Congestion at Locks on Inland Waterways: An Experimental Testbed of a Policy of Tradable Priority Permits for Lock Access

This research is focused on the problem of congestion at locks on the inland waterways of the United States, and particularly on the Mississippi and Illinois Rivers. The current policy of first-come-first-served exacerbates the problem and adds to delays and inefficiency. An alternative policy of marketable priority access permits is proposed and studied. The dimensions of the policy relative to the needs of operators are discussed. Well established economic theory suggests that the system of marketable priority permits will increase the economic efficiency with which locks operate and that by the endowing of current operators with these permits will increase their profitability. A testbed experiment was conducted to illustrate how the principles operate. The policy objective of increased efficiency is observed thereby establishing proof of principle. More importantly, the policy works according to all of the many predictions that theory holds thereby establishing design consistency. Not only is the value of system use increased, prices converge to the competitive levels, the removal of delay for certain classes of permits transforms system use to higher valued activities and operator profitability is increased. In the testbed, the policy produces the desired outcomes and it does so for understandable reasons

Generic protease detection technology for monitoring periodontal disease

Periodontal diseases are inflammatory conditions that affect the supporting tissues of teeth and can lead to destruction of the bone support and ultimately tooth loss if untreated. Progression of periodontitis is usually site specific but not uniform, and currently there are no accurate clinical methods for distinguishing sites where there is active disease progression from sites that are quiescent. Consequently, unnecessary and costly treatment of periodontal sites that are not progressing may occur. Three proteases have been identified as suitable markers for distinguishing sites with active disease progression and quiescent sites: human neutrophil elastase, cathepsin G and MMP8. Generic sensor materials for the detection of these three proteases have been developed based on thin dextran hydrogel films cross-linked with peptides. Degradation of the hydrogel films was monitored using impedance measurements. The target proteases were detected in the clinically relevant range within a time frame of 3 min. Good specificity for different proteases was achieved by choosing appropriate peptide cross-linkers.<br/

Climate\u27s Role in Polar Bear Past [Letters]

Striking temporal concordance between the new date for divergence of polar bears and persistent freezing of the Arctic Ocean suggests that this may be one of relatively few instances in which a specific paleoclimatological episode can be convincingly linked to a specific evolutionary event, and it provides vivid demonstration of climatic forcing as a determinant of diversification in biological systems

Generic Utilization Rates, Real Pharmaceutical Prices, and Research and Development Expenditures

Generic utilization rates have risen substantially since the enactment of The Drug Price Competition and Patent Term Restoration Act (Hatch-Waxman) in 1984. In the year Hatch-Waxman was enacted, generic utilization rates were 19 percent; in contrast, today, the generic utilization rate is approximately 70 percent. Striking a balance between access to existing medicines and access to yet-to-be-discovered (and developed) drugs, through research incentives, was the principal objective of this landmark legislation. However, given the current rate of generic utilization, it seems plausible, if not likely, that any balance achieved by the 1984 Act has since shifted away from research incentives and towards improved access, ceteris paribus. Among other factors, recent mandatory substitution laws in most states have driven up generic utilization rates. In the current paper, we employ semi-annual data from 1992 to 2008 to examine the link between generic utilization rates and real U.S. prescription drug prices. This link is important because previous research has identified a causal relationship between real drug prices in the U.S. and industry-level R&D investment intensity. We identify a statistically significant, positive relationship between generic utilization rates in the U.S. and real U.S. prescription drug prices. Specifically, we estimate an elasticity of real drug prices to generic utilization rates of -0.15. This finding, when coupled with previous empirical work on the determinants of pharmaceutical R&D intensity, suggests an elasticity of R&D to generic utilization rates of about 0.090. While the magnitude of this elasticity is modest, as theory would predict—the effect of greater generic erosion of brand sales at patent expiration is heavily discounted due to the long time horizon to generic erosion when an R&D project is in clinical development. However, because there has been a very substantial increase in generic utilization rates since 1984, the impact on R&D is nevertheless quite large. We explore this and other issues in the current paper.

