Does early combination vs. Monotherapy improve clinical outcomes of clinically extremely vulnerable patients with COVID-19? Results from a retrospective propensity-weighted analysis.

BACKGROUND: The potential efficacy of early combination therapy, based on an antiviral plus a monoclonal antibody, for COVID-19 in severely immunocompromised patients is matter of debate. OBJECTIVES: Our aim was to describe the impact on clinical outcomes of COVID-19 treatments in severely immunocompromised individuals, evaluating differences between a combination and a monotherapy. METHODS: We included severely immunocompromised outpatients with mild-to-moderate COVID-19 who received an early treatment (either monotherapy with nirmatrelvir/ritonavir or remdesivir or the combination of an antiviral plus sotrovimab). We then assessed differences between the two treatment strategies on three main outcomes (30-day mortality, access to emergency department, hospitalization), separately and as a composite by using a propensity score weighted (PSW) approach. RESULTS: Eighty one severely immunocompromised patients were included, 39 receiving early combination therapy and 42 receiving monotherapy. No significant difference was observed in the 30-day mortality rate and hospitalization rate between subjects in the two groups, while access to the emergency department following treatment administration was significantly higher in people who received a combination therapy. After applying the PSW, it was observed that combination therapy impacted favourably on the composite outcome, in a statistically significant fashion. In addition, PSW approach for mortality showed that age was the only significant factor influencing the death as stand-alone outcome. CONCLUSIONS: Early combination therapy showed a favourable impact on a composite outcome (including mortality, hospitalizations and access to emergency department) in severely immunocompromised hosts who were all vaccinated. However, further studies are needed to support our results.

Multicentric aggressive unclassified hematopoietic neoplasm involving the placenta in a pregnant bitch.

Hematopoietic neoplasms are common in dogs; however, their association with pregnancy has not been previously reported in veterinary medicine. This rare occurrence presents a variety of diagnostic, therapeutic, prognostic, and ethical challenges. We report a case of a 3-year-old pregnant Bernese Mountain Dog diagnosed with multicentric aggressive unclassified hematopoietic cancer associated with paraneoplastic hypercalcemia during pregnancy. The dog died 7 days after diagnosis, and at Day 36 of pregnancy before any treatment decision could be made. Post-mortem evaluation, including histology, immunohistochemistry, and clonality analysis, led to the diagnosis of an unclassified hematopoietic cancer affecting the uterus and placenta, with no evidence of fetal involvement. The placenta likely acted as a barrier, preventing neoplastic involvement of the fetuses. Alternatively, the pregnancy might have been too early for the hematopoietic neoplasm to affect the labyrinth zone of the placenta and the fetuses. The dramatic disease progression could be explained by compromised cell-mediated immunity during pregnancy. This immunodeficient state is induced by embryonic, maternal, and hormonal factors, which suppress the response to mitogens to prevent rejection of the placenta and the conceptuses. Thus, pregnant dogs might exhibit increased vulnerability to cancer and infectious diseases that rely on cell-mediated immunity for host defense.

Atomic-Scale View of Water Chemistry on Nanostructured Iron Oxide Films.

The interaction of water with solid surfaces is crucial for a wide range of disciplines, including catalysis, environmental science, corrosion, geology, and biology. In this study, we present a combined experimental and theoretical investigation that elucidates the interaction of water with a model iron oxide surface under near ambient conditions (i.e., room temperature and water vapor in the mbar range). Our findings reveal that surface hydroxylation can be controlled at the nanoscale by the local properties of the oxide film, such as local rumpling and electrostatic potential. The iron oxide surface presents alternating hydrophilic and hydrophobic domains, creating after water exposure a hexagonal pattern with a pitch of approximately 3 nm, where the highly hydroxylated regions act as nucleation centers for nanoconfined water molecule clusters.

Combined generalized and focal epilepsy with reflex features in Adaptor protein complex 4-associated hereditary spastic paraplegias: A cohort observational study.

