Economic and health outcomes of capsule endoscopy: Opportunities for improved management of the diagnostic process for obscure gastrointestinal bleeding

The estimated annual incidence of gastrointestinal bleeding in the United States is approximately 100 episodes per 100,000 persons, resulting in 300,000 hospitalizations annually. Diagnostic tools such as radiologic studies and endoscopic examination often fail to identify a source of bleeding, resulting in a cycle of repetitive testing over months or even years. Costs associated with the diagnostic process, and with interim treatment for anemia and other symptoms, can be significant. The diagnostic process also takes a toll on the patient, in terms of worry, pain, and discomfort. Capsule endoscopy, a technology that received FDA clearance in August, 2001, consists of a video capsule that is ingested by the patient, and that transmits images to a wireless data recorder worn on the belt. The recorded stream of approximately 50,000 images can be reviewed on a computer workstation by a physician to identify nature and location of potential sources of bleeding. This paper presents a framework for economic analysis of this new technology. First, we present a review of the literature on the current diagnostic methods. Next, we present a conceptual model for examining contributors to costs in diagnosing obscure intestinal bleeds. We conclude by exploring the potential economic impact of the technology. Analysis of data from the first U.S. clinical trial of capsule endoscopy demonstrates its high diagnostic yield, and patient satisfaction. While further study is required, this analysis indicates that capsule endoscopy may reduce total medical utilization and costs and improve patient quality of life, when used for appropriate indications

FHF-independent conduction of action potentials along the leak-resistant cerebellar granule cell axon

Neurons in vertebrate central nervous systems initiate and conduct sodium action potentials in distinct subcellular compartments that differ architecturally and electrically. Here, we report several unanticipated passive and active properties of the cerebellar granule cell’s unmyelinated axon. Whereas spike initiation at the axon initial segment relies on sodium channel (Nav)-associated fibroblast growth factor homologous factor (FHF) proteins to delay Nav inactivation, distal axonal Navs show little FHF association or FHF requirement for high-frequency transmission, velocity and waveforms of conducting action potentials. In addition, leak conductance density along the distal axon is estimated as o1% that of somatodendritic membrane. The faster inactivation rate of FHF-free Navs together with very low axonal leak conductance serves to minimize ionic fluxes and energetic demand during repetitive spike conduction and at rest. The absence of FHFs from Navs at nodes of Ranvier in the central nervous system suggests a similar mechanism of current flux minimization along myelinated axons

Source and possible tectonic driver for Jurassic–Cretaceous gold deposits in the West Qinling Orogen, China

The West Qinling Orogen (WQO) in Central China Orogenic Belt contains numerous metasedimentary rock-hosted gold deposits (>2000 t Au), which mainly formed during two pulses: one previously recognized in the Late Triassic to Early Jurassic (T3–J1) and one only recently identified in the Late Jurassic to Early Cretaceous (J3–K1). Few studies have focused on the origin and geotectonic setting of the J3–K1 gold deposits. Textural relationships, LA-ICP-MS trace element and sulfur isotope compositions of pyrites in hydrothermally altered T3 dykes within the J3–K1 Daqiao deposit were used to constrain relative timing relationships between mineralization and pyrite growth in the dykes, and to characterize the source of ore fluid. These results are integrated with an overview of the regional geodynamic setting, to advance understanding of the tectonic driver for J3–K1 hydrothermal gold systems. Pyrite in breccia- and dyke-hosted gold ores at Daqiao have similar chemical and isotopic compositions and are considered to be representative of J3–K1 gold deposits in WQO. Co/Ni and sulfur isotope ratios suggest that ore fluids were derived from underlying Paleozoic Ni- and Se-rich carbonaceous sedimentary rocks. The geochemical data do not support the involvement of magmatic fluids. However, in the EQO (East Qinling Orogen), J3–K1 deposits are genetically related to magmatism. Gold mineralization in WQO is contemporaneous with magmatic deposits in the EQO and both are mainly controlled by NE- and EW-trending structures produced by changes in plate motion of the Paleo-Pacific plate as it was subducted beneath the Eurasian continent. We therefore infer that the J3–K1 structural regime facilitated the ascent of magma in the EQO and metamorphic fluids in the WQO with consequent differences in the character of contemporaneous ore deposits. If this is correct, then the far-field effects of subduction along the eastern margin of NE Asia extended 1000's of km into the continental interior

