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.
One of the main scientific goals of the TESS mission is the discovery of transiting small planets around the closest and brightest stars in the sky. Here, using data from the CARMENES, MAROON-X, and ...HIRES spectrographs together with TESS, we report the discovery and mass determination of aplanetary system around the M1.5 V star GJ 806 (TOI-4481). GJ 806 is a bright (
V
≈ 10.8mag,
J
≈ 7.3 mag) and nearby (
d
= 12 pc) M dwarf that hosts at least two planets. The innermost planet, GJ 806 b, is transiting and has an ultra-short orbital period of 0.93 d, a radius of 1.331 ± 0.023
R
⊕
, a mass of 1.90 ± 0.17
M
⊕
, a mean density of 4.40 ± 0.45 g cm
−3
, and an equilibrium temperature of 940 ± 10 K. We detect a second, non-transiting, super-Earth planet in the system, GJ 806 c, with an orbital period of 6.6 d, a minimum mass of 5.80 ± 0.30
M
⊕
, and an equilibrium temperature of 490 ± 5 K. The radial velocity data also shows evidence for a third periodicity at 13.6 d, although the current dataset does not provide sufficient evidence to unambiguously distinguish between a third super-Earth mass (
M
sin
i
= 8.50 ± 0.45
M
⊕
) planet or stellar activity. Additionally, we report one transit observation of GJ 806 b taken with CARMENES in search of a possible extended atmosphere of H or He, but we can only place upper limits to its existence. This is not surprising as our evolutionary models support the idea that any possible primordial H/He atmosphere that GJ 806 b might have had would be long lost. However, the bulk density of GJ 806 b makes it likely that the planet hosts some type of volatile atmosphere. With transmission spectroscopy metrics (TSM) of 44 and emission spectroscopy metrics (ESM) of 24, GJ 806 b is to date the third-ranked terrestrial planet around an M dwarf suitable for transmission spectroscopy studies using JWST, and the most promising terrestrial planet for emission spectroscopy studies. GJ 806b is also an excellent target for the detection of radio emission via star-planet interactions.
Implant-associated osteomyelitis is a chronic infection that complicates orthopaedic surgeries. Once infected, 50 % of patients suffer treatment failure, resulting in high healthcare costs. While ...various small animal models have been developed to investigate the efficacy of prophylactic and therapeutic treatments, the minute scale of murine-model bone and hardware has been prohibitive for evaluating interventions with a complete implant exchange in the setting of an infected critical defect. To address this, the aim of the present study was to develop a murine femur model in which an initial mid-diaphyseal infection was established by surgical implantation of a titanium screw contaminated with bioluminescent Staphylococcus aureus (Xen36). 7 d after the infection was established, an ostectomy was performed to remove the middle segment (3 mm flanking the infected screw hole) and a bone-cement spacer, with or without impregnated gentamicin, was secured with a plate and screws to fix the septic segmental defect. Longitudinal bioluminescent imaging revealed a significant decrease in Xen36 growth following one-stage revision, with the antibiotic-impregnated spacer treated systemically with vancomycin (p < 0.05). This result was corroborated by a significant decrease in colony forming units (CFU) recovered from spacer, bone, soft tissue and hardware 12 d post-operative (p < 0.05). However, ~ 105 CFU/g Xen36 still persisted within the bone despite a clinical therapeutic regimen. Therefore, the model enables the investigation of new therapeutic strategies to improve upon the current standard of care in a mouse model of implant-associated osteomyelitis that employs reconstruction of a critical defect.
