Accumulation of Multiple Mutations In Vivo Confers Cross-Resistance to New and Existing Integrase Inhibitors.

Bictegravir (BIC) and cabotegravir (CAB) are the latest available HIV integrase inhibitors in clinical trials. The combination of major integrase inhibitor substitutions G140S/Q148H has been shown to confer high-level resistance to the approved integrase inhibitors raltegravir (RAL) and elvitegravir (EVG) but not necessarily dolutegravir (DTG). We assayed recombinant viruses made from patient-derived RNA extracts for resistance phenotype for a panel of viruses containing G140S/Q148H with additional accessory substitutions. The accumulation of multiple integrase substitutions confers high-level resistance to all 5 integrase inhibitors. There is extensive cross-resistance between DTG, BIC, and CAB (r = 0.96-0.97).

A Novel Method for Quantifying Intracranial Volume Change by Distraction Osteogenesis for Craniosynostosis.

INTRODUCTION: Methods of reporting quantitative results for distraction osteogenesis (DO) of craniosynostosis have been inconsistent. Therefore, the efficacy of differing techniques and timing in regard to volume change is not well established, with no uniform metric for comparisons. Given that cranial vault remodeling with DO may be completed with different approaches, analysis was made to determine (1) the relative efficiency of different approaches in expanding intracranial volume (ICV) and (2) the impact of adjusting for ICV growth on measured DO efficiency. METHODS: Patients with craniosynostosis were treated with open cranial vault reconstruction combined with internal distraction. Preoperative and postoperative computed tomography scans were used to quantify ICV change. The metric was determined by dividing percent ICV change by total distraction length. The metric was used as a proxy for efficiency to compare posterior and anterior distraction between groups using the Mann-Whitney U test and within a subgroup of patients who underwent 2-stage distraction using the Wilcoxon matched-pairs signed rank test. RESULTS: Twenty patients underwent cranial vault remodeling with DO: 14 unicoronal, 3 bicoronal, 2 multisutural, and 1 lambdoid. Results are reported in medians. Distraction efficiency was 0.99%/mm for primary anterior, unilateral distraction for unicoronal patients (n = 13, aged 9.1 months) and 4.28%/mm for posterior distraction using multiple distractors (n = 4, aged 6.3 months). In terms of the metric, primary posterior distraction was significantly more efficient than primary anterior distraction (P = 0.007). Three patients who had undergone primary posterior distraction later underwent secondary anterior distraction. Again, posterior distraction was shown to be significantly more efficient (5.16 vs 0.62, P = 0.050). For the unicoronal patients who received anterior unilateral distraction, an adjusted metric was calculated to account for normal intracranial growth. This was found to be 0.39%/mm, which was significantly different from the unadjusted metric (P = 0.0001). CONCLUSIONS: Posterior distraction is more efficient for ICV expansion than anterior distraction, which may have implications for the choice of approach for craniosynostosis repair. In addition, this is the first report of a novel standardized metric for analyzing ICV change achieved by DO. This tool allows for adjusting the efficiency metric for expected ICV growth, which significantly impacts its value.

Dense suspension splat: monolayer spreading and hole formation after impact.

We use experiments and minimal numerical models to investigate the rapidly expanding monolayer formed by the impact of a dense suspension drop against a smooth solid surface. The expansion creates a lacelike pattern of particle clusters separated by particle-free regions. Both the expansion and the development of the spatial inhomogeneity are dominated by particle inertia and, therefore, are robust and insensitive to details of the surface wetting, capillarity, and viscous drag.

Still water: dead zones and collimated ejecta from the impact of granular jets.

When a dense granular jet hits a target, it forms a large dead zone and ejects a highly collimated conical sheet with a well-defined opening angle. Using experiments, simulations, and continuum modeling, we find that this opening angle is insensitive to the precise target shape and the dissipation mechanisms in the flow. We show that this surprising insensitivity arises because dense granular jet impact, though highly dissipative, is nonetheless controlled by the limit of perfect fluid flow.

Impact of a viscous liquid drop.

We simulate the impact of a viscous liquid drop onto a smooth dry solid surface. As in experiments, when ambient air effects are negligible, impact flattens the falling drop without producing a splash. The no-slip boundary condition at the wall produces a boundary layer inside the liquid. Later, the flattening surface of the drop traces out the boundary layer. As a result, the eventual shape of the drop is a "pancake" of uniform thickness except at the rim, where surface tension effects are significant. The thickness of the pancake is simply the height where the drop surface first collides with the boundary layer.

Prevalence of Human Immunodeficiency Virus-1 Integrase Strand Transfer Inhibitor Resistance in British Columbia, Canada Between 2009 and 2016: A Longitudinal Analysis.