Fhf2 gene deletion causes temperature-sensitive cardiac conduction failure

Fever is a highly conserved systemic response to infection dating back over 600 million years. Although conferring a survival benefit, fever can negatively impact the function of excitable tissues, such as the heart, producing cardiac arrhythmias. Here we show that mice lacking fibroblast growth factor homologous factor 2 (FHF2) have normal cardiac rhythm at baseline, but increasing core body temperature by as little as 3 C causes coved-type STelevations and progressive conduction failure that is fully reversible upon return to normothermia. FHF2-deficient cardiomyocytes generate action potentials upon current injection at 25 C but are unexcitable at 40 C. The absence of FHF2 accelerates the rate of closed-state and open-state sodium channel inactivation, which synergizes with temperature-dependent enhancement of inactivation rate to severely suppress cardiac sodium currents at elevated temperatures. Our experimental and computational results identify an essential role for FHF2 in dictating myocardial excitability and conduction that safeguards against temperature-sensitive conduction failure

Methodological Insights, Advantages and Innovations Manuscript Title: Lessons Learned in Conducting Qualitative Healthcare Research Interviews in Malawi: A Qualitative Evaluation

With the growth of qualitative health research in low- and middle-income countries, local health professionals are increasingly involved in facilitating interviews with their fellow health workers. Understanding the methodological implications of such situations is required to ensure high-quality study findings and to build capacity and skills for interviewers with clinical backgrounds working with limited resources. This article reports a qualitative process evaluation of a study that assessed barriers and enablers of implementing bubble continuous positive airway pressure in Malawi. Findings were summarized through an iterative process of reflection on what worked, what did not work, areas for improvement, structural challenges, negotiating dual roles as nurses and researchers and the professional hierarchy within the health care system. Comprehensive practical training was critical to conducting qualitative research in a health setting. Interviewers were health workers themselves and required skills in reflexivity to effectively probe and navigate interviewing other health professionals, including senior staff. The main challenge in conducting interviews in a resource-limited healthcare setting was time constraints, which were compounded by staffing shortages. Lessons from this qualitative evaluation highlight the importance of training in reflexivity, engaging interviewers as collaborators and reserving adequate time to accommodate healthcare workers’ multiple roles and responsibilities

Commercialization of the Internet: The Interaction of Public Policy and Private Actions,” in

