Multicenter, Prospective, Randomized Controlled Trial of High-Sensitivity Cardiac Troponin I-Guided Combination Angiotensin Receptor Blockade and Beta-Blocker Therapy to Prevent Anthracycline Cardiotoxicity: The Cardiac CARE Trial.

BACKGROUND: Anthracycline-induced cardiotoxicity has a variable incidence, and the development of left ventricular dysfunction is preceded by elevations in cardiac troponin concentrations. Beta-adrenergic receptor blocker and renin-angiotensin system inhibitor therapies have been associated with modest cardioprotective effects in unselected patients receiving anthracycline chemotherapy. METHODS: In a multicenter, prospective, randomized, open-label, blinded end-point trial, patients with breast cancer and non-Hodgkin lymphoma receiving anthracycline chemotherapy underwent serial high-sensitivity cardiac troponin testing and cardiac magnetic resonance imaging before and 6 months after anthracycline treatment. Patients at high risk of cardiotoxicity (cardiac troponin I concentrations in the upper tertile during chemotherapy) were randomized to standard care plus cardioprotection (combination carvedilol and candesartan therapy) or standard care alone. The primary outcome was adjusted change in left ventricular ejection fraction at 6 months. In low-risk nonrandomized patients with cardiac troponin I concentrations in the lower 2 tertiles, we hypothesized the absence of a 6-month change in left ventricular ejection fraction and tested for equivalence of ±2%. RESULTS: Between October 2017 and June 2021, 175 patients (mean age, 53 years; 87% female; 71% with breast cancer) were recruited. Patients randomized to cardioprotection (n=29) or standard care (n=28) had left ventricular ejection fractions of 69.4±7.4% and 69.1±6.1% at baseline and 65.7±6.6% and 64.9±5.9% 6 months after completion of chemotherapy, respectively. After adjustment for age, pretreatment left ventricular ejection fraction, and planned anthracycline dose, the estimated mean difference in 6-month left ventricular ejection fraction between the cardioprotection and standard care groups was -0.37% (95% CI, -3.59% to 2.85%; P=0.82). In low-risk nonrandomized patients, baseline and 6-month left ventricular ejection fractions were 69.3±5.7% and 66.4±6.3%, respectively: estimated mean difference, 2.87% (95% CI, 1.63%-4.10%; P=0.92, not equivalent). CONCLUSIONS: Combination candesartan and carvedilol therapy had no demonstrable cardioprotective effect in patients receiving anthracycline-based chemotherapy with high-risk on-treatment cardiac troponin I concentrations. Low-risk nonrandomized patients had similar declines in left ventricular ejection fraction, bringing into question the utility of routine cardiac troponin monitoring. Furthermore, the modest declines in left ventricular ejection fraction suggest that the value and clinical impact of early cardioprotection therapy need to be better defined in patients receiving high-dose anthracycline. REGISTRATION: URL: https://doi.org; Unique identifier: 10.1186/ISRCTN24439460. URL: https://www.clinicaltrialsregister.eu/ctr-search/search; Unique identifier: 2017-000896-99.

Cross-scale energy cascade powered by magnetospheric convection.

Plasma convection in the Earth's magnetosphere from the distant magnetotail to the inner magnetosphere occurs largely in the form of mesoscale flows, i.e., discrete enhancements in the plasma flow with sharp dipolarizations of magnetic field. Recent spacecraft observations suggest that the dipolarization flows are associated with a wide range of kinetic processes such as kinetic Alfvén waves, whistler-mode waves, and nonlinear time-domain structures. In this paper we explore how mesoscale dipolarization flows produce suprathermal electron instabilities, thus providing free energy for the generation of the observed kinetic waves and structures. We employ three-dimensional test-particle simulations of electron dynamics one-way coupled to a global magnetospheric model. The simulations show rapid growth of interchanging regions of parallel and perpendicular electron temperature anisotropies distributed along the magnetic terrain formed around the dipolarization flows. Unencumbered in test-particle simulations, a rapid growth of velocity-space anisotropies in the collisionless magnetotail plasma is expected to be curbed by the generation of plasma waves. The results are compared with in situ observations of an isolated dipolarization flow at one of the Magnetospheric Multiscale Mission spacecraft. The observations show strong wave activity alternating between broad-band wave activity and whistler waves. With estimated spatial extent being similar to the characteristic size of the temperature anisotropy patches in our test-particle simulations, the observed bursts of the wave activity are likely to be produced by the parallel and perpendicular electron energy anisotropies driven by the dipolarization flow, as suggested by our modeling results.

Behavior of compressed plasmas in magnetic fields.

