51 research outputs found
Off-label, but on target: the evidence needed to implement alternative dosing regimens of anticancer drugs.
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Vertical structure of stratospheric water vapour trends derived from merged satellite data
Stratospheric water vapour is a powerful greenhouse gas. The longest available record from balloon observations over Boulder, Colorado, USA shows increases in stratospheric water vapour concentrations that cannot be fully explained by observed changes in the main drivers, tropical tropopause temperatures and methane. Satellite observations could help resolve the issue, but constructing a reliable long-term data record from individual short satellite records is challenging. Here we present an approach to merge satellite data sets with the help of a chemistry–climate model nudged to observed meteorology. We use the models’ water vapour as a transfer function between data sets that overcomes issues arising from instrument drift and short overlap periods. In the lower stratosphere, our water vapour record extends back to 1988 and water vapour concentrations largely follow tropical tropopause temperatures. Lower and mid-stratospheric long-term trends are negative, and the trends from Boulder are shown not to be globally representative. In the upper stratosphere, our record extends back to 1986 and shows positive long-term trends. The altitudinal differences in the trends are explained by methane oxidation
together with a strengthened lower-stratospheric and a weakened upper stratospheric circulation inferred by this analysis. Our results call into question previous estimates of surface radiative forcing based on presumed global long-term increases in water vapour concentrations in the lower stratosphere
Precambrian non-marine stromatolites in alluvial fan deposits, the Copper Harbor Conglomerate, upper Michigan
Laminated cryptalgal carbonates occur in the Precambrian Copper Harbor Conglomerate of northern Michigan, which was deposited in the Keweenawan Trough, an aborted proto-oceanic rift. This unit is composed of three major facies deposited by braided streams on a large alluvial-fan complex. Coarse clastics were deposited in braided channels, predominantly as longitudinal bars, whereas cross-bedded sandstones were deposited by migrating dunes or linguoid bars. Fine-grained overbank deposits accumulated in abandoned channels. Gypsum moulds and carbonate-filled cracks suggest an arid climate during deposition. Stromatolites interstratified with these clastic facies occur as laterally linked drapes over cobbles, as laterally linked contorted beds in mudstone, as oncolites, and as poorly developed mats in coarse sandstones. Stromatolites also are interbedded with oolitic beds and intraclastic conglomerates. Stromatolitic microstructure consists of alternating detrital and carbonate laminae, and open-space structures. Radial-fibrous calcite fans are superimposed on the laminae. The laminae are interpreted as algal in origin, whereas the origin of the radial fibrous calcite is problematic. The stromatolites are inferred to have grown in lakes which occupied abandoned channels on the fan surface. Standing water on a permeable alluvial fan in an arid climate requires a high water table maintained by high precipitation, or local elevation of the water table, possibly due to the close proximity of a lake. Occurrence of stromatolites in the upper part of the Copper Harbor Conglomerate near the base of the lacustrine Nonesuch Shale suggests that these depositional sites may have been near the Nonesuch Lake.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72022/1/j.1365-3091.1983.tb00713.x.pd
Long-term safety and efficacy of Eculizumab in Aquaporin-4 IgG-positive NMOSD
Objective
During PREVENT (NCT01892345), eculizumab significantly reduced relapse risk versus placebo in patients with aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder (AQP4-IgG+ NMOSD). We report an interim analysis of PREVENT's ongoing open-label extension (OLE; NCT02003144) evaluating eculizumab's long-term safety and efficacy.
Methods
Patients who completed PREVENT could enroll in the OLE to receive eculizumab (maintenance dose = 1,200 mg/2 weeks, after a blinded induction phase). Safety and efficacy data from PREVENT and its OLE (interim data cut, July 31, 2019) were combined for this analysis.
Results
Across PREVENT and the OLE, 137 patients received eculizumab and were monitored for a median (range) of 133.3 weeks (5.1–276.9 weeks), for a combined total of 362.3 patient-years (PY). Treatment-related adverse event (AE) and serious adverse event (SAE) rates were 183.5 in 100 PY and 8.6 in 100 PY, respectively. Serious infection rates were 10.2 in 100 PY in eculizumab-treated patients versus 15.1 in 100 PY in the PREVENT placebo group. No patient developed a meningococcal infection. At 192 weeks (3.7 years), 94.4% (95% confidence interval [CI], 88.6–97.3) of patients remained adjudicated relapse-free. The adjudicated annualized relapse rate was 0.025 (95% CI = 0.013–0.048) in all eculizumab-treated patients versus 0.350 (95% CI = 0.199–0.616) in the PREVENT placebo group. During the OLE, 37% of patients (44 of 119 patients) stopped or decreased background immunosuppressive therapy use.
Interpretation
This analysis demonstrates that eculizumab's long-term safety profile in NMOSD is consistent with its established profile across other indications. This analysis also demonstrated the sustained ability of long-term eculizumab treatment to reduce relapse risk in patients with AQP4-IgG+ NMOSD. ANN NEUROL 2021;89:1088–109
Off-label, but on target: the evidence needed to implement alternative dosing regimens of anticancer drugs.
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