Copanlisib population pharmacokinetics from phase I–III studies and exposure–response relationships in combination with rituximab

Copanlisib dose selection was established under the maximum tolerated dose paradigm, and no dedicated dose-finding studies have investigated copanlisib dose selection when used in combination with rituximab. In CHRONOS-3, copanlisib plus rituximab demonstrated significantly improved progression-free survival versus placebo plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma (iNHL). We conducted a comprehensive investigation of copanlisib population pharmacokinetics (PopPK) from a pooled analysis of 712 patients across nine copanlisib phase I–III studies and exposure–response (ER) relationships for efficacy and safety from the 1-year follow-up of CHRONOS-3. PopPK analyses examined the impact of demographic, laboratory, and comedication covariates on copanlisib between-patient PK variability. Individual static and time-varying exposure estimates were derived to investigate exposure–efficacy and exposure–safety relationships. Multivariate Cox proportional hazards and logistic regression analyses examined ER relationships with consideration of predefined potentially prognostic demographic-, laboratory-, and/or disease-related baseline covariates. Copanlisib PK were best described by a three-compartment model with first-order elimination. Individual identified covariates had modest effects on copanlisib PK and were generally in line with known copanlisib disposition properties. In CHRONOS-3, ER analyses showed a significant relationship between time-varying exposure estimates and progression-free survival, and no significant exposure–safety relationships. Thus, lower copanlisib doses may result in reduced efficacy but not necessarily improved safety or tolerability. These outcomes substantiate the current intermittent dosing regimen of copanlisib 60 mg on days 1, 8, and 15 of a 28-day cycle and support the observed clinical results of copanlisib in combination with rituximab in the iNHL population

Aerodynamics of Pitching Wings: Theory and Experiments

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140444/1/6.2014-2881.pd

Overlapping political budget cycle

We advance the literature on political budget cycles by testing for cycles in expenditures for elections to the legislative and the executive branches. Using municipal data, we identify cycles independently for the two branches, evaluate the effects of overlaps, and account for general year effects. We find sizable effects on expenditures before legislative elections and even larger effects before joint elections to the legislature and the office of mayor. In the case of coincident elections, we show that it is important whether the incumbent chief executive seeks reelection. To account for the potential endogeneity of that decision, we apply an IV approach using age and pension eligibility rules

A conscious rethink : Why is brain tissue commonly preserved in the archaeological record? Commentary on: Petrone P, Pucci P, Niola M, et al. Heat-induced brain vitrification from the Vesuvius eruption in C.E. 79. N Engl J Med 2020;382:383-4. DOI: 10.1056/NEJMc1909867

Brain tissue is ubiquitous in the archaeological record. Multiple, independent studies report the finding of black, resinous or shiny brain tissue, and Petrone et al. [2020 “Heat-induced Brain Vitrification from the Vesuvius Eruption in C.E. 79.” N Engl J Med. 382: 383–384; doi:10.1056/NEJMc1909867] raise the intriguing prospect of a role for vitrification in the preservation of ancient biomolecules. However, Petrone et al. (2020) have not made their raw data available, and no detailed laboratory or analytical methodology is offered. Issues of contamination and misinterpretation hampered a decade of research in biomolecular archaeology, such that addressing these sources of bias and facilitating validation of specious findings has become both routine and of paramount importance in the discipline. We argue that the evidence they present does not support their conclusion of heat-induced vitrification of human brain tissue, and that future studies should share palaeoproteomic data in an open access repository to facilitate comparative analysis of the recovery of ancient proteins and patterns of their degradation

Turnout and Closeness: Evidence from 60 Years of Bavarian Mayoral Elections

One prediction of the calculus of voting is that electoral closeness positively affects turnout via a higher probability of one vote being decisive. I test this theory with data on all mayoral elections in the German state of Bavaria between 1946 and 2009. Importantly, I use constitutionally prescribed two-round elections to measure electoral closeness and thereby improve on existing work that mostly uses ex- post measures that are prone to endogeneity. The results suggest that electoral closeness matters: A one standard deviation increase in close- ness increases turnout by 1.68 percentage points, which corresponds to 1 6 of a standard deviation in this variable. I also evaluate how other factors like electorate size or rain on election day affect turnout differentially depending on the closeness of the race

Conjugation of Organoruthenium(II) 3-(1H-Benzimidazol-2-yl)pyrazolo[3,4-b]pyridines and Indolo[3,2-d]benzazepines to Recombinant Human Serum Albumin: a Strategy To Enhance Cytotoxicity in Cancer Cells

