A phase 2, double-blind, multicenter, randomized, placebo-controlled, dose‑ranging study of the efficacy and safety of Astodrimer Gel for the treatment of bacterial vaginosis

Background Astodrimer Gel contains a novel dendrimer intended to treat and prevent bacterial vaginosis. We assessed the efficacy and safety of Astodrimer Gel for treatment of bacterial vaginosis. Methods 132 women with bacterial vaginosis were randomized 1:1:1:1 to Astodrimer 0.5% (N = 34), 1% (N = 33), or 3% (N = 32) Gel or hydroxyethyl cellulose placebo gel (N = 33) at a dose of 5 g vaginally once daily for 7 days at 6 centers in the United States. The primary endpoint was clinical cure (no bacterial vaginosis vaginal discharge and no more than one of 1) vaginal pH ≥4.5; 2) ≥20% clue cells; or 3) positive whiff test) at study days 21–30. Secondary analyses included clinical cure at study days 9–12, patient-reported symptoms, acceptability and adverse events. Results The Astodrimer 1% Gel dose was superior to placebo for the primary and selected secondary efficacy measures in the modified intent-to-treat population. Clinical cure rates at day 9–12 were superior to placebo for the Astodrimer 3%, 1% and 0.5% Gel groups (62.5% [15/24; P = .002], 74.1% [20/27; P < .001], and 55.2% [16/29; P = .001], respectively, vs. 22.2% [6/27]). At day 21–30, clinical cure rates were 46.2% (12/26) for the 1% dose vs. 11.5% for placebo (3/26; P = .006). A greater proportion of patients reported absence of vaginal discharge and vaginal odor at day 9–12 and day 21–30 for Astodrimer Gel groups compared with placebo. Adverse events considered potentially treatment-related occurred in only 25% of Astodrimer Gel-treated patients vs. 22% of placebo patients. Conclusion Astodrimer Gel once daily for 7 days was superior to placebo for treatment of bacterial vaginosis and was well-tolerated. The 1% dose consistently showed the strongest efficacy across endpoints. These results support a role for Astodrimer Gel, 1%, as an effective treatment for bacterial vaginosis

Timing of Initiation of Antiretroviral Therapy and Risk of Preterm Birth in Studies of HIV-infected Pregnant Women: The Role of Selection Bias

Background: Women who initiate antiretroviral therapy (ART) during pregnancy are reported to have lower risk of preterm birth compared with those who enter pregnancy care already receiving ART. We hypothesize this association can be largely attributed to selection bias. Methods: We simulated a cohort of 1000 preconceptional, HIV-infected women, where half were randomly allocated to receive immediate ART and half to delay ART until their presentation for pregnancy care. Gestational age at delivery was drawn from population data unrelated to randomization group (i.e., the true effect of delayed ART was null). Outcomes of interest were preterm birth (<37 weeks), very preterm birth (<32 weeks), and extreme preterm birth (<28 weeks). We analyzed outcomes in 2 ways: (1) a prospectively enrolled clinical trial, where all women were considered (the intent-to-treat (ITT) analysis); and (2) an observational study, where women who deliver before initiating ART were excluded (the naïve analysis). We explored the impact of later ART initiation and gestational age measurement error on our findings. Results: Preconception ART initiation was not associated with preterm birth in ITT analyses. Risk ratios (RRs) for the effect of preconception ART initiation were RR = 1.10 (preterm), RR = 1.41 (very preterm), and RR = 5.01 (extreme preterm) in naïve analyses. Selection bias increased in the naïve analysis with advancing gestational age at ART initiation and with introduction of gestational age measurement error. Conclusions: Analyses of preterm birth that compare a preconception exposure to one that occurs in pregnancy are at risk of selection bias. See video abstract at, http://links.lww.com/EDE/B313

Missing Outcome Data in Epidemiologic Studies

Missing data are pandemic and a central problem for epidemiology. Missing data reduce precision and can cause notable bias. There remain too few simple published examples detailing types of missing data and illustrating their possible impact on results. Here we take an example randomized trial that was not subject to missing data and induce missing data to illustrate 4 scenarios in which outcomes are 1) missing completely at random, 2) missing at random with positivity, 3) missing at random without positivity, and 4) missing not at random. We demonstrate that accounting for missing data is generally a better strategy than ignoring missing data, which unfortunately remains a standard approach in epidemiology

