Direct Evidence for Fluid Pressure, Dilatancy, and Compaction Affecting Slip in Isolated Faults

Earthquake instability occurs as a result of strength loss during sliding on a fault. It has been known for over 50 years that fault compaction or dilatancy may cause significant weakening or strengthening by dramatically changing the fluid pressure trapped in faults. Despite this fundamental importance, we have no real understanding of the exact conditions that lead to compaction or dilation during nucleation or rupture. To date, no direct measurements of pore pressure changes during slip in hydraulically isolated faults have been reported. We show direct examples of fluid pressure variations during nucleation and rupture using a miniature pressure transducer embedded in an experimental fault. We demonstrate that fluids not only are significant in controlling fault behavior but can provide the dominant mechanism controlling fault stability. The effect of fluid pressure changes can exceed frictional variations predicted by rate‐ and state‐dependent friction laws, exerting fundamental controls on earthquake rupture initiation

Artificial intelligence and real-world data for drug and food safety - A regulatory science perspective

In 2013, the Global Coalition for Regulatory Science Research (GCRSR) was established with members from over ten countries (www.gcrsr.net). One of the main objectives of GCRSR is to facilitate communication among global regulators on the rise of new technologies with regulatory applications through the annual conference Global Summit on Regulatory Science (GSRS). The 11th annual GSRS conference (GSRS21) focused on "Regulatory Sciences for Food/Drug Safety with Real-World Data (RWD) and Artificial Intelligence (AI)." The conference discussed current advancements in both AI and RWD approaches with a specific emphasis on how they impact regulatory sciences and how regulatory agencies across the globe are pursuing the adaptation and oversight of these technologies. There were presentations from Brazil, Canada, India, Italy, Japan, Germany, Switzerland, Singapore, the United Kingdom, and the United States. These presentations highlighted how various agencies are moving forward with these technologies by either improving the agencies' operation and/or preparing regulatory mechanisms to approve the products containing these innovations. To increase the content and discussion, the GSRS21 hosted two debate sessions on the question of "Is Regulatory Science Ready for AI?" and a workshop to showcase the analytical data tools that global regulatory agencies have been using and/or plan to apply to regulatory science. Several key topics were highlighted and discussed during the conference, such as the capabilities of AI and RWD to assist regulatory science policies for drug and food safety, the readiness of AI and data science to provide solutions for regulatory science. Discussions highlighted the need for a constant effort to evaluate emerging technologies for fit-for-purpose regulatory applications. The annual GSRS conferences offer a unique platform to facilitate discussion and collaboration across regulatory agencies, modernizing regulatory approaches, and harmonizing efforts

Clinical information modeling processes for semantic interoperability of electronic health records: systematic review and inductive analysis

This is a pre-copyedited, author-produced PDF of an article accepted for publication in Journal of the American Medical Informatics Association following peer review. The version of record is available online at: http://dx.doi.org/10.1093/jamia/ocv008[EN] [Objective] This systematic review aims to identify and compare the existing processes and methodologies that have been published in the literature for defining clinical information models (CIMs) that support the semantic interoperability of electronic health record (EHR) systems. [Material and Methods] Following the preferred reporting items for systematic reviews and meta-analyses systematic review methodology, the authors reviewed published papers between 2000 and 2013 that covered that semantic interoperability of EHRs, found by searching the PubMed, IEEE Xplore, and ScienceDirect databases. Additionally, after selection of a final group of articles, an inductive content analysis was done to summarize the steps and methodologies followed in order to build CIMs described in those articles. [Results] Three hundred and seventy-eight articles were screened and thirty six were selected for full review. The articles selected for full review were analyzed to extract relevant information for the analysis and characterized according to the steps the authors had followed for clinical information modeling. [Discussion] Most of the reviewed papers lack a detailed description of the modeling methodologies used to create CIMs. A representative example is the lack of description related to the definition of terminology bindings and the publication of the generated models. However, this systematic review confirms that most clinical information modeling activities follow very similar steps for the definition of CIMs. Having a robust and shared methodology could improve their correctness, reliability, and quality. [Conclusion] Independently of implementation technologies and standards, it is possible to find common patterns in methods for developing CIMs, suggesting the viability of defining a unified good practice methodology to be used by any clinical information modeler.This research has been partially funded by the Instituto de Salud Carlos III (Platform for Innovation in Medical Technologies and Health), grant PT13/0006/0036 and the Spanish Ministry of Economy and Competitiveness, grants TIN2010-21388-C02-01 and PTQ-12-05620.Moreno-Conde, A.; Moner Cano, D.; Da Cruz, WD.; Santos, MR.; Maldonado Segura, JA.; Robles Viejo, M.; Kalra, D. (2015). 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International Journal of Medical Informatics, 77(9), 576-588. doi:10.1016/j.ijmedinf.2007.11.005Bax, M. P., Kalra, D., & Santos, M. R. (2012). Dealing with the Archetypes Development Process for a Regional EHR System. Applied Clinical Informatics, 03(03), 258-275. doi:10.4338/aci-2011-12-ra-0074Moner D Moreno A Maldonado JA . Using archetypes for defining CDA templates. Stud Health Technol Inform. 2012;180:53–57.Moner D Maldonado JA Boscá D . CEN EN13606 normalisation framework implementation experiences. In: Seamless Care, Safe Care: The Challenges of Interoperability and Patient Safety in Health Care: Proceedings of the EFMI Special Topic Conference, June 2–4, 2010; Reykjavik, Iceland. IOS Press; 2010: 136.Marcos, M., Maldonado, J. A., Martínez-Salvador, B., Boscá, D., & Robles, M. (2013). Interoperability of clinical decision-support systems and electronic health records using archetypes: A case study in clinical trial eligibility. 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The EHR-ARCHE project: Satisfying clinical information needs in a Shared Electronic Health Record System based on IHE XDS and Archetypes. International Journal of Medical Informatics, 82(12), 1195-1207. doi:10.1016/j.ijmedinf.2013.08.002Dias, R. D., Cook, T. W., & Freire, S. M. (2011). Modeling healthcare authorization and claim submissions using the openEHR dual-model approach. BMC Medical Informatics and Decision Making, 11(1). doi:10.1186/1472-6947-11-60Buck, J., Garde, S., Kohl, C. D., & Knaup-Gregori, P. (2009). Towards a comprehensive electronic patient record to support an innovative individual care concept for premature infants using the openEHR approach. International Journal of Medical Informatics, 78(8), 521-531. doi:10.1016/j.ijmedinf.2009.03.001Puentes, J., Roux, M., Montagner, J., & Lecornu, L. (2012). Development framework for a patient-centered record. 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Impaired contractile function of the supraspinatus in the acute period following a rotator cuff tear