Five organoruthenium complexes [RuCl(η6-arene)(L)]Cl with a modified arene ligand, namely, 4-formylphenoxyacetyl-η6-benzylamide, and L = 3-(1H-benzimidazol-2-yl)-1H-pyrazolo[3,4-b]pyridines or indolo[3,2-d]benzazepines were synthesized and conjugated to recombinant human serum albumin in order to improve their drug targeting and delivery to cancer cells, and a marked increase in cytotoxicity was observed

Interactions of a streamwise-oriented vortex with a finite wing

AbstractA canonical study is developed to investigate the unsteady interactions of a streamwise-oriented vortex impinging upon a finite surface using high-fidelity simulation. As a model problem, an analytically defined vortex superimposed on a free stream is convected towards an aspect-ratio-six ($\mathit{AR}=6$) plate oriented at an angle of ${\it\alpha}=4^{\circ }$ and Reynolds number of $\mathit{Re}=20\,000$ in order to characterize the unsteady modes of interaction resulting from different spanwise positions of the incoming vortex. Outboard, tip-aligned and inboard positioning are shown to produce three distinct flow regimes: when the vortex is positioned outboard of, but in close proximity to, the wingtip, it pairs with the tip vortex to form a dipole that propels itself away from the plate through mutual induction, and also leads to an enhancement of the tip vortex. When the incoming vortex is aligned with the wingtip, the tip vortex is initially strengthened by the proximity of the incident vortex, but both structures attenuate into the wake as instabilities arise in the pair’s feeding sheets from the entrainment of opposite-signed vorticity into either structure. Finally, when the incident vortex is positioned inboard of the wingtip, the vortex bifurcates in the time-mean sense with portions convecting above and below the wing, and the tip vortex is mostly suppressed. The time-mean bifurcation is actually a result of an unsteady spiralling instability in the vortex core that reorients the vortex as it impacts the leading edge, pinches off, and alternately attaches to either side of the wing. The increased effective angle of attack inboard of impingement enhances the three-dimensional recirculation region created by the separated boundary layer off the leading edge which draws fluid from the incident vortex inboard and diminishes its impact on the outboard section of the wing. The slight but remaining downwash present outboard of impingement reduces the effective angle of attack in that region, resulting in a small separation bubble on either side of the wing in the time-mean solution, effectively unloading the tip outboard of impingement and suppressing the tip vortex. All incident vortex positions provide substantial increases in the wing’s lift-to-drag ratio; however, significant sustained rolling moments also result. As the vortex is brought inboard, the rolling moment diminishes and eventually switches sign as the reduced outboard loading balances the augmented sectional lift inboard of impingement.</jats:p

Dynamics of revolving wings for various aspect ratios

AbstractHigh-fidelity, direct numerical simulations (DNSs) are conducted to examine the vortex structure and aerodynamic loading of unidirectionally revolving wings in quiescent fluid. Wings with aspect ratios$({\mathit{AR}}) = 1$, 2 and 4 are considered at a fixed root-based Reynolds number of 1000. Each wing is shown to generate a coherent leading-edge vortex (LEV) that remains in close proximity to the surface and provides persistent suction throughout the motion. Towards the tip, the LEV lifts off as an arch-like structure and reorients itself along the chord through its connection with the tip vortex. The substantial and sustained aerodynamic loads achieved during the motion saturate with aspect ratio resulting from the chordwise growth of the LEV along the span eventually becoming geometrically constrained by the trailing edge. Further, for${\mathit{AR}}=4$, substructures develop in the feeding sheet of the LEV, which appear to directly correlate with the local, span-based Reynolds number achieved during rotation. The lower-aspect-ratio wings do not have sufficient spans for these transitional elements to manifest. In contrast, vortex breakdown, which occurs around midspan for each aspect ratio, shows a strong dependence on the spanwise pressure gradient established between the root and tip of the wing and not local Reynolds number. This independent development of shear-layer substructures and vortex breakdown parallels very closely with what has been observed in delta wing flow. Next, the centrifugal, Coriolis and pressure gradient forces are also analysed at several spanwise locations across each wing, and the centrifugal and pressure gradient forces are shown to be responsible for the spanwise flow above the wing. The Coriolis force is directed away from the surface at the base of the LEV, indicating that it is not a contributor to LEV attachment, which is contrary to previous hypotheses. Finally, as a means of emphasizing the importance of the centrifugal force on LEV attachment, the${\mathit{AR}}=2$wing is simulated with the addition of a source term in the governing equations to oppose and eliminate the centrifugal force near the surface. The initial formation and development of the LEV is unhindered by the absence of this force; however, later in the motion, the outboard lift-off of the LEV moves inboard. Without the opposing outboard-directed centrifugal force to keep the separation past midspan, the entire vortex eventually separates and moves away from the surface.</jats:p