Successful treatment of persistent SARS-CoV-2 infection with nirmatrelvir/ritonavir plus sotrovimab in four immunocompromised patients.

Immunocompromised patients with leukemia/lymphoma often have a suboptimal response to vaccination against SARS-CoV-2 and, if infected, can develop a persistent infection.SARS-CoV-2 PCR was performed on nasopharingeal swabs and serum IgG anti-SARS-CoV-2 trimeric spike glycoprotein antibodies were measured during persistence of infection. Treatment with a combination of nirmatrelvir/ritonavir plus sotrovimab led to viral clearance in three patients with leukaemia or lymphoma with persistent SARS-CoV-2 and negative SARS-CoV-2 antibody tests. No standardized treatments for persistent infection with SARS-CoV-2 infection are available. We have reported the viral clearance in two immunocompromised patients treated with antiviral drug nirmatrelvir/ritonavir and monoclonal antibody sotrovimab. We suggest that this strategy should be tested in clinical trials to find the right strategy for a clinical problem with public health implications to SARS-CoV-2 evolution and immune escape in these sub-set of patients.

Real-world persistence with direct oral anticoagulants (DOACs) in naïve patients with non-valvular atrial fibrillation.

BACKGROUND: Anticoagulation therapy is central for the management of stroke in patients with non-valvular atrial fibrillation (NVAF). Persistence with oral anticoagulation is essential to prevent thromboembolic complications. METHODS: We performed a population-based retrospective cohort study in the Veneto Region (north-eastern Italy, about 5 million inhabitants) using the regional health system databases. Naïve patients initiating direct oral anticoagulants (DOACs) for stroke prevention in NVAF from July 2013 to September 2017 were included in the study. Patients were identified using Anatomical Therapeutic Chemical (ATC) codes, excluding other indications for anticoagulation therapy using ICD-9CM codes. Treatment persistence was defined as the time from initiation to discontinuation of the therapy, including any therapeutic switching among DOACs. Baseline characteristics and comorbidities associated to the persistence of therapy with DOACs were explored by means of Kaplan-Meier curves and assessed through Cox regression. RESULTS: Naïve patients initiating direct oral anticoagulants for stroke prevention in NVAF identified in a 4.25-year period are 17,920. After one year, the persistence to the DOACs is 72.9%. Approximately 9.8% of the discontinuations are due to switch to vitamin k antagonists (VKAs). On multivariate analysis, factors negatively affecting persistence were female gender, age <65 years, renal disease and history of bleeding. On the other hand, persistence was better in patients with hypertension, previous cerebral ischemic events, and previous acute myocardial infarction. CONCLUSION: In this study of real world data, one out four naive patients stopped treatment with DOACs within 12 months. Some characteristics may identify patients with poor persistence.

Effectiveness and safety of oral anticoagulation with non-vitamin K antagonists compared to well-managed vitamin K antagonists in naïve patients with non-valvular atrial fibrillation: Propensity score matched cohort study.

BACKGROUND: The global real-life impact of non-vitamin K antagonist oral anticoagulants (NOACs) introduction in the healthcare system in a setting of well-managed vitamin K antagonist (VKA) therapy has not been specifically addressed. METHODS: We did a population-based retrospective cohort study in naïve patients initiating oral anticoagulants for stroke prevention in atrial fibrillation in a region with a well-managed VKA therapy. NOAC and VKA cohorts were identified using Anatomical Therapeutic Chemical (ATC) codes, while excluding other indications for anticoagulation therapy using ICD-9CM codes. Propensity score was conducted using two different approaches: stratification and 1:1 matching. Event-rates were assessed using both an intention to treat (ITT) and as treated analyses. RESULTS: Of the 137,800 selected patients, 40,411 (6923 treated with NOACs and 33,488 with VKAs) were identified (June 2013-December 2015). Overall ischaemic stroke and major bleeding risk did not significantly differ between the groups both in the ITT and as treated analyses. Noteworthy, intracranial bleeding risk was lower with NOACs (stratified model HR=0.69; 95%CI 0.48-0.99; 1:1 matched model HR=0.73; 95%CI 0.47-1.13) reaching statistical significance in the as treated analysis in both stratified and 1:1 matched models (HR=0.51; 95%CI 0.32-0.80 and HR=0.52; 95%CI 0.30-0.90, respectively). CONCLUSION: Despite well-managed anticoagulation with VKAs, NOACs' introduction has a positive global impact in the public healthcare system in terms of effectiveness and safety especially by lowering intracranial bleeding.

