Vemurafenib improves muscle histopathology in a mouse model of LAMA2-related congenital muscular dystrophy.

Laminin-α2-related congenital muscular dystrophy (LAMA2-CMD) is a neuromuscular disease affecting around 1-9 in 1,000,000 children. LAMA2-CMD is caused by mutations in the LAMA2 gene resulting in the loss of laminin-211/221 heterotrimers in skeletal muscle. LAMA2-CMD patients exhibit severe hypotonia and progressive muscle weakness. Currently, there is no effective treatment for LAMA2-CMD and patients die prematurely. The loss of laminin-α2 results in muscle degeneration, defective muscle repair and dysregulation of multiple signaling pathways. Signaling pathways that regulate muscle metabolism, survival and fibrosis have been shown to be dysregulated in LAMA2-CMD. As vemurafenib is a US Food and Drug Administration (FDA)-approved serine/threonine kinase inhibitor, we investigated whether vemurafenib could restore some of the serine/threonine kinase-related signaling pathways and prevent disease progression in the dyW-/- mouse model of LAMA2-CMD. Our results show that vemurafenib reduced muscle fibrosis, increased myofiber size and reduced the percentage of fibers with centrally located nuclei in dyW-/- mouse hindlimbs. These studies show that treatment with vemurafenib restored the TGF-ß/SMAD3 and mTORC1/p70S6K signaling pathways in skeletal muscle. Together, our results indicate that vemurafenib partially improves histopathology but does not improve muscle function in a mouse model of LAMA2-CMD.

Transient ice loss in the Patagonia Icefields during the 2015-2016 El Niño event.

The Patagonia Icefields (PIF) are the largest non-polar ice mass in the southern hemisphere. The icefields cover an area of approximately 16,500 km2 and are divided into the northern and southern icefields, which are ~ 4000 km2 and ~ 12,500 km2, respectively. While both icefields have been losing mass rapidly, their responsiveness to various climate drivers, such as the El Niño-Southern Oscillation, is not well understood. Using the elastic response of the earth to loading changes and continuous GPS data we separated and estimated ice mass changes observed during the strong El Niño that started in 2015 from the complex hydrological interactions occurring around the PIF. During this single event, our mass balance estimates show that the northern icefield lost ~ 28 Gt of mass while the southern icefield lost ~ 12 Gt. This is the largest ice loss event in the PIF observed to date using geodetic data.

A Paradigm Shift in Critical Care Infrastructure in Complex Settings: Evaluating an Ultraportable Operating Room to Improve Field Surgical Safety.

INTRODUCTION: Scarcity of operating rooms and personal protective equipment in far-forward field settings make surgical infections a potential concern for combat mortality and morbidity. Surgical and transport personnel also face infectious risks from bodily fluid exposures. Our study aimed to describe the serial, proof-of-concept testing of the SurgiBox technology: an inflatable sterile environment that addresses the aforementioned problems, fits on gurneys and backpacks, and drapes over incisions. MATERIALS AND METHODS: The SurgiBox environmental control unit and inflatable enclosure were optimized over five generations based on iterative feedback from stakeholders experienced in surgery in austere settings. The airflow system was developed by analytic modeling, verified through in silico modeling in SOLIDWORKS, and confirmed with prototype smoke-trail checking. Particulate counts evaluated the enclosure's ability to control and mitigate users' exposures to potentially infectious contaminants from the surgical field in various settings. SurgiBox enclosures were setup over a mannequin's torso, in a configuration and position for either thoracic or abdominal surgery. A particle counter was serially positioned in sternotomy and laparotomy positions, as well as bilateral flank positions. This setup was repeated with open ports exposing the enclosure to the external environment. To simulate stress scenarios, sampling was repeated with enclosure measurements during an increase in external particulate concentration. RESULTS: The airflow technology effectively kept contaminants away from the incision and maintained a pressure differential to reduce particle entry. Benchtop testing demonstrated that even when ports were opened or the external environment had high contaminant burden, the enclosed surgical field consistently registered 0 particle count in all positions. Time from kit opening to incision averaged 54.5 seconds, with the rate-limiting step being connecting the environmental control unit to the enclosure. The portable kit weighted 5.9 lbs. CONCLUSIONS: Analytic, in silico, and mechanical airflow modeling and benchtop testing have helped to quantify the SurgiBox system's reliability in creating and maintaining an operating room-quality surgical field within the enclosure as well as protecting the surgical team outside the enclosure. More recent and ongoing work has focused on specifying optimal use settings in the casualty chain of care, expanding support for circumferential procedures, automating airflow control, and accelerating system setup. SurgiBox's ultimate goal is to take timely, safe surgery to patients in even the most austere of settings.