Optimal low-thrust trajectories to asteroids through an algorithm based on differential dynamic programming

In this paper an optimisation algorithm based on Differential Dynamic Programming is applied to the design of rendezvous and fly-by trajectories to near Earth objects. Differential dynamic programming is a successive approximation technique that computes a feedback control law in correspondence of a fixed number of decision times. In this way the high dimensional problem characteristic of low-thrust optimisation is reduced into a series of small dimensional problems. The proposed method exploits the stage-wise approach to incorporate an adaptive refinement of the discretisation mesh within the optimisation process. A particular interpolation technique was used to preserve the feedback nature of the control law, thus improving robustness against some approximation errors introduced during the adaptation process. The algorithm implements global variations of the control law, which ensure a further increase in robustness. The results presented show how the proposed approach is capable of fully exploiting the multi-body dynamics of the problem; in fact, in one of the study cases, a fly-by of the Earth is scheduled, which was not included in the first guess solution

Quantifying bias between reported last menstrual period and ultrasonography estimates of gestational age in Lusaka, Zambia

Objective To quantify differences in assessing preterm delivery when calculating gestational age from last menstrual period (LMP) versus ultrasonography biometry. Methods The Zambian Preterm Birth Prevention Study is an ongoing prospective cohort study that commenced enrolment in August 2015 at Women and Newborn Hospital of University Teaching Hospital in Lusaka, Zambia. Women at less than 20 weeks of pregnancy who were enrolled between August 17, 2015, and August 31, 2017, and underwent ultrasonography examination were included in the present analysis. The primary outcome was the difference between ultrasonography‐ and LMP‐based estimated gestational age. Associations between baseline predictors and outcomes were assessed using simple regression. The proportion of preterm deliveries using LMP‐ and ultrasonography‐derived gestational dating was calculated using Kaplan–Meier analysis. Results The analysis included 942 women. The discrepancy between estimating gestational age using ultrasonography and LMP increased with greater gestational age at presentation and among patients with no history of preterm delivery. In a Kaplan‐Meier analysis of 692 deliveries, 140 (20.2%, 95% confidence interval [CI] 17.7–23.0) and 79 (11.4%, 95% CI 9.6–13.6) deliveries were classified as preterm by LMP and ultrasonography estimates, respectively. Conclusion Taking ultrasonography as a standard, a bias was observed in LMP‐based gestational age estimates, which increased with advancing gestation at presentation. This resulted in misclassification of term deliveries as preterm

Second order gauge invariant gravitational perturbations of a Kerr black hole

We investigate higher than the first order gravitational perturbations in the Newman-Penrose formalism. Equations for the Weyl scalar $\psi_4,$ representing outgoing gravitational radiation, can be uncoupled into a single wave equation to any perturbative order. For second order perturbations about a Kerr black hole, we prove the existence of a first and second order gauge (coordinates) and tetrad invariant waveform, $\psi_I$, by explicit construction. This waveform is formed by the second order piece of $\psi_4$ plus a term, quadratic in first order perturbations, chosen to make $\psi_I$ totally invariant and to have the appropriate behavior in an asymptotically flat gauge. $\psi_I$ fulfills a single wave equation of the form ${\cal T}\psi_I=S,$ where ${\cal T}$ is the same wave operator as for first order perturbations and $S$ is a source term build up out of (known to this level) first order perturbations. We discuss the issues of imposition of initial data to this equation, computation of the energy and momentum radiated and wave extraction for direct comparison with full numerical approaches to solve Einstein equations.Comment: 19 pages, REVTEX. Some misprints corrected and changes to improve presentation. Version to appear in PR

Maternal HIV Infection and Spontaneous Versus Provider-Initiated Preterm Birth in an Urban Zambian Cohort

