The ongoing quest for the first total artificial heart as destination therapy.

Many patients with end-stage heart disease die because of the scarcity of donor hearts. A total artificial heart (TAH), an implantable machine that replaces the heart, has so far been successfully used in over 1,700 patients as a temporary life-saving technology for bridging to heart transplantation. However, after more than six decades of research on TAHs, a TAH that is suitable for destination therapy is not yet available. High complication rates, bulky devices, poor durability, poor biocompatibility and low patient quality of life are some of the major drawbacks of current TAH devices that must be addressed before TAHs can be used as a destination therapy. Quickly emerging innovations in battery technology, wireless energy transmission, biocompatible materials and soft robotics are providing a promising opportunity for TAH development and might help to solve the drawbacks of current TAHs. In this Review, we describe the milestones in the history of TAH research and reflect on lessons learned during TAH development. We summarize the differences in the working mechanisms of these devices, discuss the next generation of TAHs and highlight emerging technologies that will promote TAH development in the coming decade. Finally, we present current challenges and future perspectives for the field.

Does being in the hot seat matter? Effect of passive vs active learning in surgical simulation.

BACKGROUND: Participation in simulation can improve future performance, but it is unclear if observation of simulation scenarios can produce an equivalent benefit. METHODS: First-year surgical residents were exposed to various simulation scenarios in groups of 4 or 5, either through active participation or passive observation. Residents were individually assessed on 3 of the scenarios. Scores were categorized based on resident level of exposure to the scenario and analyzed using a multivariate analysis. RESULTS: 32 residents were enrolled and 28 underwent testing. Previous exposure to the scenario as a participant or observer led to improved performance on medical management and overall performance compared to those who had not been exposed (p < 0.02). However, active participation did not improve performance relative to passive observation (p > 0.1). Previous exposure did not improve communication aspects of the scenarios. CONCLUSION: Analyses confirmed the advantage of simulation-based training, but additionally suggest that the benefits for similar in both active participants and passive observers. This supports the idea of group based simulation training which can be more cost and time efficient.

Google Maps offers a new way to evaluate claudication.

BACKGROUND: Accurate determination of walking capacity is important for the clinical diagnosis and management plan for patients with peripheral arterial disease. The current "gold standard" of measurement is walking distance on a treadmill. However, treadmill testing is not always reflective of the patient's natural walking conditions, and it may not be fully accessible in every vascular clinic. The objective of this study was to determine whether Google Maps, the readily available GPS-based mapping tool, offers an accurate and accessible method of evaluating walking distances in vascular claudication patients. METHODS: Patients presenting to the outpatient vascular surgery clinic between November 2013 and April 2014 at the Ottawa Hospital with vasculogenic calf, buttock, and thigh claudication symptoms were identified and prospectively enrolled in our study. Onset of claudication symptoms and maximal walking distance (MWD) were evaluated using four tools: history; Walking Impairment Questionnaire (WIQ), a validated claudication survey; Google Maps distance calculator (patients were asked to report their daily walking routes on the Google Maps-based tool runningmap.com, and walking distances were calculated accordingly); and treadmill testing for onset of symptoms and MWD, recorded in a double-blinded fashion. RESULTS: Fifteen patients were recruited for the study. Determination of walking distances using Google Maps proved to be more accurate than by both clinical history and WIQ, correlating highly with the gold standard of treadmill testing for both claudication onset (r = .805; P < .001) and MWD (r = .928; P < .0001). In addition, distances were generally under-reported on history and WIQ. The Google Maps tool was also efficient, with reporting times averaging below 4 minutes. CONCLUSIONS: For vascular claudicants with no other walking limitations, Google Maps is a promising new tool that combines the objective strengths of the treadmill test and incorporates real-world walking environments. It offers an accurate, efficient, inexpensive, and readily accessible way to assess walking distances in patients with peripheral vascular disease.

Active Transport of Phosphorylated Carbohydrates Promotes Intestinal Colonization and Transmission of a Bacterial Pathogen.

