (2/7, 28.5%), and pharmaco-resistant in five (5/7, 71.5%). Splice-site variants identified in five patients (5/7, 71.5%) were the most common mutational finding. Our observation expands the phenotypic and genetic spectrum of biallelic CNTNAP2 alterations focusing on the neuroimaging features and provides evidence for an elective bilateral anatomoelectroclinical involvement of the temporal lobes in the associated epilepsy, with relevant implications on clinical management.

Computational Understanding of Delithiation, Overlithiation, and Transport Properties in Disordered Cubic Rock-Salt Type Li2TiS3.

Lithium-titanium-sulfur cathodes have gained attention because of their unique properties and have been studied for their application in lithium-ion batteries. They offer different advantages such as lower cost, higher safety, and higher energy density with respect to commonly adopted transition metal oxides. Moreover, this family of compounds is free from critical raw materials such as cobalt and nickel. For cathode materials, a crucial aspect is evaluating the evolution and behavior of the structure and properties during the cycling process, which means simulating the system under lithium extraction and insertion. Structural optimization, electronic band structures, density of states, and Raman spectra were simulated, looking for fingerprints and peculiar aspects related to the delithiation and overlithiation process. Lithium transport properties were also investigated through the nudged elastic band methodology. This allowed us to evaluate the diffusion coefficient of lithium, which is a crucial parameter for cathode performance evaluation.

Stability and Formation of the Li3PS4/Li, Li3PS4/Li2S, and Li2S/Li Interfaces: A Theoretical Study.

Solid electrolytes have shown superior behavior and many advantages over liquid electrolytes, including simplicity in battery design. However, some chemical and structural instability problems arise when solid electrolytes form a direct interface with the negative Li-metal electrode. In particular, it was recognized that the interface between the ß-Li3PS4 crystal and lithium anode is quite unstable and tends to promote structural defects that inhibit the correct functioning of the device. As a possible way out of this problem, we propose a material, Li2S, as a passivating coating for the Li/ß-Li3PS4 interface. We investigated the mutual affinity between Li/Li2S and Li2S/ß-Li3PS4 interfaces by DFT methods and investigated the structural stability through the adhesion energy and mechanical stress. Furthermore, a topological analysis of the electron density identified preferential paths for the migration of Li ions.

Understanding Ionic Diffusion Mechanisms in Li2S Coatings for Solid-State Batteries: Development of a Tailored Reactive Force Field for Multiscale Simulations.

In order to investigate Li2S as a potential protective coating for lithium anode batteries using superionic electrolytes, we need to describe reactions and transport for systems at scales of >10,000 atoms for time scales beyond nanoseconds, which is most impractical for quantum mechanics (QM) calculations. To overcome this issue, here, we first report the development of the reactive analytical force field (ReaxFF) based on density functional theory (DFT) calculations on model systems at the PBE0/TZVP and M062X/TZVP levels. Then, we carry out reactive molecular dynamics simulations (RMD) for up to 20 ns to investigate the diffusion mechanisms in bulk Li2S as a function of vacancy density, determining the activation barrier for diffusion and conductivity. We show that RMD predictions for diffusion and conductivity are comparable to experiments, while results on model systems are consistent with and validated by short (10-100 ps) ab initio molecular dynamics (AIMD). This new ReaxFF for Li2S systems enables practical RMD on spatial scales of 10-100 nm (10,000 to 10 million atoms) for the time scales of 20 ns required to investigate predictively the interfaces between electrodes and electrolytes, electrodes and coatings, and coatings and electrolytes during the charging and discharging processes.

Innovative Bioplasticizers from Residual Cynara cardunculus L. Biomass-Derived Levulinic Acid and Their Environmental Impact Assessment by LCA Methodology.

This work is focused on the application of Life Cycle Assessment (LCA) methodology for the quantification of the potential environmental impacts associated with the obtainment of levulinic acid from residual Cynara cardunculus L. biomass and its subsequent valorization in innovative bioplasticizers for tuning the properties as well as the processability of biopolymers. This potentially allows the production of fully biobased and biodegradable bioplastic formulations, thus addressing the issues related to the fossil origin and nonbiodegradability of conventional additives, such as phthalates. Steam explosion pretreatment was applied to the epigean residue of C. cardunculus L. followed by a microwave-assisted acid-catalyzed hydrolysis. After purification, the as-obtained levulinic acid was used to synthesize different ketal-diester derivatives through a three-step selective synthesis. The levulinic acid-base additives demonstrated remarkable plasticizing efficiency when added to biobased plastics. The LCA results were used in conjunction with those from the experimental activities to find the optimal compromise between environmental impacts and mechanical and thermal properties, induced by the bioadditives in poly(3-hydroxybutyrate), PHB biopolymer.

Venetoclax durable response in adult relapsed/refractory Philadelphia-negative acute lymphoblastic leukemia with JAK/STAT pathway alterations.