Objective: We investigated the effect of maternal HIV and its treatment on spontaneous and provider-initiated preterm birth (PTB) in an urban African cohort. Methods: The Zambian Preterm Birth Prevention Study enrolled pregnant women at their first antenatal visit in Lusaka. Participants underwent ultrasound, laboratory testing, and clinical phenotyping of delivery outcomes. Key exposures were maternal HIV serostatus and timing of antiretroviral therapy initiation. We defined the primary outcome, PTB, as delivery between 16 and 37 weeks’ gestational age, and differentiated spontaneous from provider-initiated parturition. Results: Of 1450 pregnant women enrolled, 350 (24%) had HIV. About 1216 (84%) were retained at delivery, 3 of whom delivered,16 weeks. Of 181 (15%) preterm deliveries, 120 (66%) were spontaneous, 56 (31%) were provider-initiated, and 5 (3%) were unclassified. In standardized analyses using inverse probability weighting, maternal HIV increased the risk of spontaneous PTB [RR 1.68; 95% confidence interval (CI): 1.12 to 2.52], but this effect was mitigated on overall PTB [risk ratio (RR) 1.31; 95% CI: 0.92 to 1.86] owing to a protective effect against provider-initiated PTB. HIV reduced the risk of preeclampsia (RR 0.32; 95% CI: 0.11 to 0.91), which strongly predicted provider-initiated PTB (RR 17.92; 95% CI: 8.13 to 39.53). The timing of antiretroviral therapy start did not affect the relationship between HIV and PTB. Conclusion: The risk of HIV on spontaneous PTB seems to be opposed by a protective effect of HIV on provider-initiated PTB. These findings support an inflammatory mechanism underlying HIV-related PTB and suggest that published estimates of PTB risk overall underestimate the risk of spontaneous PTB

Double-Layer Systems at Zero Magnetic Field

We investigate theoretically the effects of intralayer and interlayer exchange in biased double-layer electron and hole systems, in the absence of a magnetic field. We use a variational Hartree-Fock-like approximation to analyze the effects of layer separation, layer density, tunneling, and applied gate voltages on the layer densities and on interlayer phase coherence. In agreement with earlier work, we find that for very small layer separations and low layer densities, an interlayer-correlated ground state possessing spontaneous interlayer coherence (SILC) is obtained, even in the absence of interlayer tunneling. In contrast to earlier work, we find that as a function of total density, there exist four, rather than three, distinct noncrystalline phases for balanced double-layer systems without interlayer tunneling. The newly identified phase exists for a narrow range of densities and has three components and slightly unequal layer densities, with one layer being spin polarized, and the other unpolarized. An additional two-component phase is also possible in the presence of sufficiently strong bias or tunneling. The lowest-density SILC phase is the fully spin- and pseudospin-polarized ``one-component'' phase discussed by Zheng {\it et al.} [Phys. Rev. B {\bf 55}, 4506 (1997)]. We argue that this phase will produce a finite interlayer Coulomb drag at zero temperature due to the SILC. We calculate the particle densities in each layer as a function of the gate voltage and total particle density, and find that interlayer exchange can reduce or prevent abrupt transfers of charge between the two layers. We also calculate the effect of interlayer exchange on the interlayer capacitance.Comment: 35 pages, 19 figures included. To appear in PR

Spontaneous Coherence and Collective Modes in Double-Layer Quantum Dot Systems

We study the ground state and the collective excitations of parabolically-confined double-layer quantum dot systems in a strong magnetic field. We identify parameter regimes where electrons form maximum density droplet states, quantum-dot analogs of the incompressible states of the bulk integer quantum Hall effect. In these regimes the Hartree-Fock approximation and the time-dependent Hartree-Fock approximations can be used to describe the ground state and collective excitations respectively. We comment on the relationship between edge excitations of dots and edge magneto-plasmon excitations of bulk double-layer systems.Comment: 20 pages (figures included) and also available at http://fangio.magnet.fsu.edu/~jhu/Paper/qdot_cond.ps, replaced to fix figure

Dynamical properties of liquid Al near melting. An orbital-free molecular dynamics study

The static and dynamic structure of liquid Al is studied using the orbital free ab-initio molecular dynamics method. Two thermodynamic states along the coexistence line are considered, namely T = 943 K and 1323 K for which X-ray and neutron scattering data are available. A new kinetic energy functional, which fulfills a number of physically relevant conditions is employed, along with a local first principles pseudopotential. In addition to a comparison with experiment, we also compare our ab-initio results with those obtained from conventional molecular dynamics simulations using effective interionic pair potentials derived from second order pseudopotential perturbation theory.Comment: 15 pages, 12 figures, 2 tables, submitted to PR