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Clinical studies comparing vancomycin with alternative therapy for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia are limited. The objective of this study was to compare outcomes of early daptomycin versus vancomycin treatment for MRSA bacteremia with high vancomycin MICs in a geographically diverse multicenter evaluation. This nationwide, retrospective, multicenter (N = 11), matched, cohort study compared outcomes of early daptomycin with vancomycin for MRSA bloodstream infection (BSI) with vancomycin MICs 1.5 to 2 µg/mL. Matching variables, based on propensity regression analysis, included age, intensive care unit (ICU), and type of BSI. Outcomes were as follows: (1) composite failure (60-day all-cause mortality, 7-day clinical or microbiologic failure, 30-day BSI relapse, or end-of-treatment failure (EOT; discontinue/change daptomycin or vancomycin because of treatment failure or adverse event]); (2) nephrotoxicity; and (2) day 4 BSI clearance. A total of 170 patients were included. The median (interquartile range) age was 60 years (50–74); the median (range) Acute Physiology and Chronic Health Evaluation II score was 15 (10–18); 31% were in an ICU; and 92% had an infectious disease consultation. BSI types included endocarditis/endovascular (39%), extravascular (55%), and central catheter (6%). The median daptomycin dose was 6 mg/kg, and the vancomycin trough level was 17 mg/L. Overall composite failure was 35% (59 of 170): 15% due to 60-day all-cause mortality, 14% for lack of clinical or microbiologic response by 7 days, and 17% due to failure at end of therapy (discontinue/change because of treatment failure or adverse event). Predictors of composite failure according to multivariate analysis were age >60 years (odds ratio, 3.7; P < 0.01) and ICU stay (odds ratio, 2.64; P = 0.03). Notable differences between treatment groups were seen with: (1) end of therapy failure rates (11% vs 24% for daptomycin vs vancomycin; P = 0.025); (2) acute kidney injury rates (9% vs 23% for daptomycin vs vancomycin; P = 0.043); and (3) day 4 bacteremia clearance rates for immunocompromised patients (n = 26) (94% vs 56% for daptomycin vs vancomycin; P = 0.035). Results from this multicenter study provide, for the first time, a geographically diverse evaluation of daptomycin versus vancomycin for patients with vancomycin-susceptible MRSA bacteremia with vancomycin MIC values >1 µg/mL. Although the overall composite failure rates did not differ between the vancomycin and daptomycin groups when intensively matched according to risks for failure, the rates of acute kidney injury were significantly lower in the daptomycin group. These findings suggest that daptomycin is a useful therapy for clinicians treating patients who have MRSA bacteremia. Prospective, randomized trials should be conducted to better assess the potential significance of elevated vancomycin MIC.

Hearing loss is a serious illness affecting people’s normal life enormously. The acoustic properties of a tympanic membrane play an important role in hearing, and highly depend on its geometry, composition, microstructure and connection to the surrounding annulus. While the conical geometry of the tympanic membrane is critical to the sound propagation in the auditory system, it presents significant challenges to the study of the 3D microstructure of the tympanic membrane using traditional 2D imaging techniques. To date, most of our knowledge about the 3D microstructure and composition of tympanic membranes is built from 2D microscopic studies, which precludes an accurate understanding of the 3D microstructure, acoustic behaviors and biology of the tissue. Although the tympanic membrane has been reported to contain elastic fibers, the morphological characteristic of the elastic fibers and the spatial arrangement of the elastic fibers with the predominant collagen fibers have not been shown in images. We have developed a 3D imaging technique for the three-dimensional examination of the microstructure of the full thickness of the tympanic membranes in mice without requiring tissue dehydration and stain. We have also used this imaging technique to study the 3D arrangement of the collagen and elastic fibrillar network with the capillaries and cells in the pars tensa-annulus unit at a status close to the native. The most striking findings in the study are the discovery of the 3D form of the elastic and collagen network, and the close spatial relationships between the elastic fibers and the elongated fibroblasts in the tympanic membranes. The 3D imaging technique has enabled to show the 3D waveform contour of the collagen and elastic scaffold in the conical tympanic membrane. Given the close relationship among the acoustic properties, composition, 3D microstructure and geometry of tympanic membranes, the findings may advance the understanding of the structure—acoustic functionality of the tympanic membrane. The knowledge will also be very helpful in the development of advanced cellular therapeutic technologies and 3D printing techniques to restore damaged tympanic membranes to a status close to the native.