High-risk relapsed/refractory adult Philadelphia-negative (Ph-) B-cell acute lymphoblastic leukemia (B-ALL) is a great challenge due to limited possibilities to achieve and maintain a complete response. This also applies to cases with extramedullary (EM) involvement that have poor outcomes and no accepted standard therapeutic approaches. The incidence of EM localization in relapsed/refractory B-ALL is poorly investigated: data on patients treated with blinatumomab reported a 40% rate. Some responses were reported in EM patients with relapsed/refractory B-ALL treated with inotuzumab ozogamicin or CAR-T. However, molecular mechanisms of response or refractoriness are usually investigated neither at the medullary nor at EM sites. In the complex scenario of pluri-relapsed/refractory B-ALL patients, new target therapies are needed. Our analysis started with the case of an adult pluri-relapsed Ph- B-ALL patient, poorly sensitive to inotuzumab ozogamicin, donor lymphocyte infusions, and blinatumomab in EM disease, who achieved a durable/complete response after treatment with the BCL2-inhibitor venetoclax. The molecular characterization of medullary and EM samples revealed a tyrosine kinase domain JAK1 mutation in the bone marrow and EM samples at relapse. By comparing the expression level of BCL2- and JAK/STAT pathway-related genes between the patient samples, 136 adult JAK1 wt B-ALL, and 15 healthy controls, we identified differentially expressed genes, including LIFR, MTOR, SOCS1/2, and BCL2/BCL2L1, that are variably modulated at diverse time points and might explain the prolonged response to venetoclax (particularly in the EM site, which was only partially affected by previous therapies). Our results suggest that the deep molecular characterization of both medullary and EM samples is fundamental to identifying effective and personalized targeted therapies.

MEK1/2 regulate normal BCR and ABL1 tumor-suppressor functions to dictate ATO response in TKI-resistant Ph+ leukemia.

Resistance to tyrosine kinase inhibitors (TKIs) remains a clinical challenge in Ph-positive variants of chronic myeloid leukemia. We provide mechanistic insights into a previously undisclosed MEK1/2/BCR::ABL1/BCR/ABL1-driven signaling loop that may determine the efficacy of arsenic trioxide (ATO) in TKI-resistant leukemic patients. We find that activated MEK1/2 assemble into a pentameric complex with BCR::ABL1, BCR and ABL1 to induce phosphorylation of BCR and BCR::ABL1 at Tyr360 and Tyr177, and ABL1, at Thr735 and Tyr412 residues thus provoking loss of BCR's tumor-suppression functions, enhanced oncogenic activity of BCR::ABL1, cytoplasmic retention of ABL1 and consequently drug resistance. Coherently, pharmacological blockade of MEK1/2 induces dissociation of the pentameric MEK1/2/BCR::ABL1/BCR/ABL1 complex and causes a concurrent BCRY360/Y177, BCR::ABL1Y360/Y177 and cytoplasmic ABL1Y412/T735 dephosphorylation thereby provoking the rescue of the BCR's anti-oncogenic activities, nuclear accumulation of ABL1 with tumor-suppressive functions and consequently, growth inhibition of the leukemic cells and an ATO sensitization via BCR-MYC and ABL1-p73 signaling axes activation. Additionally, the allosteric activation of nuclear ABL1 was consistently found to enhance the anti-leukemic effects of the MEK1/2 inhibitor Mirdametinib, which when combined with ATO, significantly prolonged the survival of mice bearing BCR::ABL1-T315I-induced leukemia. These findings highlight the therapeutic potential of MEK1/2-inhibitors/ATO combination for the treatment of TKI-resistant leukemia.

Clinical Course May Be Independent from Neuroimaging in DEPDC-5-Related Epilepsy.

DEPDC5 is an upstream repressor of the mechanistic target of rapamycin pathway via the GATOR-1 complex. Pathogenic variants causing loss of function typically result in familial focal epilepsy with variable foci. Neuroimaging may either be normal or show brain malformations. Lesional and nonlesional cases may be present within the same family. Here, we describe a parent-child dyad affected by a truncating DEPDC5 pathogenic variant (c.727C > T; p.Arg243*), analyze the epilepsy clinical course, and describe neuroimaging characteristics from a 3T brain magnetic resonance imaging. Despite sharing the same variant, patients diverged both in terms of epilepsy severity and neuroimaging features. Surprisingly, the mother is still suffering from drug-resistant seizures and has normal neuroimaging, while the child has been experiencing prolonged seizure freedom notwithstanding a bottom-of-sulcus focal cortical dysplasia. An increasing gradient of severity has been proposed for families with GATOR1-related epilepsies. We confirm clinical and neuroradiological expressivities are variable and also suggest the prognostication of epilepsy outcome may be particularly difficult. The epilepsy outcome could partially be independent from brain structural abnormalities.

Glycaemic Imbalances in Seizures and Epilepsy of Paediatric Age: A Literature Review.