BACKGROUND: Integrase strand transfer inhibitors (INSTIs) are highly efficacious and well tolerated antiretrovirals with fewer adverse side-effects relative to other classes of antiretrovirals. The use of INSTIs raltegravir, elvitegravir, and dolutegravir has increased dramatically over recent years. However, there is limited information about the evolution and prevalence of INSTI resistance mutations in clinical human immunodeficiency virus populations. METHODS: Human immunodeficiency virus-1-positive individuals ≥19 years were included if they received ≥1 dispensed prescription of antiretroviral therapy (ART) in British Columbia between 2009 and 2016 (N = 9358). Physician-ordered drug resistance tests were analyzed and protease inhibitor (PI), reverse-transcriptase inhibitor (RT), and INSTI resistance were defined as having ≥1 sample with a combined, cumulative score ≥30 by Stanford HIV Drug Resistance Algorithm version 7.0.1. RESULTS: Although most ART-treated individuals were tested for PI and RT resistance, INSTI resistance testing lagged behind the uptake of INSTIs among INSTI-treated individuals (11% in 2009; 34% in 2016). The prevalence of INSTI resistance was relatively low, but it increased from 1 to 7 per 1000 ART-treated individuals between 2009 and 2016 (P < .0001, R2 = 0.98). Integrase strand transfer inhibitor resistance mutations increased at integrase codons 66, 97, 140, 148, 155, and 263. CONCLUSIONS: The prevalence of INSTI resistance remains low compared with PI and RT resistance in ART-treated populations but is expanding with increased INSTI use.

Emergent drug resistance with integrase strand transfer inhibitor-based regimens.

OBJECTIVES: To estimate the incidence of and risk factors for emergent resistance to integrase strand transfer inhibitor (INSTI) and nucleoside(-tide) reverse transcriptase inhibitors (NRTI) in HIV-1-infected adults receiving an INSTI and two NRTIs. DESIGN: Retrospective cohort study. METHODS: Persons aged at least 19 years were included if they received their first prescription for raltegravir, elvitegravir or dolutegravir in British Columbia, Canada in 2012-2014 and were followed to 31 December 2015. Emergent resistance was defined as new mutations conferring intermediate-high level NRTI or INSTI resistance (score ≥30, Stanford HIV Drug Resistance Algorithm v.7.0.1). First-year resistance rates and 95% confidence intervals (95% CI) were estimated for 'any' (INSTI or NRTI) resistance using Poisson regression. The relationship between any emergent resistance and explanatory variables was modeled by Cox proportional hazards. RESULTS: There were 270 raltegravir, 323 elvitegravir and 392 dolutegravir-treated persons who were predominantly male (77%), antiretroviral therapy (ART)-experienced (81%), with low prevalence of preexisting drug resistance (16%). INSTI and NRTI resistance emerged in both ART-experienced and ART-naive persons (including dolutegravir-treated ART-naive), with no statistically significant differences in 'any' resistance rates (95% CI) between INSTIs: raltegravir 3.80 (1.90, 7.60), elvitegravir 2.37 (1.06, 5.27) and dolutegravir 1.48 (0.62, 3.55)/100 person-years. The strongest factors associated with emergent resistance were CD4 less than 200 cells/µl, adjusted hazard ratio (95% CI) 10.46 (4.67, 23.41) and less than 80% adherence to the INSTI regimen hazard ratio 2.52 (1.11, 5.71). CONCLUSION: Incident drug resistance rates were low with 'real-world' use of INSTI-based regimens. However, incomplete ART adherence and low CD4 cell count were associated with increased resistance rates regardless of which INSTI was prescribed. Provide adherence support and monitor for drug resistance.

From splashing to bouncing: The influence of viscosity on the impact of suspension droplets on a solid surface.

We experimentally investigated the splashing of dense suspension droplets impacting a solid surface, extending prior work to the regime where the viscosity of the suspending liquid becomes a significant parameter. The overall behavior can be described by a combination of two trends. The first one is that the splashing becomes favored when the kinetic energy of individual particles at the surface of a droplet overcomes the confinement produced by surface tension. This is expressed by a particle-based Weber number We_{p}. The second is that splashing is suppressed by increasing the viscosity of the solvent. This is expressed by the Stokes number St, which influences the effective coefficient of restitution of colliding particles. We developed a phase diagram where the splashing onset is delineated as a function of both We_{p} and St. A surprising result occurs at very small Stokes number, where not only splashing is suppressed but also plastic deformation of the droplet. This leads to a situation where droplets can bounce back after impact, an observation we are able to reproduce using discrete particle numerical simulations that take into account viscous interaction between particles and elastic energy.

Impact dynamics of granular jets with noncircular cross sections.

Using high-speed photography, we investigate two distinct regimes of the impact dynamics of granular jets with noncircular cross sections. In the steady-state regime, we observe the formation of thin granular sheets with anisotropic shapes and show that the degree of anisotropy increases with the aspect ratio of the jet's cross section. Our results illustrate the liquidlike behavior of granular materials during impact and demonstrate that a collective hydrodynamic flow emerges from strongly interacting discrete particles. We discuss the analogy between our experiments and those from the Relativistic Heavy Ion Collider, where similar anisotropic ejecta from a quark-gluon plasma have been observed in heavy-ion impact.