Frameless Stereotactic Navigation during Insular Glioma Resection using Fusion of Three-Dimensional Rotational Angiography and Magnetic Resonance Imaging.

BACKGROUND: Perioperative cerebral infarction is a potential complication of glioma resection, of which insular tumors are at higher risk because of the proximity of middle cerebral artery branches, including the lateral lenticulostriates and long insular arteries. In this study, 3 patients received three-dimensional rotational angiography, which was fused with magnetic resonance imaging (MRI) for frameless stereotactic navigation during dominant-hemisphere insular glioma resection. METHODS: All patients obtained a preoperative catheter angiogram with a three-dimensional rotational acquisition of the ipsilateral internal carotid artery. The pixel-based axial three-dimensional angiography data, thin-cut structural MRI, tractography from diffusion tensor imaging, and expressive language activation from functional MRI were uploaded into the iPlan software (Brainlab, Heimstetten, Germany) and fused. The target tumor, regional blood vessels, adjacent functional areas, and their associated fiber tracts were segmented and overlaid on the appropriate MRI sequence. This image fusion was used preoperatively to visualize the relationship of the mass with the adjacent vasculature and intraoperatively for frameless stereotactic navigation to optimize preservation of arterial structures. RESULTS: Three patients aged 27-60 years with excellent baseline functional status presented with seizures and were found to have a large dominant-hemisphere T2 hyperintense nonenhancing insular mass. Surgical resection was performed using multimodality neuronavigation. None sustained a postoperative arterial infarction or a perioperative neurologic deficit. CONCLUSIONS: Neuronavigation using a fusion of three-dimensional rotational angiography with MRI is a technique that can be used for preoperative planning and during resection of insular gliomas to optimize preservation of adjacent arteries.

Illuminating subduction zone rheological properties in the wake of a giant earthquake.

Deformation associated with plate convergence at subduction zones is accommodated by a complex system involving fault slip and viscoelastic flow. These processes have proven difficult to disentangle. The 2010 M w 8.8 Maule earthquake occurred close to the Chilean coast within a dense network of continuously recording Global Positioning System stations, which provide a comprehensive history of surface strain. We use these data to assemble a detailed picture of a structurally controlled megathrust fault frictional patchwork and the three-dimensional rheological and time-dependent viscosity structure of the lower crust and upper mantle, all of which control the relative importance of afterslip and viscoelastic relaxation during postseismic deformation. These results enhance our understanding of subduction dynamics including the interplay of localized and distributed deformation during the subduction zone earthquake cycle.

Observed rapid bedrock uplift in Amundsen Sea Embayment promotes ice-sheet stability.

The marine portion of the West Antarctic Ice Sheet (WAIS) in the Amundsen Sea Embayment (ASE) accounts for one-fourth of the cryospheric contribution to global sea-level rise and is vulnerable to catastrophic collapse. The bedrock response to ice mass loss, glacial isostatic adjustment (GIA), was thought to occur on a time scale of 10,000 years. We used new GPS measurements, which show a rapid (41 millimeters per year) uplift of the ASE, to estimate the viscosity of the mantle underneath. We found a much lower viscosity (4 × 1018 pascal-second) than global average, and this shortens the GIA response time scale from tens to hundreds of years. Our finding requires an upward revision of ice mass loss from gravity data of 10% and increases the potential stability of the WAIS against catastrophic collapse.

Factors influencing particle number concentrations, size distributions and modal parameters at a roof-level and roadside site in Leicester, UK.

Measurements of urban particle number concentrations and size distributions in the range 5-1000 nm were taken at elevated (roof-level) and roadside sampling sites on Narborough Road in Leicester, UK, along with simultaneous measurements of traffic, NO(x), CO and 1,3-butadiene concentrations and meteorological parameters. A fitting program was used to determine the characteristics of up to five modal groups present in the particle size distributions. All particle modal concentrations peaked during the morning and evening rush hours. Additional events associated with the smallest mode, that were not observed to be connected to primary emissions, were also present suggesting that this mode consisted of newly formed secondary particles. These events included peaks in concentration which coincided with peaks in solar radiation, and lower concentrations of the larger modes. Investigation into the relationships between traffic flow and occupancy indicated three flow regimes; free-flow, unstable and congested. During free-flow conditions, positive linear relationships existed between traffic flow and particle modal number concentrations. However, during unstable and congested periods, this relationship was shown to break-down. Similar trends were observed for concentrations of the gas phase pollutants NO(x), CO and 1,3-butadiene. Strong linear relationships existed between NO(x), CO, 1,3-butadiene concentrations, nucleation and Aitken mode concentrations at both sampling locations, indicating a local traffic related emission source. At the roadside, both nucleation and Aitken mode are best represented by a decreasing exponential function with wind speed, whereas at the roof-level this relationship only occurred for Aitken mode particles. The differing relationships at the two sampling locations are most likely due to a combination of meteorological factors and distance from the local emission source.