seminar participants for comments. I am particularly grateful to Zvi Griliches who encouraged this research when it was at a formative stage. All remaining errors are mine alone. Abstract Why did commercialization of the Internet go so well? This paper examines events in the Internet access market as a window on this broad question. The study emphasizes four themes. First, commercializing Internet access did not give rise to many of the anticipated technical and operational challenges. Entrepreneurs quickly learned that the Internet access business was commercially feasible. Second, Internet access was malleable as a technology and as an economic unit. Third, privatization fostered attempts to adapt the technology in new uses, new locations, new market settings, new applications and in conjunction with other lines of business. These went beyond what anyone would have forecast by examining the uses for the technology prior to 1992. Fourth, and not trivially, the NSF was lucky in one specific sense. The Internet access industry commercialized at a propitious moment, at the same time as the growth of an enormous new technological opportunity, the World Wide Web. As it turned out, the Web thrived under market-oriented, decentralized and independent decision making. The paper draws lessons for policies governing the commercialization of other government managed technologies and for the Internet access market moving forward. 1 Motivation The "commercialization of the Internet" is shorthand for three nearly simultaneous events: the removal of restrictions by the National Science Foundation (NSF) over use of the Internet for commercial purposes, the browser wars initiated by the founding of Netscape, and the rapid entry of tens of thousands of firms into commercial ventures using technologies which employ the suite of TCP/IP standards. These events culminated years of work at NSF to transfer the Internet into commercial hands from its exclusive use for research activity in government funded laboratories and universities. Sufficient time has passed to begin to evaluate how the market performed after commercialization. Such an evaluation is worth doing. Actual events have surpassed the forecasts of the most optimistic managers at NSF. Was this due to mere good fortune or something systematic whose lessons illuminate the market today? Other government managed technologies usually face vexing technical and commercial challenges that prevent the technology from diffusing quickly, if at all. Can we draw lessons from this episode for the commercialization of other government managed technologies? In that spirit, this paper examines the Internet access market and one set of actors, Internet Service Provides (ISPs). ISPs provide Internet access for most of the households and business users in the country (NTIA, 1999), usually for a fee or, more recently, in exchange for advertising. Depending on the user facilities, whether it is a business or personal residence, access can involve dial-up to a local number or 1-800 number at different speeds, or direct access to the user's server employing one of several high-speed access technologies. The largest ISP in the United States today is America-On-Line, to which approximately half the households in the US subscribe. There also are many national ISPs with recognizable names, such as AT&T Worldnet, MCI WorldCom/UUNet, Mindspring/Earthlink, and PSINet, as well as thousands of smaller regional ISPs. The Internet access market is a good case to examine. Facilities for similar activity existed prior to commercialization, but there was reason to expect a problematic migration into commercial use. This activity 2 appeared to possess idiosyncratic technical features and uneconomic operational procedures which made it unsuitable in other settings. The Internet's exclusive use by academics and researchers fostered cautious predictions that unanticipated problems would abound and commercial demand might not materialize. In sharp contrast to cautious expectations, however, the ISP market displayed three extraordinary features. For one, this market grew rapidly, attracting thousands of entrants and many users, quickly achieving mass-market status. Second, firms offering this service became nearly geographically pervasive, a diffusion pattern rarely found in new infrastructure markets. And third, firms did not settle on a standard menu of services to offer, indicative of new commercial opportunities and also a lack of consensus about the optimal business model for this opportunity. Aside from defying expectations, all three traits --rapid growth, geographic pervasiveness and the absence of settlement --do not inherently go together in most markets. The presence of restructuring should have interfered with rapid growth and geographic expansion. So explaining this market experience is also interesting in its own right. What happened to make commercialization go so well? This paper's examination reveals four themes. First, commercialization did not give rise to many of the anticipated technical and operational challenges. Entrepreneurs quickly learned that the Internet access business was commercially feasible. This happened for a variety of economic reasons. ISPs began offering commercial service after making only incremental changes to familiar operating procedures borrowed from the academic setting. It was technically easy to collect revenue at what used to be the gateway functions of academic modem pools. Moreover, the academic model of Internet access migrated into commercial operation without any additional new equipment suppliers. Second, Internet access was malleable as a technology and as an economic unit. This is because the foundation for Internet inter-connectivity, TCP/IP, is not a single invention, diffusing across time and space without changing form. Instead, it is embedded in equipment which uses a suite of communication technologies, protocols and standards for networking between computers. This technology obtains economic value in combination with complementary invention, investment and equipment. While commercialization did 3 give rise to restructuring of Internet access to suit commercial users, the restructuring did not stand in the way of diffusion, nor interfere with the initial growth of demand. Third, privatizing Internet access fostered customizing Internet access technology to a wide variety of locations, circumstances and users. As it turned out, the predominant business model was feasible at small scale and, thus, at low levels of demand. This meant that the technology was commercially viable at low densities of population, whether or not it was part of a national branded service or a local geographically Fourth, and not trivially, the NSF was lucky in a particular sense of the word. It enabled the commercialization of the Internet access industry at a propitious moment, at the same time as the growth of an enormous new technological opportunity, the World Wide Web. This invention motivated further experimentation to take advantage of the new opportunity, which, as it turned out, thrived under marketoriented and decentralized decision making. The paper first develop