Cerebral excitability and systemic metabolic balance are closely interconnected. Energy supply to neurons depends critically on glucose, whose fluctuations can promote immediate hyperexcitability resulting in acute symptomatic seizures. On the other hand, chronic disorders of sugar metabolism (e.g., diabetes mellitus) are often associated with long-term epilepsy. In this paper, we aim to review the existing knowledge on the association between acute and chronic glycaemic imbalances (hyper- and hypoglycaemia) with seizures and epilepsy, especially in the developing brain, focusing on clinical and instrumental features in order to optimize the care of children and adolescents and prevent the development of chronic neurological conditions in young patients.

Detection of a Novel MSI2-C17orf64 Transcript in a Patient with Aggressive Adenocarcinoma of the Gastroesophageal Junction: A Case Report.

Adenocarcinoma of the esophagus (EAC) and gastroesophageal junction (GEJ-AC) is associated with poor prognosis, treatment resistance and limited systemic therapeutic options. To deeply understand the genomic landscape of this cancer type, and potentially identify a therapeutic target in a neoadjuvant chemotherapy non-responder 48-year-old man, we adopted a multi-omic approach. We simultaneously evaluated gene rearrangements, mutations, copy number status, microsatellite instability and tumor mutation burden. The patient displayed pathogenic mutations of the TP53 and ATM genes and variants of uncertain significance of three kinases genes (ERBB3, CSNK1A1 and RPS6KB2), along with FGFR2 and KRAS high copy number amplification. Interestingly, transcriptomic analysis revealed the Musashi-2 (MSI2)-C17orf64 fusion that has never been reported before. Rearrangements of the RNA-binding protein MSI2 with a number of partner genes have been described across solid and hematological tumors. MSI2 regulates several biological processes involved in cancer initiation, development and resistance to treatment, and deserves further investigation as a potential therapeutic target. In conclusion, our extensive genomic characterization of a gastroesophageal tumor refractory to all therapeutic approaches led to the discovery of the MSI2-C17orf64 fusion. The results underlie the importance of deep molecular analyses enabling the identification of novel patient-specific markers to be monitored during therapy or even targeted at disease evolution.

Risk of hospitalization and sequelae in patients with COVID-19 treated with 3-day early remdesivir vs. controls in the vaccine and Omicron era: A real-life cohort study.

Recently, a benefit from administration of a 3-day course of early remdesivir (ER) in the outpatients' setting was reported. However, real-life data on its use is scarce. Therefore, we explored the ER clinical outcome in our outpatients' s cohort, compared to untreated controls. We included all patients who were prescribed ER from February to May 2022 and followed them up for 3 months and compared patients who received treatment with untreated controls. In the two groups the following outcomes were investigated: hospitalization and mortality rate, time of negativization and symptom's resolution, and postacute coronavirus disease 19 (COVID-19) syndrome prevalence. Overall, 681 patients were analyzed, mostly females (53.6%), and with a median age of 66 years (interquartile range: 54-77), 316 (46.4%) patients received ER, and 365 (53.6%) did not receive antiviral treatment (control group). Overall, 8.5% patients eventually required oxygen support, 8.7% were hospitalized for COVID-19, and 1.5% died. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunization and ER (adjusted odds ratio [aOR]: 0.049 [0.015; 0.16], p < 0.001) independently reduced hospitalization risk. ER was significantly associated with a shorter duration of SARS-CoV-2 positivity at nasopharyngeal swabs (aß -8.15 [-9.21; -7.09], p < 0.001) and of symptoms (aß -5.11 [-5.82; -4.39], p < 0.001), and with lower rate of COVID-19 sequelae compared to control group (aOR: 0.18 [0.10; 0.31], p < 0.001). Even in the SARS-CoV-2 vaccination and Omicron era, in patients at high risk of developing severe disease, ER demonstrated to have a good safety profile and to significantly reduce the risk of disease progression and COVID-19 sequelae compared to untreated controls.

Correlations between Molecular Alterations, Histopathological Characteristics, and Poor Prognosis in Esophageal Adenocarcinoma.

Esophageal adenocarcinoma (EAC) is a severe malignancy with increasing incidence, poorly understood pathogenesis, and low survival rates. We sequenced 164 EAC samples of naïve patients (without chemo-radiotherapy) with high coverage using next-generation sequencing technologies. A total of 337 variants were identified across the whole cohort, with TP53 as the most frequently altered gene (67.27%). Missense mutations in TP53 correlated with worse cancer-specific survival (log-rank p = 0.001). In seven cases, we found disruptive mutations in HNF1alpha associated with other gene alterations. Moreover, we detected gene fusions through massive parallel sequencing of RNA, indicating that it is not a rare event in EAC. In conclusion, we report that a specific type of TP53 mutation (missense changes) negatively affected cancer-specific survival in EAC. HNF1alpha was identified as a new EAC-mutated gene.