ABSTRACT
We report the discovery of two mini-Neptunes in near 2:1 resonance orbits (P = 7.610303 d for HIP 113103 b and P = 14.245651 d for HIP 113103 c) around the adolescent K-star HIP 113103 (TIC ...121490076). The planet system was first identified from the TESS mission, and was confirmed via additional photometric and spectroscopic observations, including a ∼17.5 h observation for the transits of both planets using ESA CHEOPS. We place ≤4.5 min and ≤2.5 min limits on the absence of transit timing variations over the 3 yr photometric baseline, allowing further constraints on the orbital eccentricities of the system beyond that available from the photometric transit duration alone. With a planetary radius of Rp = $1.829_{-0.067}^{+0.096}$ R⊕, HIP 113103 b resides within the radius gap, and this might provide invaluable information on the formation disparities between super-Earths and mini-Neptunes. Given the larger radius Rp = $2.40_{-0.08}^{+0.10}$ R⊕ for HIP 113103 c, and close proximity of both planets to HIP 113103, it is likely that HIP 113103 b might have lost (or is still losing) its primordial atmosphere. We therefore present simulated atmospheric transmission spectra of both planets using JWST, HST, and Twinkle. It demonstrates a potential metallicity difference (due to differences in their evolution) would be a challenge to detect if the atmospheres are in chemical equilibrium. As one of the brightest multi sub-Neptune planet systems suitable for atmosphere follow up, HIP 113103 b and HIP 113103 c could provide insight on planetary evolution for the sub-Neptune K-star population.
Cetuximab plus irinotecan/folinic acid/5-fluorouracil (5-FU) (IF) was evaluated as first-line treatment of patients with advanced gastric cancer and gastroesophageal junction tumors. Preplanned ...analyses of the influence of tumor biomarkers on treatment outcome were carried out.
Patients received weekly cetuximab (400 mg/m2 on day 1, subsequently 250 mg/m2) plus irinotecan (80 mg/m2) and a 24-hour continuous infusion of folinic acid (200 mg/m2) and 5-FU (1500 mg/m2) on days 1, 8, 15, 22, 29 and 36 of a 50-day cycle, until progressive disease (PD).
The most common grade 3/4 toxic effects in 49 patients were diarrhea (15%) and skin toxic effects (14%). In 48 assessable patients, the overall response rate was 46% and disease control rate was 79%. Median progression-free survival (PFS) and overall survival (OS) was 9.0 months 95% confidence interval (CI) 7.1–15.6 and 16.5 months (95% CI 11.7–30.1), respectively. Tumor response was more common than nonresponse in epidermal growth factor receptor-expressing tumors (P = 0.041). Tumor PTEN expression was associated with longer PFS (P = 0.035) and OS (P = 0.0127) than no PTEN expression.
Cetuximab plus IF was well tolerated and efficacy data were encouraging. This treatment combination and the role of selected biomarkers are under investigation in the ongoing phase III EXPAND trial.
Platelets are the key to thrombus formation and play a role in the development of atherosclerosis. Noninvasive imaging of activated platelets would be of great clinical interest. Here, we evaluate ...the ability of a magnetic resonance imaging (MRI) contrast agent consisting of microparticles of iron oxide (MPIOs) and a single-chain antibody targeting ligand-induced binding sites (LIBS) on activated glycoprotein IIb/IIIa to image carotid artery thrombi and atherosclerotic plaques.
Anti-LIBS antibody or control antibody was conjugated to 1-microm MPIOs (LIBS MPIO/control MPIO). Nonocclusive mural thrombi were induced in mice with 6% ferric chloride. MRI (at 9.4 T) was performed once before and repeatedly in 12-minute-long sequences after LIBS MPIO/control MPIO injection. After 36 minutes, a significant signal void, corresponding to MPIO accumulation, was observed with LIBS MPIOs but not control MPIOs (P<0.05). After thrombolysis, in LIBS MPIO-injected mice, the signal void subsided, indicating successful thrombolysis. On histology, the MPIO content of the thrombus, as well as thrombus size, correlated significantly with LIBS MPIO-induced signal void (both P<0.01). After ex vivo incubation of symptomatic human carotid plaques, MRI and histology confirmed binding to areas of platelet adhesion/aggregation for LIBS MPIOs but not for control MPIOs.
LIBS MPIOs allow in vivo MRI of activated platelets with excellent contrast properties and monitoring of thrombolytic therapy. Furthermore, activated platelets were detected on the surface of symptomatic human carotid plaques by ex vivo MRI. This approach represents a novel noninvasive technique allowing the detection and quantification of platelet-containing thrombi.
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