Surgical implant-associated bone infections (osteomyelitis) have severe clinical and socioeconomic consequences. Treatment of chronic bone infections often involves antibiotics given systemically and ...locally to the affected site in poly (methyl methacrylate) (PMMA) bone cement. Given the high antibiotic concentrations required to affect bacteria in biofilm, local delivery is important to achieve high doses at the infection site. PMMA is not suitable to locally-deliver some biofilm-specific antibiotics, including rifampin, due to interference with PMMA polymerisation. To examine the efficacy of localised, combinational antibiotic delivery compared to PMMA standards, we fabricated rifampin- and vancomycin-laden calcium phosphate scaffolds (CPS) by three-dimensional (3D) printing to treat an implant-associated Staphylococcus aureus bone infection in a murine model. All vancomycin- and rifampin-laden CPS treatments significantly reduced the bacterial burden compared with vancomycin-laden PMMA. The bones were bacteria culture negative in 50 % of the mice that received sustained release vancomycin- and rifampin-laden CPS. In contrast, 100 % of the bones treated with vancomycin monotherapy using PMMA or CPS were culture positive. Yet, the monotherapy CPS significantly reduced the bacterial metabolic load following revision compared to PMMA. Biofilm persisted on the fixation hardware, but the infection-induced bone destruction was significantly reduced by local rifampin delivery. These data demonstrate that, despite the challenging implant-retaining infection model, co-delivery of rifampin and vancomycin from 3D printed CPS, which is not possible with PMMA, significantly improved the outcomes of implant-associated osteomyelitis. However, biofilm persistence on the fixation hardware reaffirms the importance of implant exchange or other biofilm eradication strategies to complement local antibiotics.
Staphylococcus aureus (S. aureus) osteomyelitis is a significant complication for orthopaedic patients undergoing surgery, particularly with fracture fixation and arthroplasty. Given the difficulty ...in studying S. aureus infections in human subjects, animal models serve an integral role in exploring the pathogenesis of osteomyelitis, and aid in determining the efficacy of prophylactic and therapeutic treatments. Animal models should mimic the clinical scenarios seen in patients as closely as possible to permit the experimental results to be translated to the corresponding clinical care. To help understand existing animal models of S. aureus, we conducted a systematic search of PubMed and Ovid MEDLINE to identify in vivo animal experiments that have investigated the management of S. aureus osteomyelitis in the context of fractures and metallic implants. In this review, experimental studies are categorised by animal species and are further classified by the setting of the infection. Study methods are summarised and the relevant advantages and disadvantages of each species and model are discussed. While no ideal animal model exists, the understanding of a model's strengths and limitations should assist clinicians and researchers to appropriately select an animal model to translate the conclusions to the clinical setting.
Staphylococcus aureus (S. aureus) osteomyelitis remains a major clinical problem. Anti-glucosaminidase (Gmd) antibodies (1C11) are efficacious in prophylactic and therapeutic murine models. ...Feasibility, safety and pharmacokinetics of 1C11 passive immunisation in sheep and endogenous anti-Gmd levels were quantified in osteomyelitis patients. 3 sheep received a 500 mg intravenous (i.v.) bolus of 1C11 and its levels in sera were determined by enzyme-linked immunosorbent assay (ELISA) over 52 d. A humanised anti-Gmd monoclonal antibody, made by grafting the antigen-binding fragment (Fab) portion of 1C11 onto the fragment crystallisable region (Fc) of human IgG1, was used to make a standard curve of mean fluorescent intensity versus concentration of anti-Gmd. Anti-Gmd serum levels were determined in 297 patients with culture-confirmed S. aureus osteomyelitis and 40 healthy controls. No complications or adverse events were associated with the sheep 1C11 i.v. infusion and the estimated circulating half-life of 1C11 was 23.7 d. Endogenous anti-Gmd antibody levels in sera of osteomyelitis patients ranged from < 1 ng/mL to 300 µg/mL, with a mean concentration of 21.7 µg/mL. The estimated circulating half-life of endogenous anti-Gmd antibodies in sera of 12 patients with cured osteomyelitis was 120.4 d. A clinically relevant administration of anti-Gmd (500 mg i.v. = 7 mg/kg/70 kg human) was safe in sheep. This dose was 8 times more than the endogenous anti-Gmd levels observed in osteomyelitis patients and was predicted to have a half-life of > 3 weeks. Anti-Gmd passive immunisation has potential to prevent and treat S. aureus osteomyelitis. Further clinical development is warranted.
Data collated from around the world indicate that, for every tonne of shoot dry matter produced by crop legumes, the symbiotic relationship with rhizobia is responsible for fixing, on average on a ...whole plant basis (shoots and nodulated roots), the equivalent of 30–40 kg of nitrogen (N). Consequently, factors that directly influence legume growth (e.g. water and nutrient availability, disease incidence and pests) tend to be the main determinants of the amounts of N
2
fixed. However, practices that either limit the presence of effective rhizobia in the soil (no inoculation, poor inoculant quality), increase soil concentrations of nitrate (excessive tillage, extended fallows, fertilizer N), or enhance competition for soil mineral N (intercropping legumes with cereals) can also be critical. Much of the N
2
fixed by the legume is usually removed at harvest in high-protein seed so that the net residual contributions of fixed N to agricultural soils after the harvest of legumegrain may be relatively small.Nonetheless, the inclusion of legumes in a cropping sequence generally improves the productivity of following crops. Whilesome of these rotational effects may be associated with improvements in availability of N in soils, factors unrelated to N also play an important role. Recent results suggest that one such non-N benefit may be due to the impact on soil biology of hydrogenemitted from nodules as a by-product of N
2
, fixation.