these themes. Then it describes recent experience. It ends by discussing how these themes continue to resonate today. Challenges during technology transfer: an overview Conventional approaches to technological development led most observers in 1992 to be cautious about the commercialization of the Internet. To understand how this prediction went awry, it is important to understand its foundations. For example, military users frequently require electronic components to meet specifications that suit 6 the component to battle conditions. Extensive technical progress is needed to tailor a product design to meet these requirements. Yet, and this is difficult to anticipate prior to commercialization, an additional amount of invention is often needed to bring such a product design and to bring its manufacturing to a price/point with features that meet more cost-conscious or less technically stringent commercial requirements. Commercial challenges arise when commercial markets require substantial adaptation of operation and business processes in order to put technologies into use. In other words, government users or users in a research environment often tolerate operational processes that do not translate profitably to commercial environments. After a technology transfers out of government sponsorship, it may not be clear how to balance costs and revenues for technologies that had developed under settings with substantial subsidies underwriting losses, and research goals justifying expenditures. Hence, many government managed technologies require considerable experimentation with business models before they begin to grow, if they grow at all. For example, the supersonic transport actually met its engineering targets, but still failed to satisfy basic operational economics in most settings. Being technically sleek was insufficient to attract enough interest to generate the revenue which covered operating costs on any but a small set of routes. No amount of operational innovations and marketing campaigns were able to overcome these commercial problems. New technologies are also vulnerable to structural challenges that impede pathways to commercialization. Commercial and structural challenges are not necessarily distinct, though the latter are typically more complex. Structural challenges are those which require change to the bundle of services offered, change to the boundary of the firms offering or using the new technology, or dramatic change to the operational structure of the service organization. These challenges arise because technologies developed under government auspices may presume implementation at a particular scale or with a set of technical standards, but require a different set of organizational arrangements to support commercial applications. For example, while many organizations provided the technical advances necessary for scientific 7 computing in academic settings during the 1950s, very few of these same firms migrated into supporting large customer bases among business users. As it turned out, the required changes were too dramatic for many companies to make. The structure of the support and sales organization were very different, and so too were the product designs. Of course, the few who successfully made the transition to commercial users, such as IBM, did quite well, but doing so required overcoming considerable obstacles. In summary, conventional analysis forecasts that migrating Internet access into commercial use would engender technical, commercial and structural challenges. Why did the migration proceed so different than expected? The absence of challenge in the Internet Access industry An ISP is a commercial firm who provides access, maintains it for a fee and develop related applications as users require. While sometimes this is all they do, with business users they often do much more. Sometimes ISPs do simple things such as filtering. Sometimes it involves managing and designing email accounts, data-bases and web pages. Some ISPs label this activity consulting and charge for it separately; others do not consider it distinct from the normal operation of the Internet access services. On the surface the record of achievement for ISPs is quite remarkable. Most recent surveys show that no more than 10 percent of US households get their Internet access from university-sponsored Internet access providers, the predominant provider of such access prior to commercialization. Today almost all users go to a commercial providers By the end of the century the ISP market had obtained a remarkable structure. One firm, America On-line, provided access to close to half the households in the US market, while several score of other ISPs provided access to millions of households and businesses on a nationwide basis. Thousands of ISPs also 8 provided access for limited geographic areas, such as one city or region. Such small ISPs accounted for roughly a quarter of household use and another fraction of business use. Technical challenges did not get in the way The Internet access market did suffer from some technical challenges, but not enough to prevent rapid diffusion. Commercialization induced considerable technical innovation in complementary inventive activities. Much of this innovative activity became associated with developing new applications for existing users and new users. It is often forgotten that when the electronic commerce first developed based on TCP/IP standards, it was relatively mature in some applications, such as e-mail and file transfers, which were the most popular applications (these programs continue to be the most popular today, NTIA [1999]). To be sure, TCP/IP based programs were weak in others areas, such as commercial data base and software applications for business use, but those uses did not necessarily have to come immediately. The invention of the World Wide Web in the early 1990s further stretched the possibilities for potential applications and highlighted these weaknesses. More important for the initial diffusion, little technical invention was required for commercial vendors to put this technology into initial mainstream use. Academic modem pools and computing centers tended to use technologies similar to their civilian counterparts --such as bulletin board operators --while buying most equipment from commercial suppliers. Moving this activity into the mainstream commercial sector did not necessitate building a whole new Internet equipment industry; it was already there, supplying goods and services to the universities and to home PC users. Similarly, much of the software continued to be usefuli.e., Unix systems, the gate-keeping software, and the basic communication protocols. Indeed, every version of Unix software had been TPC/IP compatible for many years due to Department of Defense requirements. A simple commercial operation only needed to add a billing component to the gate-keeping software to turn an academic modem pool into a rudimentary commercial operation. 9 Technical information about these operations was easy to obtain if one had sufficient technical background; a BA in basic electrical engineering or computer science was far more than adequate. Many IS