Plasma in the earth's magnetosphere is subjected to compression during geomagnetically active periods and relaxation in subsequent quiet times. Repeated compression and relaxation is the origin of much of the plasma dynamics and intermittency in the near-earth environment. An observable manifestation of compression is the thinning of the plasma sheet resulting in magnetic reconnection when the solar wind mass, energy, and momentum floods into the magnetosphere culminating in the spectacular auroral display. This phenomenon is rich in physics at all scale sizes, which are causally interconnected. This poses a formidable challenge in accurately modeling the physics. The large-scale processes are fluid-like and are reasonably well captured in the global magnetohydrodynamic (MHD) models, but those in the smaller scales responsible for dissipation and relaxation that feed back to the larger scale dynamics are often in the kinetic regime. The self-consistent generation of the small-scale processes and their feedback to the global plasma dynamics remains to be fully explored. Plasma compression can lead to the generation of electromagnetic fields that distort the particle orbits and introduce new features beyond the purview of the MHD framework, such as ambipolar electric fields, unequal plasma drifts and currents among species, strong spatial and velocity gradients in gyroscale layers separating plasmas of different characteristics, etc. These boundary layers are regions of intense activity characterized by emissions that are measurable. We study the behavior of such compressed plasmas and discuss the relaxation mechanisms to understand their measurable signatures as well as their feedback to influence the global scale plasma evolution.

Kinetic Equilibrium of Dipolarization Fronts.

The unprecedented high-resolution data from the Magnetospheric Multi-Scale (MMS) satellites is revealing the physics of dipolarization fronts created in the aftermath of magnetic reconnection in extraordinary detail. The data shows that the fronts contain structures on small spatial scales beyond the scope of fluid framework. A new kinetic analysis, applied to MMS data here, predicts that global plasma compression produces a unique particle distribution in a narrow boundary layer with separation of electron and ion scale physics. Layer widths on the order of an ion gyro-diameter lead to an ambipolar potential across the magnetic field resulting in strongly sheared flows. Gradients along the magnetic field lines create a potential difference, which can accelerate ions and electrons into beams. These small-scale kinetic effects determine the plasma dynamics in dipolarization fronts, including the origin of the distinctive broadband emissions.

Deferoxamine-Soaked Suture Improves Angiogenesis and Repair Potential After Acute Injury of the Chicken Achilles Tendon.

BACKGROUND: A major obstacle to the treatment of soft tissue injuries is the hypovascular nature of the tissues. Deferoxamine (DFO) has been shown to stimulate angiogenesis by limiting the degradation of intracellular hypoxia-inducible factor 1-alpha. HYPOTHESIS: DFO-saturated suture would induce angiogenesis and improve the markers of early healing in an Achilles tendon repair model. STUDY DESIGN: Controlled laboratory study. METHODS: Broiler hens were randomly assigned to the control (CTL) group or DFO group (n = 9 per group). The right Achilles tendon was partially transected at its middle third. The defect was surgically repaired using 3-0 Vicryl suture soaked in either sterile water (CTL group) or 324 mM DFO solution (DFO group). All animals were euthanized 2 weeks after the injury, and the tendon was harvested. Half of the tendon was used to evaluate angiogenesis via hemoglobin content and tissue repair via DNA content and proteoglycan (PG) content. The other half of the tendon was sectioned and stained with hematoxylin and eosin, safranin O, and lectin to evaluate vessel density. RESULTS: Hemoglobin content (percentage of wet tissue weight) was significantly increased in the DFO group compared with the CTL group (0.081 ± 0.012 vs 0.063 ± 0.016, respectively; P = .046). DNA content (percentage of wet tissue weight) was also significantly increased in the DFO group compared with the CTL group (0.31 ± 0.05 vs 0.23 ± 0.03, respectively; P = .024). PG content (percentage of wet tissue weight) was significantly decreased in the DFO group compared with the CTL group (0.26 ± 0.02 vs 0.33 ± 0.08, respectively; P = .035). Total chondroid area (number of vessels per mm2 of tissue area evaluated) was significantly decreased in the DFO group compared with the CTL group (17.2 ± 6.6 vs 24.6 ± 5.1, respectively; P = .038). Articular zone vessel density (vessels/mm2) was significantly increased in the DFO group compared with the CTL group (7.1 ± 2.5 vs 2.1 ± 0.9, respectively; P = .026). CONCLUSION: The significant increase in hemoglobin content as well as articular zone vessel density in the DFO group compared with the CTL group is evidence of increased angiogenesis in the fibrocartilaginous region of the tendon exposed to DFO. The DFO group also displayed a significantly greater level of DNA and significantly lower level of PG, suggesting enhanced early healing by fibrous tissue formation. CLINICAL RELEVANCE: Stimulating angiogenesis by DFO-saturated suture may be clinically useful to improve healing of poorly vascularized tissues.