Reconstruction of earth fissures 3-D from videos

Earth fissures are pervasive cracks that develop on valley floors as a consequence of land subsidence associated with extensive groundwater withdrawal. To capture geometrical, geological and geotechnical information of ground fissures is of paramount importance for their characterization. Recent advances in remote sensing techniques and the accessibility to remotely piloted aircraft systems (RPAS) as well as the evolution of onboard digital cameras enable the capture of digital photos and videos. Using digital photos along with the Structure from Motion (SfM) technique and following certain strategies, we can reconstruct a 3-D model of the earth fissures under study. This technique requires digital photos, but when a digital video is available, we can convert it into a set of frames and equally apply the procedure. Besides, the extraction of frames from a video assures a key condition for the SfM technique: the overlap between photos. The resulting 3-D model should be scaled and oriented using a rigid transformation matrix or even better including ground control points (GCP) into the captured photos or frames. The latter enables the geo-referencing of the point cloud and the correction of linear and non-linear deformations. In this work, the proposed methodology is illustrated through the application of SfM technique to a high-resolution video downloaded from YouTube (i.e. https://youtu.be/9xdAnftBKvY, last access: 20 February 2020). The video shows a mile-long earth fissure that appeared sometime between March 2014 and December 2014 near the Tator Hills (Arizona, USA) over Quaternary sediments. The Arizona Geological Survey captured these videos using an RPAS. The frames of the video were downloaded and extracted using a simple Matlab code. Then, we sub-sampled the frames and processed them using the software Agisoft Metashape Professional. Finally, we got metric data from Google Earth and generated a 3-D model. The quality of the 3-D model strongly depends on the quality of the photos and the GCP. However, this study shows the potential of this technique, instrumentation and data available on Internet for the development of 3-D point clouds and 3-D models for the detailed analysis of earth fissures.This research has been supported by the Spanish Ministry of Economy and Competitiveness (MINECO) and the European Funds for Regional Development (FEDER) (grant no. TEC2017-85244-C2-1-P), the UNESCO (grant no. ICGP641 project), the Universidad de Alicante (grant no. GRE17-11), the Universidad de Alicante (grant no. GRE18-15), and the Universidad de Alicante (grant no. vigrob-157)

Fluorescent Imaging of Antigen Released by a Skin-Invading Helminth Reveals Differential Uptake and Activation Profiles by Antigen Presenting Cells

Infection of the mammalian host by the parasitic helminth Schistosoma mansoni is accompanied by the release of excretory/secretory molecules (ES) from cercariae which aid penetration of the skin. These ES molecules are potent stimulants of innate immune cells leading to activation of acquired immunity. At present however, it is not known which cells take up parasite antigen, nor its intracellular fate. Here, we develop a technique to label live infectious cercariae which permits the imaging of released antigens into macrophages (MΦ) and dendritic cells (DCs) both in vitro and in vivo. The amine reactive tracer CFDA-SE was used to efficiently label the acetabular gland contents of cercariae which are released upon skin penetration. These ES products, termed ‘0-3hRP’, were phagocytosed by MHC-II+ cells in a Ca+ and actin-dependent manner. Imaging of a labelled cercaria as it penetrates the host skin over 2 hours reveals the progressive release of ES material. Recovery of cells from the skin shows that CFDA-SE labelled ES was initially (3 hrs) taken up by Gr1+MHC-II− neutrophils, followed (24 hrs) by skin-derived F4/80+MHC-IIlo MΦ and CD11c+ MHC-IIhi DC. Subsequently (48 hrs), MΦ and DC positive for CFDA-SE were detected in the skin-draining lymph nodes reflecting the time taken for antigen-laden cells to reach sites of immune priming. Comparison of in vitro-derived MΦ and DC revealed that MΦ were slower to process 0-3hRP, released higher quantities of IL-10, and expressed a greater quantity of arginase-1 transcript. Combined, our observations on differential uptake of cercarial ES by MΦ and DC suggest the development of a dynamic but ultimately balanced response that can be potentially pushed towards immune priming (via DC) or immune regulation (via MΦ)

732-1 An Institutional Experience with Second and Third Stage Palliative Procedures for Hypoplastic Left Heart Syndrome: The Impact of the Bidirectional Cavopulmonary Shunt