Cardiomyocyte ploidy has been described but remains obscure in cardiac interstitial cells. Ploidy of c-kit+ cardiac interstitial cells was assessed using confocal, karyotypic, and flow cytometric technique. Notable differences were found between rodent (rat, mouse) c-kit+ cardiac interstitial cells possessing mononuclear tetraploid (4n) content, compared to large mammals (human, swine) with mononuclear diploid (2n) content. In-situ analysis, confirmed with fresh isolates, revealed diploid content in human c-kit+ cardiac interstitial cells and a mixture of diploid and tetraploid content in mouse. Downregulation of the p53 signaling pathway provides evidence why rodent, but not human, c-kit+ cardiac interstitial cells escape replicative senescence. Single cell transcriptional profiling reveals distinctions between diploid versus tetraploid populations in mouse c-kit+ cardiac interstitial cells, alluding to functional divergences. Collectively, these data reveal notable species-specific biological differences in c-kit+ cardiac interstitial cells, which could account for challenges in extrapolation of myocardial from preclinical studies to clinical trials. Broughton et al. report differences between rodent and large mammals with respect to ploidy of the cardiac interstitial cell population. These species-specific differences in ploidy of cardiac interstitial cells suggest potential challenges in extrapolating myocardial preclinical studies from rodent to large mammals.

One possible cause of patellofemoral pain syndrome is excessive lateral force acting on the patella. Although several treatment methods focus on decreasing the lateral force acting on the patella, the relationship between the lateral force and the patellofemoral contact pressure distribution is unclear. A computational model has been developed to determine how loading variations alter the patellofemoral force and pressure distributions for individual knees. The model allows variation in the quadriceps and patella tendon forces, and calculates the predicted contact pressure distribution using the discrete element analysis technique. To characterize the accuracy of the model, four cadaver knees were flexed on a knee simulator with three initial Q-angles, while recording the force and pressure distributions with a pressure sensor. A model of each knee was created from CT data. Using the external force applied to the knee, the geometry of the knee, and the quadriceps origin as input, the pressure distribution was calculated during flexion. Similar trends were noted for the computational and experimental results. The percentage of the total force applied to the lateral cartilage increased with the Q-angle. The maximum contact pressure increased during flexion. The maximum lateral contact pressure increased with the Q-angle for three knees. For the other knee, increasing the Q-angle decreased the maximum lateral pressure. The maximum medial contact pressure decreased as the Q-angle increased. By characterizing the influence of patellofemoral loading on the force and pressure distributions, the computational model could be used to evaluate treatment methods prescribed for patellofemoral pain.

In our backyard by the river surrounded by copper tubs, brimming with tanning soup, brewed from bloodwood and wild-apple bark.

Purpose Optical coherence tomography (OCT) is an emerging imaging modality which is non-invasive, can be employed in vivo, and can record both anatomy and vibrations. The purpose here is to explore the application of finite-element (FE) modelling to OCT data. Methods We recorded vibrations for three human cadaver middle ears using OCT. We also have X-ray microCT images from the same ears. Three FE models were built based on geometries obtained from the microCT images. The material properties and boundary conditions of the models were obtained from previously reported studies. Results Tympanic-membrane (TM) vibration patterns were computed for the three models and compared with the patterns measured using OCT. Frequency responses were also computed for all three models for several locations in the middle ear and compared with the OCT displacements and with the literature. The three models were compared with each other in terms of geometry and function. Parameter sensitivity analyses were done and the results were compared among the models and with the literature. The simulated TM displacement patterns are qualitatively similar to the OCT results. The simulated displacements are closer to the OCT results for 500 Hz and 1 kHz but the differences are greater at 2 kHz. Conclusion This study provides an initial look at the combined use of OCT measurements and FE modelling based on subject-specific anatomy. The geometries and parameters of the existing FE models could be modified for individual patients in the future to help identify abnormalities in the middle ear.