Background: Rotator cuff (RTC) tears are a common clinical problem resulting in adverse changes to the muscle, but there is limited information comparing histopathology to contractile function. This study assessed supraspinatus force and susceptibility to injury in the rat model of RTC tear, and compared these functional changes to histopathology of the muscle. Methods: Unilateral RTC tears were induced in male rats via tenotomy of the supraspinatus and infraspinatus. Maximal tetanic force and susceptibility to injury of the supraspinatus muscle were measured in vivo at day 2 and day 15 after tenotomy. Supraspinatus muscles were weighed and harvested for histologic analysis of the neuromuscular junction (NMJ), intramuscular lipid, and collagen. Results: Tenotomy resulted in eventual atrophy and weakness. Despite no loss in muscle mass at day 2 there was a 30% reduction in contractile force, and a decrease in NMJ continuity and size. Reduced force persisted at day 15, a time point when muscle atrophy was evident but NMJ morphology was restored. At day 15, torn muscles had decreased collagen-packing density and were also more susceptible to contraction-induced injury. Conclusion: Muscle size and histopathology are not direct indicators of overall RTC contractile health. Changes in NMJ morphology and collagen organization were associated with changes in contractile function and thus may play a role in response to injury. Although our findings are limited to the acute phase after a RTC tear, the most salient finding is that RTC tenotomy results in increased susceptibility to injury of the supraspinatus

Unitary Ca2+ current through recombinant type 3 InsP3 receptor channels under physiological ionic conditions

The ubiquitous inositol 1,4,5-trisphosphate (InsP3) receptor (InsP3R) channel, localized primarily in the endoplasmic reticulum (ER) membrane, releases Ca2+ into the cytoplasm upon binding InsP3, generating and modulating intracellular Ca2+ signals that regulate numerous physiological processes. Together with the number of channels activated and the open probability of the active channels, the size of the unitary Ca2+ current (iCa) passing through an open InsP3R channel determines the amount of Ca2+ released from the ER store, and thus the amplitude and the spatial and temporal nature of Ca2+ signals generated in response to extracellular stimuli. Despite its significance, iCa for InsP3R channels in physiological ionic conditions has not been directly measured. Here, we report the first measurement of iCa through an InsP3R channel in its native membrane environment under physiological ionic conditions. Nuclear patch clamp electrophysiology with rapid perfusion solution exchanges was used to study the conductance properties of recombinant homotetrameric rat type 3 InsP3R channels. Within physiological ranges of free Ca2+ concentrations in the ER lumen ([Ca2+]ER), free cytoplasmic [Ca2+] ([Ca2+]i), and symmetric free [Mg2+] ([Mg2+]f), the iCa–[Ca2+]ER relation was linear, with no detectable dependence on [Mg2+]f. iCa was 0.15 ± 0.01 pA for a filled ER store with 500 µM [Ca2+]ER. The iCa–[Ca2+]ER relation suggests that Ca2+ released by an InsP3R channel raises [Ca2+]i near the open channel to ∼13–70 µM, depending on [Ca2+]ER. These measurements have implications for the activities of nearby InsP3-liganded InsP3R channels, and they confirm that Ca2+ released by an open InsP3R channel is sufficient to activate neighboring channels at appropriate distances away, promoting Ca2+-induced Ca2+ release

Lawson criterion for ignition exceeded in an inertial fusion experiment

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion

T-cell recognition of chemicals, protein allergens and drugs: towards the development of in vitro assays

Chemicals can elicit T-cell-mediated diseases such as allergic contact dermatitis and adverse drug reactions. Therefore, testing of chemicals, drugs and protein allergens for hazard identification and risk assessment is essential in regulatory toxicology. The seventh amendment of the EU Cosmetics Directive now prohibits the testing of cosmetic ingredients in mice, guinea pigs and other animal species to assess their sensitizing potential. In addition, the EU Chemicals Directive REACh requires the retesting of more than 30,000 chemicals for different toxicological endpoints, including sensitization, requiring vast numbers of animals. Therefore, alternative methods are urgently needed to eventually replace animal testing. Here, we summarize the outcome of an expert meeting in Rome on 7 November 2009 on the development of T-cell-based in vitro assays as tools in immunotoxicology to identify hazardous chemicals and drugs. In addition, we provide an overview of the development of the field over the last two decades