Lu-, Sm-, and Gd-Doped Ceria: A Comparative Approach to Their Structural Properties.

A room temperature structural study has been performed through the whole compositional range of the (Ce1-xLux)O2-x/2 system by synchrotron X-ray diffraction and µ-Raman spectroscopy. Samples were synthesized by thermal treatment in air at 1373 K of coprecipitated mixed oxalates. A CeO2-based solid solution with a fluorite-type structure (F) was found to be stable up to x = 0.4, while at higher Lu content a (F + C) biphasic region was observed, with C being the cubic atomic arrangement typical of sesquioxides of the heaviest rare earths. A comparative approach including also results deriving from other (Ce1-xREx)O2-x/2 systems (RE ≡ Gd and Sm) allowed us to conclude that the compositional extent of the F solid solution is a complex function of RE3+ size and RE compressibility. On this basis, the dependence of ionic conductivity on the RE identity was interpreted as related both to the Ce4+/RE3+ size closeness and to RE compressibility. Ce4+/RE3+ dimensional issues were also revealed to rule the appearance of the hybrid structure observed in the two aforementioned systems, consisting of the intimate intergrowth of C microdomains within the F-based host lattice. Moreover, a more extended definition of F-based solid solution, including also the hybrid structure, is formulated; the latter is meant as a modification of the former, occurring when mainly RE-vacancy aggregates are incorporated into the host lattice in spite of isolated RE ions. By µ-Raman spectroscopy it was possible to demonstrate that the mechanism of oxygen vacancy formation is common to all the systems studied, provided that the structure of the F-based solid solution, also including the hybrid structure, is retained.

Correlations between Structural and Electronic Properties in the Filled Skutterudite Smy(FexNi1-x)4Sb12.

A structural study of the filled skutterudite Smy(FexNi1-x)4Sb12 was performed by means of X-ray powder diffraction and µ-Raman spectroscopy with the aim to unveil the correlations between structural and electronic properties of this material and to favor the improvement of its thermoelectric performance. Samples were prepared by direct reaction of the elements at 1223 K, followed by quenching and subsequent sintering at 873 K; microstructure and composition of the obtained products were determined by SEM-EDS. The position of the boundary separating regions that obey hole- and electron-based conduction mechanisms was found by X-ray diffraction at x ≈ 0.63 and y ≈ 0.30, confirmed by measurements of room-temperature Seebeck coefficient, and discussed on the basis of crystallographic data. The presence of a discontinuity is observed in several structural and spectroscopic parameters at the p/n crossover; it is interpreted as associated with the change in the conduction mechanism. The role of the rare earth filling fraction in driving the structural response of the material is investigated too. The advantage of using X-ray diffraction and µ-Raman spectroscopy as aids in the study of electronic properties of this material is highlighted, as well as the complementarity of the two techniques.

Structural features of Sm- and Gd-doped ceria studied by synchrotron X-ray diffraction and µ-Raman spectroscopy.

A structural study of Sm- and Gd-doped ceria was performed with the aim to clarify some unexplained structural features. (Ce1-xREx)O2-x/2 samples (RE ≡ Sm, Gd; x = 0, 0.1, ..., 1) were prepared by coprecipitation of mixed oxalates and subsequent thermal treatment at 1473, 1173, or 1073 K in air; they were then analyzed at room temperature both by synchrotron X-ray diffraction and µ-Raman spectroscopy. Two structural models were adopted to fit the experimental data, namely, a fluoritic one, resembling the CeO2 structure at low RE content, and a hybrid one at higher RE content, intermediate between the CeO2 and the RE2O3 structures. Two main transitions were detected along the compositional range: (a) an RE-dependent transition at the boundary between the fluoritic and the hybrid regions, of a chemical nature; (b) an RE-independent transition within the hybrid region at ∼0.5, having a purely geometrical nature. The presence of two finely interlaced F- and C-based structures within the hybrid region was confirmed, and hints of their composition were obtained by µ-Raman spectroscopy. The obtained results indicate a possible explanation for the non-Vegard behavioral trend of the cell parameters.