Prognostic Significance of Surgical Margin Size After Neoadjuvant FOLFOX and/or FOLFIRI for Colorectal Liver Metastases.

PURPOSE: Optimal margin size when resecting colorectal liver metastases (CRLM) remains unclear, particularly in the setting of perioperative chemotherapy. We evaluated the prognostic significance of margin size in patients who received neoadjuvant FOLFOX and/or FOLFIRI prior to resection of CRLM. METHODS: Clinicopathologic factors were collected for patients who underwent curative liver resections for CRLM between 4/2004-1/2016 and received neoadjuvant oxaliplatin and/or irinotecan and 5-FU (FOLFOX, FOLFIRI). Margins were categorized as < 1, ≥ 1-< 5, ≥ 5-< 10, or ≥ 10 mm and evaluated for association with overall survival (OS) and disease-free survival (DFS) by Cox multiple regression analysis. Margin status was classified as positive (< 1 mm) or negative (≥ 1 mm) and similarly evaluated. RESULTS: Of 227 patients, the median age was 58 years and most had synchronous (80%) lesions. The majority had colon cancers (75%). Margin sizes were 13% < 1 mm, 27% ≥ 1-< 5 mm, 23% ≥ 5-< 10 mm, 36% ≥ 10 mm. Most (63%) received chemotherapy post-liver resection. Five-year OS and DFS were 54% (95% CI 46-62%) and 22% (95% CI 16-28%), respectively. Positive margins significantly increased the risk of death without post-liver resection chemotherapy (HR = 3.32, p = 0.0077), but not with post-liver resection chemotherapy (HR = 1.00, p = 0.99). Negative margin sizes of ≥ 1-< 5, ≥ 5-< 10, and ≥ 10 mm were not significant predictors of OS (p > 0.05). CONCLUSION: Patients undergoing liver resection for CRLM should receive post-resection chemotherapy if negative margins (≥ 1 mm) cannot be achieved. For patients receiving FOLFOX and/or FOLFIRI chemotherapy, wider margins did not improve OS.

Polymer Chain Behavior in Polymer Nanocomposites with Attractive Interactions.

Chain behavior has been determined in polymer nanocomposites (PNCs) comprised of well-dispersed 12 nm diameter silica nanoparticles (NPs) in poly(methyl methacrylate) (PMMA) matrices by Small-Angle Neutron Scattering (SANS) measurements under the Zero Average Contrast (ZAC) condition. In particular, we directly characterize the bound polymer layer surrounding the NPs, revealing the bound layer profile. The SANS spectra in the high-q region also show no significant change in the bulk polymer radius of gyration on the addition of the NPs. We thus suggest that the bulk polymer conformation in PNCs should generally be determined using the high q region of SANS data.

Does It Cost More to Train Residents or to Replace Them?: A Look at the Costs and Benefits of Operating Graduate Medical Education Programs.

The policy issue underlying this study is whether Medicare support for graduate medical education (GME) should be restructured to differentiate between programs that are less costly or are self-sustaining and those that are more costly to the sponsoring institution and its educational partners. The authors used available literature, interviews with individuals involved in operating GME programs, and analysis of administrative data to explore how the financial impact of operating residency training programs might differ by specialty. The study does not quantify the variation in financial impact, but it provides a framework for examining both the costs and benefits of operating GME programs to the sponsoring institution and its educational partners. It also identifies the major factors that are likely to affect financial performance and influence program offerings and size. Marginal financial impacts are more likely to influence sponsor decisions on changes in GME program size and offerings and help explain why GME program expansions are occurring without additional Medicare funding. If the hospital has service needs, there is a marginal benefit to adding a resident, particularly in the more-lucrative specialty and subspecialty programs, before considering the additional benefits of any Medicare GME-related revenues.