Interim analysis:Open-label extension study of leniolisib for patients with APDS

Background: Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS; or p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency) is an inborn error of immunity caused by PI3Kδ hyperactivity. Resultant immune deficiency and dysregulation lead to recurrent sinopulmonary infections, herpes viremia, autoimmunity, and lymphoproliferation. Objective: Leniolisib, a selective PI3Kδ inhibitor, demonstrated favorable impact on immune cell subsets and lymphoproliferation over placebo in patients with APDS over 12 weeks. Here, we report results from an interim analysis of an ongoing open-label, single-arm extension study. Methods: Patients with APDS aged 12 years or older who completed NCT02435173 or had previous exposure to PI3Kδ inhibitors were eligible. The primary end point was safety, assessed via investigator-reported adverse events (AEs) and clinical/laboratory evaluations. Secondary and exploratory end points included health-related quality of life, inflammatory markers, frequency of infections, and lymphoproliferation. Results: Between September 2016 and August 2021, 37 patients (median age, 20 years; 42.3% female) were enrolled. Of these 37 patients, 26, 9, and 2 patients had previously received leniolisib, placebo, or other PI3Kδ inhibitors, respectively. At the data cutoff date (December 13, 2021), median leniolisib exposure was 102 weeks. Overall, 32 patients (87%) experienced an AE. Most AEs were grades 1 to 3; none were grade 4. One patient with severe baseline comorbidities experienced a grade 5 AE, determined as unrelated to leniolisib treatment. While on leniolisib, patients had reduced annualized infection rates (P =.004), and reductions in immunoglobulin replacement therapy occurred in 10 of 27 patients. Other observations include reduced lymphadenopathy and splenomegaly, improved cytopenias, and normalized lymphocyte subsets. Conclusions: Leniolisib was well tolerated and maintained durable outcomes with up to 5 years of exposure in 37 patients with APDS. ClinicalTrials.gov identifier: NCT02859727.</p

Exploring non-linear associations between atmospheric new-particle formation and ambient variables: a mutual information approach

Atmospheric new-particle formation (NPF) is a very non-linear process that includes atmospheric chemistry of precursors and clustering physics as well as subsequent growth before NPF can be observed. Thanks to ongoing efforts, now there exists a tremendous amount of atmospheric data, obtained through continuous measurements directly from the atmosphere. This fact makes the analysis by human brains difficult but, on the other hand, enables the usage of modern data science techniques. Here, we calculate and explore the mutual information (MI) between observed NPF events (measured at Hyytiälä, Finland) and a wide variety of simultaneously monitored ambient variables: trace gas and aerosol particle concentrations, meteorology, radiation and a few derived quantities. The purpose of the investigations is to identify key factors contributing to the NPF. The applied mutual information method finds that the formation events are strongly linked to sulfuric acid concentration and water content, ultraviolet radiation, condensation sink (CS) and temperature. Previously, these quantities have been well-established to be important players in the phenomenon via dedicated field, laboratory and theoretical research. The novelty of this work is to demonstrate that the same results are now obtained by a data analysis method which operates without supervision and without the need of understanding the physics deeply. This suggests that the method is suitable to be implemented widely in the atmospheric field to discover other interesting phenomena and their relevant variables.</p

Kinetic and mechanistic studies on substitution reactions of oxalato ligands from tris(oxalato )chromate (lll) with bis-(2-aminoethyl)-amin-N, N, N', N", N"- pentaacetic acid (DTPA)

148-150The kinetics of substitution of oxalato from tris(oxalato) chromate(III) with bis-(2-aminoethyl)-amin- N,N,N',N'',N"-pentaacetic acid (DTPA) has been studied spectrophotometrically in alkaline medium. From the observed dependence of the rate on pH and DTPA concentration a probable mechanism has been suggested for the overall change involving two concurrent paths; corresponding H† and S† values have also been determined. The rates are found to be dependent on ionic strength and independent of nature of different electrolytes