NIR persistent luminescence of lanthanide ion-doped rare-earth oxycarbonates: the effect of dopants.

A series of luminescent rare-earth ion-doped hexagonal II-type Gd oxycarbonate phosphors Gd2-xRExO2CO3 (RE = Eu(3+), Yb(3+), Dy(3+)) have been successfully synthesized by thermal decomposition of the corresponding mixed oxalates. The Yb(3+) doped Gd-oxycarbonate has evidenced a high persistent luminescence in the NIR region, that is independent from the temperature and makes this materials particular attractive as optical probes for bioimaging.

High temperature structural study of Gd-doped ceria by synchrotron X-ray diffraction (673 K ≤ T ≤ 1073 K).

The crystallographic features of Gd-doped ceria were investigated at the operating temperature of solid oxides fuel cells, where these materials are used as solid electrolytes. (Ce(1-x)Gd(x))O(2-x/2) samples (x = 0.1, 0.3, 0.5, 0.7) were prepared by coprecipitation of mixed oxalates, treated at 1473 K in air, and analyzed by synchrotron X-ray diffraction in the temperature range 673 K ≤ T ≤ 1073 K at the Elettra synchrotron radiation facility located in Trieste, Italy. In the whole temperature span a boundary was found at x ∼ 0.2 between a CeO2-based solid solution (for x ≤ 0.2) and a structure where Gd2O3 microdomains grow within the CeO2 matrix, taking advantage of the similarity between Gd(3+) and Ce(4+) sizes; the existence of the boundary at x ∼ 0.2 was confirmed also by measurements of ionic conductivity performed by impedance spectroscopy. Similar to what observed at room temperature, the trend of the cell parameter shows the presence of a maximum; with increasing temperature, the composition corresponding to the maximum moves toward lower Gd content. This evidence can be explained by analyzing the behavior of the coefficient of thermal expansion as a function of composition.

The role of the N-terminal domain in the regulation of the "constitutively active" conformation of protein kinase CK2α: insight from a molecular dynamics investigation.

Protein kinase CK2 is an extremely well-conserved pleiotropic protein kinase with a growing list of substrates, the majority of which are proteins implicated in signal transduction, gene expression, and transcription-related functions. Protein kinase CK2 is a ubiquitous heterotetrameric serine/threonine protein kinase made up of two α or α' catalytic subunits and two ß regulatory subunits. Moreover, protein kinase CK2 is defined as a "constitutively active" protein kinase in contrast to most other protein kinases characterized by the presence of distinct conformations associated with the active and inactive states. As previously demonstrated by in vitro mutation studies, CK2 activity is substantially regulated by the interaction between the N-terminal tail and the kinase domain. In fact, progressive deletions of the N-terminal tail show a decrease in the activity of the kinase. Even if the detrimental effects of Δ2-12 deletion can be partially reversed by the addition of a CK2ß subunit, deletions Δ2-12 and Δ2-30 progressively decrease the basal activity of CK2. In particular, as experimentally demonstrated, the Δ2-12 N-terminal deletion affects both the K(M) value for ATP and for the substrate peptide, and the k(cat) value of CK2α. In this work, molecular dynamics (MD) simulations were carried out on wild-type (wt), Δ2-12 and Δ2-30 deletion mutants of CK2α in order to explore the role of the N-terminal tail on the conformational behavior of CK2. Furthermore, classical MD simulations were carried out to assess the anticipated impact of conformational changes in a novel set of CK2α mutant forms, such as the triple mutant Y206F-R10A-Y261F and the single mutant Y125F.