Efficient acquisition of extracellular nutrients is essential for bacterial pathogenesis, however the identities and mechanisms for transport of many of these substrates remain unclear. Here, we investigate the predicted iron-binding transporter AfuABC and its role in bacterial pathogenesis in vivo. By crystallographic, biophysical and in vivo approaches, we show that AfuABC is in fact a cyclic hexose/heptose-phosphate transporter with high selectivity and specificity for a set of ubiquitous metabolites (glucose-6-phosphate, fructose-6-phosphate and sedoheptulose-7-phosphate). AfuABC is conserved across a wide range of bacterial genera, including the enteric pathogens EHEC O157:H7 and its murine-specific relative Citrobacter rodentium, where it lies adjacent to genes implicated in sugar sensing and acquisition. C. rodentium ΔafuA was significantly impaired in an in vivo murine competitive assay as well as its ability to transmit infection from an afflicted to a naïve murine host. Sugar-phosphates were present in normal and infected intestinal mucus and stool samples, indicating that these metabolites are available within the intestinal lumen for enteric bacteria to import during infection. Our study shows that AfuABC-dependent uptake of sugar-phosphates plays a critical role during enteric bacterial infection and uncovers previously unrecognized roles for these metabolites as important contributors to successful pathogenesis.

Efficacy of targeted therapy for metastatic renal cell carcinoma in the elderly patient population.

INTRODUCTION/BACKGROUND: Targeted therapy has become the mainstay of treatment for mRCC. The efficacy of this therapy in the older population is poorly understood. PATIENTS AND METHODS: Data from patients with mRCC treated with first-line anti-VEGF therapy were collected through the International mRCC Database Consortium from 12 centers. Patient characteristics, data on second-line therapy, and outcomes including treatment duration and overall survival, were evaluated using summary statistics and multivariate analysis. RESULTS: All patients (n = 1381) were treated with front-line targeted therapy; 144 (10%) were 75 years old or older. Six patients (4%) were favorable risk, 99 patients (69%) intermediate risk, and 39 patients (27%) poor risk according to Heng Journal of Clinical Oncology 2009 prognostic factors. The initial treatment for those ≥ 75 years of age was sunitinib (n = 98), sorafenib (n = 35), bevacizumab (n = 7), and AZD217 (n = 4). Twenty-three percent of older patients and 39% of the younger patients went on to receive second-line therapy (P < .0001). The overall response rate, median treatment duration, and overall survival for the older versus younger group were 18% versus 25% (P = .0975), 5.5 months versus 7.5 months (P = .1388), and 16.8 months versus 19.7 months (P = .3321), respectively. When adjusted for poor prognostic factors, age 75 years and older was not found to be associated with poorer overall survival (hazard ratio [HR], 1.002; 95% confidence interval [CI], 0.781-1.285) or shorter treatment duration (HR, 1.018; 95% CI, 0.827-1.252). The retrospective study design was the primary limitation. CONCLUSION: The use of advanced age as a selection criterion for targeted therapy requires further study, with data suggesting no clinically meaningful differences in overall response rate, treatment duration, and overall survival between older and younger age groups.

The role of vicinal tyrosine residues in the function of Haemophilus influenzae ferric-binding protein A.

The periplasmic FbpA (ferric-binding protein A) from Haemophilus influenzae plays a critical role in acquiring iron from host transferrin, shuttling iron from the outer-membrane receptor complex to the inner-membrane transport complex responsible for transporting iron into the cytoplasm. In the present study, we report on the properties of a series of site-directed mutants of two adjacent tyrosine residues involved in iron co-ordination, and demonstrate that, in contrast with mutation of equivalent residues in the N-lobe of human transferrin, the mutant FbpAs retain significant iron-binding affinity regardless of the nature of the replacement amino acid. The Y195A and Y196A FbpAs are not only capable of binding iron, but are proficient in mediating periplasm-to-cytoplasm iron transport in a reconstituted FbpABC pathway in a specialized Escherichia coli reporter strain. This indicates that their inability to mediate iron acquisition from transferrin is due to their inability to compete for iron with receptor-bound transferrin. Wild-type iron-loaded FbpA could be crystalized in a closed or open state depending upon the crystallization conditions. The synergistic phosphate anion was not present in the iron-loaded open form, suggesting that initial anchoring of iron was mediated by the adjacent tyrosine residues and that alternate pathways for iron and anion binding and release may be considered. Collectively, these results demonstrate that the presence of a twin-tyrosine motif common to many periplasmic iron-binding proteins is critical for initially capturing the ferric ion released by the outer-membrane receptor complex.