We reviewed 71 consecutive pts who underwent stage II and III operations following stage I palliation for hypoplastic left heart syndrome (HLHS) at our institution since 1983. 6 surgeons participated in the care of these pts. Follow-up is 97% complete. We examined 17 potential risk factors for mortality, including preoperative anatomic and physiologic factors, and procedural features of the stage II operation. Multivariate analysis revealed that the only significant risk factor for stage II mortality was the performance of a non-fenestrated completion Fontan procedure (p&lt;0.001). There were 9 hospital deaths (69%) in the 13 pts undergoing the Fontan procedure at stage II. In contrast, 49 pts underwent bidirectional cavopulmonary shunting (47) or hemi-Fontan procedure(2) as an intermediate step to the Fontan procedure with 4 (8%) early deaths. The first bidirectional cavopulmonary shunt was performed in this population in 1988. Median age at this stage II procedure was 8.4 months. Surgical augmentation of the pulmonary arteries was performed in 18 (37%) pts at the time of stage II surgery and was not associated with increased operative risk. Also, HLHS anatomic subtype was not a risk factor for stage II mortality or pre-stage III attrition. There have been 2 (4%) intermediate deaths prior to the performance of a stage III procedure, which at our institution is the fenestrated Fontan procedure. This has been performed in 25 pts at a median age of 30 months with 1 early death and no mortality at a median follow-up of 22 months. There are presently 34 HLHS pts who have modified Fontan anatomy following a course of surgical palliation performed entirely at this institution. Follow-up in this group ranges up to 92 months, with a median of 28 months. 33 of these patients are NYHA class 1 or 2.2 pts have required pacemaker implantation, but there have otherwise been no surgical reinterventions in pts who have completed palliation. We conclude that the incorporation of the bidirectional cavopulmonary shunt into a course of surgical palliation for HLHS has dramatically reduced mortality in this challenging group of pts, allowing them to undergo the modified fenestrated Fontan procedure with low operative mortality and good intermediate outcome

Knowing the Biosphere: Documentation, Specimens, Archives, and Names Reveal Environmental Change and Emerging Pathogens

One Health programs and trajectories are now the apparent standard for exploring the occurrence and distribution of emerging pathogens and disease. By definition, One Health has been characterized as a broadly inclusive, collaborative, and transdisciplinary approach with connectivity across local to global scales, which integrates the medical and veterinary community to recognize health outcomes emerging at the environmental nexus for people, animals, plants, and their shared landscapes. One Health has been an incomplete model, conceptually and operationally, focused on reactive and response-based foundations, to limit the impact of emerging pathogens and emerging infectious diseases and, as such, lacks a powerful proactive capacity. A proactive, predictive One Health is necessary, emanating in part from geographically/taxonomically broad and temporally deep biological collections of pathogen-host assemblages. The DAMA protocol (Document, Assess, Monitor, Act), the operational extension of the Stockholm paradigm (SP), accomplishes this task by encompassing holistic and strategic biological sampling of reservoir host assemblages and pathogens at environmental interfaces and more extensively through resurveys, with development of informatics resources digitally linked to physical specimens held in publicly accessible museum biorepositories. Archives of specimens are the foundations for accumulating interrelated archives of information (the baselines against which change can be identified and tracked), with collections serving as fundamental resources for biodiversity informatics under the conceptual evolutionary and ecological umbrella of the SP. A cultural and conceptual transformation is essential among the diverse practitioners in the One Health community, one that recognizes the necessity of placing pathogens in an evolutionary, ecological, and environmental context by integrating specimens and associated informatics into an infrastructure and networks for actionable information. As a community, it is essential to abandon response-based business as usual while looking forward toward proactive transboundary approaches that maximize our conceptual and taxonomic view of diversity across interconnected planetary scales that influence the complexity of pathogen-host interfaces. Evolution, where the past always influences the present and the future, defines our trajectory, as the need for sustained archives that describe the biosphere becomes more acute with each passing day

Connexin26 mediates CO2-dependent regulation of breathing via glial cells of the medulla oblongata

Breathing is highly sensitive to the PCO2 of arterial blood. Although CO2 is detected via the proxy of pH, CO2 acting directly via Cx26 may also contribute to the regulation of breathing. Here we exploit our knowledge of the structural motif of CO2-binding to Cx26 to devise a dominant negative subunit (Cx26DN) that removes the CO2-sensitivity from endogenously expressed wild type Cx26. Expression of Cx26DN in glial cells of a circumscribed region of the mouse medulla - the caudal parapyramidal area – reduced the adaptive change in tidal volume and minute ventilation by approximately 30% at 6% inspired CO2. As central chemosensors mediate about 70% of the total response to hypercapnia, CO2-sensing via Cx26 in the caudal parapyramidal area contributed about 45% of the centrally-mediated ventilatory response to CO2. Our data unequivocally link the direct sensing of CO2 to the chemosensory control of breathing and demonstrates that CO2-binding to Cx26 is a key transduction step in this fundamental process