Underwater bubble pinch-off: transient stretching flow.

At the point of pinch-off of an underwater air bubble, the speed of water rushing in diverges. Previous studies that assumed radial flow throughout showed that the local axial shape is two smoothly connected, slender cones that transition very slowly (logarithmically) to a cylindrical segment. Our simulations show that even with initially radial flow, a transient vertical flow develops with comparable speeds. Bernoulli pressure draws water into the singularity region while incompressibility forces it away from the neck minimum, generating significant vertical flows that rapidly slenderize and symmetrize the collapse region. This transition is due to a different mechanism, occurring much faster than previously expected. Vertical flows dictate the neck shape evolution.

Force balance at the transition from selective withdrawal to viscous entrainment.

We simulate the evolution of the steady-state interface in the selective withdrawal regime. Selective withdrawal ends when the upward pull exerted by the viscous flow in the withdrawing liquid layer overcomes the downward force due to surface tension. The lower-layer dynamics are unimportant. The dominant contribution to the surface-tension force comes from the large area where the interface is weakly deflected, instead of the small area where the surface is most distorted. A scaling estimate based on this idea yields results that agree quantitatively with both simulations and previous experiments.

Asymmetric disconnection of an underwater air bubble: persistent neck vibrations evolve into a smooth contact.

The disconnection of an underwater bubble illustrates how slight initial asymmetries can prevent the formation of a finite-time singularity. Creating a singularity by focusing a finite amount of energy dynamically into a vanishingly small amount of material requires that the initial condition be perfectly symmetric. In reality, imperfections are always present. We show a slight azimuthal asymmetry in the initial shape of the bubble neck excites vibrations that persist over time. As a result, the focusing singularity is generically preempted by a smooth contact.

Viscous withdrawal of miscible liquid layers.

In viscous withdrawal, a converging flow imposed in an upper layer of viscous liquid entrains liquid from a lower, stably stratified layer. Using the idea that a thin tendril is entrained by a local straining flow, we propose a scaling law for the volume flux of liquid entrained from miscible liquid layers. A long-wavelength model including only local information about the withdrawal flow is degenerate, with multiple tendril solutions for one withdrawal condition. Including information about the global geometry of the withdrawal flow removes the degeneracy while introducing only a logarithmic dependence on the global flow parameters into the scaling law.

Liquid transport due to light scattering.

Using experiments and theory, we show that light scattering by inhomogeneities in the index of refraction of a fluid can drive a large-scale flow. The experiment uses a near-critical, phase-separated liquid, which experiences large fluctuations in its index of refraction. A laser beam traversing the liquid produces a interface deformation on the scale of the experimental setup and can cause a liquid jet to form. We demonstrate that the deformation is produced by a scattering-induced flow by obtaining good agreements between the measured deformations and those calculated assuming this mechanism.

Breakup of air bubbles in water: memory and breakdown of cylindrical symmetry.

Using high-speed video, we have studied air bubbles detaching from an underwater nozzle. As a bubble distorts, it forms a thin neck which develops a singular shape as it pinches off. As in other singularities, the minimum neck radius scales with the time until the breakup. However, because the air-water interfacial tension does not drive the breakup, even small initial cylindrical asymmetries are preserved throughout the collapse. This novel, nonuniversal singularity retains a memory of the nozzle shape, size, and tilt angle. In the last stages, the air appears to tear instead of pinch.

Drop splashing on a dry smooth surface.

The corona splash due to the impact of a liquid drop on a smooth dry substrate is investigated with high-speed photography. A striking phenomenon is observed: splashing can be completely suppressed by decreasing the pressure of the surrounding gas. The threshold pressure where a splash first occurs is measured as a function of the impact velocity and found to scale with the molecular weight of the gas and the viscosity of the liquid. Both experimental scaling relations support a model in which compressible effects in the gas are responsible for splashing in liquid solid impacts.

Viscous entrainment from a nozzle: singular liquid spouts.

We analyze a long-wavelength model of viscous entrainment from a nozzle and show that, when appropriate large-scale boundary conditions are imposed, the entrainment transition can become continuous. As the entrainment threshold is approached from above, the entrained steady-state spout becomes vanishingly thin compared to the nozzle radius and takes the form of a thin tendril emerging from a base profile whose tip is perfectly conical.

Persistence of memory in drop breakup: the breakdown of universality.

A low-viscosity drop breaking apart inside a viscous fluid is encountered when air bubbles, entrained in thick syrup or honey, rise and break apart. Experiments, simulations, and theory show that the breakup under conditions in which the interior viscosity can be neglected produces an exceptional form of singularity. In contrast to previous studies of drop breakup, universality is violated so that the final shape at breakup retains an imprint of the initial and boundary conditions. A finite interior viscosity, no matter how small, cuts off this form of singularity and produces an unexpectedly long and slender thread. If exterior viscosity is large enough, however, the cutoff does not occur because the minimum drop radius reaches subatomic dimensions first.