SARS-CoV-2 disrupts splicing, translation, and protein trafficking to suppress host defenses

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently identified coronavirus that causes the respiratory disease known as coronavirus disease 2019 (COVID-19). Despite the urgent need, we still do not fully understand the molecular basis of SARS-CoV-2 pathogenesis. Here, we comprehensively define the interactions between SARS-CoV-2 proteins and human RNAs. NSP16 binds to the mRNA recognition domains of the U1 and U2 splicing RNAs and acts to suppress global mRNA splicing upon SARS-CoV-2 infection. NSP1 binds to 18S ribosomal RNA in the mRNA entry channel of the ribosome and leads to global inhibition of mRNA translation upon infection. Finally, NSP8 and NSP9 bind to the 7SL RNA in the signal recognition particle and interfere with protein trafficking to the cell membrane upon infection. Disruption of each of these essential cellular functions acts to suppress the interferon response to viral infection. Our results uncover a multipronged strategy utilized by SARS-CoV-2 to antagonize essential cellular processes to suppress host defenses

SARS-CoV-2 disrupts splicing, translation, and protein trafficking to suppress host defenses

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently identified coronavirus that causes the respiratory disease known as coronavirus disease 2019 (COVID-19). Despite the urgent need, we still do not fully understand the molecular basis of SARS-CoV-2 pathogenesis. Here, we comprehensively define the interactions between SARS-CoV-2 proteins and human RNAs. NSP16 binds to the mRNA recognition domains of the U1 and U2 splicing RNAs and acts to suppress global mRNA splicing upon SARS-CoV-2 infection. NSP1 binds to 18S ribosomal RNA in the mRNA entry channel of the ribosome and leads to global inhibition of mRNA translation upon infection. Finally, NSP8 and NSP9 bind to the 7SL RNA in the signal recognition particle and interfere with protein trafficking to the cell membrane upon infection. Disruption of each of these essential cellular functions acts to suppress the interferon response to viral infection. Our results uncover a multipronged strategy utilized by SARS-CoV-2 to antagonize essential cellular processes to suppress host defenses

Missense variants in the N-terminal domain of the A isoform of FHF2/FGF13 cause an X-linked developmental and epileptic encephalopathy

Fibroblast growth factor homologous factors (FHFs) are intracellular proteins which regulate voltage-gated sodium (Na v) channels in the brain and other tissues. FHF dysfunction has been linked to neurological disorders including epilepsy. Here, we describe two sibling pairs and three unrelated males who presented in infancy with intractable focal seizures and severe developmental delay. Whole-exome sequencing identified hemi- and heterozygous variants in the N-terminal domain of the A isoform of FHF2 (FHF2A). The X-linked FHF2 gene (also known as FGF13) has alternative first exons which produce multiple protein isoforms that differ in their N-terminal sequence. The variants were located at highly conserved residues in the FHF2A inactivation particle that competes with the intrinsic fast inactivation mechanism of Na v channels. Functional characterization of mutant FHF2A co-expressed with wild-type Na v1.6 (SCN8A) revealed that mutant FHF2A proteins lost the ability to induce rapid-onset, long-term blockade of the channel while retaining pro-excitatory properties. These gain-of-function effects are likely to increase neuronal excitability consistent with the epileptic potential of FHF2 variants. Our findings demonstrate that FHF2 variants are a cause of infantile-onset developmental and epileptic encephalopathy and underline the critical role of the FHF2A isoform in regulating Na v channel function