We present the first experimental realization and characterization of two-dimensional Skyrmions and half-Skyrmions in a spin-2 Bose-Einstein condensate. The continuous rotation of the local spin of ...the Skyrmion through an angle of pi (and half-Skyrmion through an angle of pi/2) across the cloud is confirmed by the spatial distribution of the three spin states as parametrized by the bending angle of the l vector. The winding number w = (0,1,2) of the internal spin states comprising the Skyrmions is confirmed through matter-wave interference.
We report on analysis of timing and spectroscopy of the Vela pulsar using eleven months of observations with the Large Area Telescope on the Fermi Gamma-Ray Space Telescope. The intrinsic brightness ...of Vela at GeV energies combined with the angular resolution and sensitivity of the LAT allow us to make the most detailed study to date of the energy-dependent light curves and phase-resolved spectra, using a LAT-derived timing model. The light curve consists of two peaks (P1 and P2) connected by bridge emission containing a third peak (P3). We have confirmed the strong decrease of the P1/P2 ratio with increasing energy seen with EGRET and previous Fermi LAT data, and observe that P1 disappears above 20 GeV. The increase with energy of the mean phase of the P3 component can be followed with much greater detail, showing that P3 and P2 are present up to the highest energies of pulsation. We find significant pulsed emission at phases outside the main profile, indicating that magnetospheric emission exists over 80% of the pulsar period. With increased high-energy counts the phase-averaged spectrum is seen to depart from a power- law with simple exponential cutoff, and is better fit with a more gradual cutoff. The spectra in fixed-count phase bins are well fit with power-laws with exponential cutoffs, revealing a strong and complex phase dependence of the cutoff energy, especially in the peaks. By combining these results with predictions of the outer magnetosphere models that map emission characteristics to phase, it will be possible to probe the particle acceleration and the structure of the pulsar magnetosphere with unprecedented detail.
We use Raman-detuned laser pulses to achieve spatially varying control of the amplitude and phase of the spinor order parameter of a Bose-Einstein condensate. We present experimental results ...confirming precise radial and azimuthal control of amplitude and phase during the creation of vortex-antivortex superposition states.
The charge-conjugation and parity-reversal (CP) symmetry of fundamental particles is a symmetry between matter and antimatter. Violation of this CP symmetry was first observed in 1964
, and CP ...violation in the weak interactions of quarks was soon established
. Sakharov proposed
that CP violation is necessary to explain the observed imbalance of matter and antimatter abundance in the Universe. However, CP violation in quarks is too small to support this explanation. So far, CP violation has not been observed in non-quark elementary particle systems. It has been shown that CP violation in leptons could generate the matter-antimatter disparity through a process called leptogenesis
. Leptonic mixing, which appears in the standard model's charged current interactions
, provides a potential source of CP violation through a complex phase δ
, which is required by some theoretical models of leptogenesis
. This CP violation can be measured in muon neutrino to electron neutrino oscillations and the corresponding antineutrino oscillations, which are experimentally accessible using accelerator-produced beams as established by the Tokai-to-Kamioka (T2K) and NOvA experiments
. Until now, the value of δ
has not been substantially constrained by neutrino oscillation experiments. Here we report a measurement using long-baseline neutrino and antineutrino oscillations observed by the T2K experiment that shows a large increase in the neutrino oscillation probability, excluding values of δ
that result in a large increase in the observed antineutrino oscillation probability at three standard deviations (3σ). The 3σ confidence interval for δ
, which is cyclic and repeats every 2π, is -3.41, -0.03 for the so-called normal mass ordering and -2.54, -0.32 for the inverted mass ordering. Our results indicate CP violation in leptons and our method enables sensitive searches for matter-antimatter asymmetry in neutrino oscillations using accelerator-produced neutrino beams. Future measurements with larger datasets will test whether leptonic CP violation is larger than the CP violation in quarks.
We have measured the spin structure functions g2p and g2d and the virtual photon asymmetries A2p and A2d over the kinematic range 0.02⩽x⩽0.8 and 0.7⩽Q2⩽20GeV2 by scattering 29.1 and 32.3 GeV ...longitudinally polarized electrons from transversely polarized NH3 and 6LiD targets. Our measured g2 approximately follows the twist-2 Wandzura–Wilczek calculation. The twist-3 reduced matrix elements d2p and d2n are less than two standard deviations from zero. The data are inconsistent with the Burkhardt–Cottingham sum rule if there is no pathological behavior as x→0. The Efremov–Leader–Teryaev integral is consistent with zero within our measured kinematic range. The absolute value of A2 is significantly smaller than the A2<R(1+A1)/2 limit.
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