Advancement of stem cell-based treatment will involve next-generation approaches to enhance therapeutic efficacy which is often modest, particularly in the context of myocardial regenerative therapy. Our group has previously demonstrated the beneficial effect of genetic modification of cardiac stem cells with Pim-1 kinase overexpression to rejuvenate aged cells as well as potentiate myocardial repair. Despite these encouraging findings, concerns were raised regarding potential for oncogenic risk associated with Pim-1 kinase overexpression. Testing of Pim-1 engineered c-kit+ cardiac interstitial cells (cCIC) derived from heart failure patient samples for indices of oncogenic risk was undertaken using multiple assessments including soft agar colony formation, micronucleation, gamma-Histone 2AX foci, and transcriptome profiling. Collectively, findings demonstrate comparable phenotypic and biological properties of cCIC following Pim-1 overexpression compared with using baseline control cells with no evidence for oncogenic phenotype. Using a highly selective and continuous sensor for quantitative assessment of PIM1 kinase activity revealed a sevenfold increase in Pim-1 engineered vs. control cells. Kinase activity profiling using a panel of sensors for other kinases demonstrates elevation of IKKs), AKT/SGK, CDK1-3, p38, and ERK1/2 in addition to Pim-1 consistent with heightened kinase activity correlating with Pim-1 overexpression that may contribute to Pim-1-mediated effects. Enhancement of cellular survival, proliferation, and other beneficial properties to augment stem cell-mediated repair without oncogenic risk is a feasible, logical, and safe approach to improve efficacy and overcome current limitations inherent to cellular adoptive transfer therapeutic interventions.

BackgroundSplit transfers of the tibialis anterior and posterior tendons are commonly performed to address hindfoot varus deformities in patients with cerebral palsy, stroke, or brain injury. Poor outcomes from these procedures are often attributed to a failure to tension the transferred tendon properly, but the mechanical effects of this aspect of the procedure have not been quantified, to our knowledge. The purpose of the present study was to use a cadaver model to examine changes in the actions of these muscles that occur when the tensions in the halves of the split tendon are intentionally balanced or unbalanced to varying degrees.MethodsTendon excursion was measured in seven cadaveric specimens before and after split tendon transfer with experimentally controlled tensions in the halves of the split tendon. The muscle moment arm, a quantitative indicator of the action of a muscle about a joint axis, was calculated as the derivative of tendon excursion with respect to the subtalar joint angle.ResultsThe tibialis anterior had an eversion moment arm with the subtalar joint in a neutral position following surgery, but the tibialis posterior had virtually no action in the neutral position. Following the split transfers with ideally balanced tension, subtalar joint rotations of >5° strongly influenced the moment arm of the tibialis posterior (p < 0.0002), indicating that its action depends on the position of the hindfoot. The moment arm of the tibialis anterior, however, was influenced only by rotations of ≥20° (p > 0.1741 for each angle pair comparison of <20°). Moment arms were generally insensitive to imbalances in tension between the medial and lateral tendon halves; significant differences in the moment arm (p < 0.05), compared with that in the balanced condition, were seen only when one half was slack or nearly so.ConclusionsThese results suggest that it is possible for a split tendon transfer to be successful over a large range of tensionings. Split transfer of the tibialis posterior tendon produced the desired mechanical outcome in that the tibialis posterior had an eversion moment arm when the foot was inverted and an inversion moment arm when the foot was everted. Split transfer of the tibialis anterior to the cuboid, however, produced a muscle that consistently functioned as an everter regardless of the position of the hindfoot.Clinical RelevanceResidual varus and overcorrection following a split tendon transfer are often attributed to technical errors in balancing the tension between the medial and lateral tendon halves. The findings of the present study, however, suggest that such surgical failures are likely caused by only the largest of imbalances in tendon tension.

Hearing remains the only human sense that can be restored if damaged.Thus, cochlear implants and other implantable hearing mechanisms have become more prevalent solutions to modern-day hearing trauma, making it imperative for clinicians to gain expertise on the subject.

A poem is presented.