BACKGROUND: Patients with genetic deficiency of the adaptor protein complex 4 (AP-4) exhibit earlyonset developmental delay, spastic diplegia, intellectual disability, speech impairment. The phenotype overlaps with other hereditary spastic paraplegias and cerebral palsies. Febrile seizures are common at onset. Epilepsy has been described in more than half of cases, arising in early infancy often with status epilepticus, but no typical seizure semiology or electroencephalographic features have been identified thus far. PURPOSE: We aimed to specifically investigate the epileptological characteristics of the syndrome to unveil possible biomarkers of seizure development and prognosis in AP-4 deficiency. METHODS: Observational cohort study on patients with bi-allelic pathogenic variants in AP-4 subunits and epilepsy. We focused on the seizure semiology, electroencephalographic characteristics and response to antiseizure medications. RESULTS: Patients harboured pathogenic variants in AP4S1 (n = 5) or AP4M1 (n = 1). The phenotype included spastic paraparesis, intellectual disability, speech/language impairment, microcephaly, and MRI evidence of hypoplasia of the corpus callosum. In 66 % of the patients, febrile seizures preceded the onset of epilepsy, which spanned from infancy to adolescence (range=14 months-13 years). Absences (66 %) and focal motor seizures (50 %) were common. No patient met the criteria for drug-resistance. Peculiar electroencephalographic features arose after the epilepsy onset and persisted at long-term follow-up: bilateral and asynchronous focal discharges combined with independent diffuse spike-wave-discharges (100 %) and reflex abnormalities (66 %). CONCLUSION: In AP-4 complex disease, epilepsy could arise beyond early infancy, until adolescence, with variable combination of generalized and focal seizures. The prognosis was favourable. We observed a common electroencephalographic signature - combined focal/generalized and reflex abnormalities - which may constitute a biomarker of AP-4 deficiency with epilepsy, applicable to inform genetic testing and disentangle the differential diagnosis.

Children and Young Adults with Epilepsy Exhibit an Interictal Autonomic Dysfunction: A Prospective Exploratory Study.

Dysautonomic disorders are an increasingly studied group of conditions, either as isolated diseases or associated with other neurological disorders. There is growing interest in understanding how dysautonomia affects people with epilepsy, who may report autonomic symptoms before, during and after seizures. Furthermore, autonomic abnormalities appear to play a role in sudden unexpected death in epilepsy, likely contributing to the increased mortality rate described in epilepsy. To better understand the association between epilepsy and dysautonomia, we explored electrochemical skin conductance in a group of 18 children and young adults with epilepsy compared to 15 age- and sex-matched healthy controls by the SudoscanTM test. We found a significant difference in terms of electrochemical skin conductance, suggesting that people with epilepsy suffer significantly reduced conductance in small nerve fibers. Within patients, values were significantly different according to the type of epilepsy and to neuroimaging results, with lower conductance values in epilepsies of unknown origin and in patients with morphological abnormalities of the brain. Using a non-invasive test, we identified altered conductance of small sympathetic nerve fibers in children and young adults with epilepsy, suggesting underlying dysautonomia. Further studies are needed to investigate this association and to clarify its neurobiological substrates.

DFT study of the moiré pattern of FeO monolayer on Au(111).

Metal oxides are a class of material of particular interest for catalytic purposes. Among them the iron oxide as a monolayer supported on gold, FeO/Au, stands out for its capability to promote the CO oxidation and the dissociation of O2 and H2. In this work, we use density functional theory calculations to characterize interfacial properties of this heterostructure. We consider a FeO/Au realistic model system, managing to reproduce the moiré pattern experimentally found. Specific features of the high-symmetry domains of the moiré are identified, providing a robust ground for establishing a structure-activity relationship and guessing how the surface would behave in catalytic conditions. We also describe a strategy to model smaller systems representative of each high-symmetry domains of the moiré, which will be useful in the future to model catalytic reaction mechanisms.

Path ahead: Tackling the Challenge of Computationally Estimating Lithium Diffusion in Cathode Materials.

In the roadmap toward designing new and improved materials for Lithium ion batteries, the ability to estimate the diffusion coefficient of Li atoms in electrodes, and eventually solid-state electrolytes, is key. Nevertheless, as of today, accurate prediction through computational tools remains challenging. Its experimental measurement does not appear to be much easier. In this work, we devise a computational protocol for the determination of the Li-migration energy barrier and diffusion coefficient, focusing on a common cathode material such as LiNiO2, which represents a prototype of the widely adopted NMC (LiNi1-x-y Mn x Co y O2) class of materials. Different methodologies are exploited, combining ab initio metadynamics, path sampling, and density functional theory. Furthermore, we propose a novel, fast, and simple 1D approximation for the estimation of the effective frequency. The outlined computational protocol aims to be generally applicable to Lithium diffusion in other materials and components for batteries, including anodes and solid electrolytes.

Environmental Impact of Fused Filament Fabrication: What Is Known from Life Cycle Assessment?

This systematic review interrogates the literature to understand what is known about the environmental sustainability of fused filament fabrication, FFF (also known as fused deposition modeling, FDM), based on life cycle assessment (LCA) results. Since substantial energy demand is systematically addressed as one of the main reasons for ecological damage in FFF, mitigation strategies are often based on reducing the printing time (for example, adopting thicker layers) or the embodied energy per part (e.g., by nesting, which means by printing multiple parts in the same job). A key parameter is the infill degree, which can be adjusted to the application requirements while saving printing time/energy and feedstock material. The adoption of electricity from renewable resources is also expected to boost the sustainability of distributed manufacturing through FFF. Meanwhile, bio-based and recycled materials are being investigated as less impactful alternatives to conventional fossil fuel-based thermoplastic filaments.

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.

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.

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.

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.

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.

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.

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.

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.

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.