Abstract
Background
The impact of pregnancy on vedolizumab (VDZ) and ustekinumab (UST) pharmacokinetics is not well defined. Similarly, the time to infant clearance and outcomes following in-utero ...exposure require elucidation. We aim to define the stability of UST and VDZ levels in pregnancy, placental drug transfer, and the time to and factors influencing infant drug clearance.
Methods
This multicentre prospective cohort study recruited women with IBD who were pregnant or planning pregnancy and receiving VDZ or UST. Trough drug levels, and clinical and biochemical data were documented pre-conception and in each trimester (T) of pregnancy. Maternal and infant drug levels were obtained at delivery and repeated in infants at intervals until clearance. Infant outcomes were assessed to 2 years of age. Drug levels were measured by ELISA (Theradiag) with a lower limit of detection of 0.25ug/mL (VDZ) and 0.4ug/mL (UST).
Results
97 women aged median 31 (IQR 29-34) y with 54 receiving VDZ (41,17 with Crohn’s disease respectively) were included. Clinical and biochemical disease remission was maintained in the majority (Table 1). Median VDZ levels decreased by 42% from T1 to T3 (p<0.001; Skilling’s Mack) without a corresponding increase in faecal calprotectin (p=0.65; Wilcoxon signed-rank), whilst UST levels were stable over the course of pregnancy (p=0.14) (Fig 1). 82% (VDZ) and 78% (UST) of participants continued drug into T3. Favourable delivery and infant outcomes were observed (Table 2). Infant:maternal drug level ratio was 1.74 (1.24-3.5, n=35) for UST and 0.71 (0.52-0.91, n=44) for VDZ. Delivery levels in infants correlated positively with concomitant maternal levels and gestation at time of final drug dose (Table 2). 67% UST and 90% VDZ exposed infants cleared drug by 15 weeks (p=0.06; two sided test of proportions), with a time to clearance of 13 (9-22) weeks for UST and 11 (8-13) weeks for VDZ (p=0.11; non-parametric comparison of medians). Time to clearance correlated positively with infant delivery level (Table 2). There was no difference in the time to infant clearance between those receiving their last dose in T2 vs T3 (UST p=0.45 or VDZ p=0.44).
Conclusion
UST levels are stable over the course of pregnancy. VDZ levels fall but without a parallel increase in biochemical disease activity. Proactive dose adjustment and level monitoring during pregnancy is therefore not necessary. Differences in placental transfer of UST and VDZ were confirmed, with the infant:maternal drug level ratio at delivery lower for VDZ than UST. Both are cleared prior to 15 weeks in the majority, but the higher placental transfer of UST results in numerically fewer exposed infants clearing drug by this timepoint. No concerning infant outcomes were identified in this cohort.
We describe the installation, commissioning, and characterization of the new injection kicker system in the Muon g−2 Experiment (E989) at Fermilab, which makes a precision measurement of the muon ...magnetic anomaly. Three Blumlein pulsers drive each of the 1.27-m-long non-ferric kicker magnets, which reside in a storage ring vacuum (SRV) that is subjected to a 1.45 T magnetic field. The new system has been redesigned relative to Muon g−2’s predecessor experiment, and we present those details in this manuscript.
This study describes the natural course of vincristine-induced peripheral neuropathy in patients with lymphoma (n = 114) receiving vincristine in two different dose intensities. Neuropathic changes ...were observed in both dose intensity groups, but the higher dose intensity group reported significantly more symptoms during therapy, whereas neurologic signs were significantly more prominent after a cumulative dose of 12 mg vincristine. Furthermore, off-therapy worsening of symptoms (24%) and signs (30%) occurred unexpectedly.
The rate of nuclear muon capture by the proton has been measured using a new technique based on a time projection chamber operating in ultraclean, deuterium-depleted hydrogen gas, which is key to ...avoiding uncertainties from muonic molecule formation. The capture rate from the hyperfine singlet ground state of the microp atom was obtained from the difference between the micro(-) disappearance rate in hydrogen and the world average for the micro(+) decay rate, yielding Lambda(S)=725.0+/-17.4 s(-1), from which the induced pseudoscalar coupling of the nucleon, g(P)(q(2)=-0.88m(2)(micro))=7.3+/-1.1, is extracted.
The electromagnetic calorimeter for the new muon (g−2) experiment at Fermilab will consist of arrays of PbF2 Cherenkov crystals read out by large-area silicon photo-multiplier (SiPM) sensors. We ...report here on measurements and simulations using 2.0–4.5GeV electrons with a 28-element prototype array. All data were obtained using fast waveform digitizers to accurately capture signal pulse shapes vs. energy, impact position, angle, and crystal wrapping. The SiPMs were gain matched using a laser-based calibration system, which also provided a stabilization procedure that allowed gain correction to a level of 10−4 per hour. After accounting for longitudinal fluctuation losses, those crystals wrapped in a white, diffusive wrapping exhibited an energy resolution σ/E of (3.4±0.1)%/E/GeV, while those wrapped in a black, absorptive wrapping had (4.6±0.3)%/E/GeV. The white-wrapped crystals—having nearly twice the total light collection—display a generally wider and impact-position-dependent pulse shape owing to the dynamics of the light propagation, in comparison to the black-wrapped crystals, which have a narrower pulse shape that is insensitive to impact position.
The MuCap experiment at the Paul Scherrer Institute has measured the rate Λ{sub S} of muon capture from the singlet state of the muonic hydrogen atom to a precision of 1%. A muon beam was stopped in ...a time projection chamber filled with 10-bar, ultrapure hydrogen gas. Cylindrical wire chambers and a segmented scintillator barrel detected electrons from muon decay. Λ{sub S} is determined from the difference between the μ{sup -} disappearance rate in hydrogen and the free muon decay rate. The result is based on the analysis of 1.2×10{sup 10} μ{sup -} decays, from which we extract the capture rate Λ{sub S} =(714.9±5.4{sub stat} ±5.1{sub syst} )s{sup -1} and derive the proton’s pseudoscalar coupling g{sub P} (q{sup 2}{sub 0} =-0.88m{sup 2}{sub μ} )=8.06±0.55 .
The rate of nuclear muon capture by the proton has been measured using a new technique based on a time projection chamber operating in ultraclean, deuterium-depleted hydrogen gas, which is key to ...avoiding uncertainties from muonic molecule formation. The capture rate from the hyperfine singlet ground state of the {mu}p atom was obtained from the difference between the {mu}{sup -} disappearance rate in hydrogen and the world average for the {mu}{sup +} decay rate, yielding {lambda}{sub S}=725.0{+-}17.4 s{sup -1}, from which the induced pseudoscalar coupling of the nucleon, g{sub P}(q{sup 2}=-0.88m{sub {mu}}{sup 2})=7.3{+-}1.1, is extracted.
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