How to Change a Running System. Infrastrukturinnovationen im Internet

Kaum ein Bereich der modernen Gesellschaft ist heutzutage ohne internetbasierte Technologien denkbar. Die Basis solcher Techniken ist eine immer komplexer werdende und sich ausbreitende Internetinfrastruktur, die permanent aufrechterhalten und den wachsenden Anforderungen entsprechend ausgebaut werden soll. Das wachsende Interesse an internetbasierten Informations- und Kommunikationstechnologien hat eine Vielzahl von Studien hervorgebracht, die sich mit der Neugestaltung und Einrichtung von Internettechnologien befassen oder deren Wirkung untersuchen. Die Umgestaltung bestehender informationstechnischer Systeme im Sinne des Umbaus der bestehenden Internetinfrastruktur wurde bislang aber gänzlich ausser Acht gelassen. Dabei ist insbesondere der Umbau der Internetinfrastruktur ausserordentlich komplex. Er bedarf besonderer Beachtung, da dieser im laufenden Betrieb unter Berücksichtigung der Interoperabilität mit bereits bestehenden Technologien in eine stetig wachsende informationstechnische Infrastruktur erfolgen muss. Die vorliegende Arbeit verfolgt daher das Ziel, diese Forschungslücke anhand der Untersuchung der Dynamiken beim Umbau der bestehenden Internetinfrastruktur ein Stück weit zu schliessen und einen Beitrag zur Weiterentwicklung der Infrastrukturforschung zu leisten. Dies geschieht am Beispiel der Analyse des Internetprotokolls; von der Einführung des TCP/IP bis zum in der Einführung befindlichen Internet Protocol Version 6 (IPv6) mit dem Ziel, eine gegenstandsbezogene Theorie zum Umbau der Internetinfrastruktur zu generieren. Dazu wird auf Basis eines systematischen Literaturreviews zum Umbau der Internetinfrastrukturforschung der Einführungsprozess detailliert am Beispiel des Internetprotokolls durch eine Methodentriangulation aus Dokumentenanalyse und Interviews historisch vergleichend rekonstruiert. Dies geschieht in Anlehnung an die Verschränkung der Makroperspektive des Ansatzes grosstechnischer Infrastruktursysteme (GTS) (vgl. etwa Mayntz 1988; Mayntz und Hughes 1988; Braun und Joerges 1994; Hughes 1983; 1987; Joerges 1988; 1996) (engl. Large Scale Infrastructures) mit der Mikroperspektive der Akteur:innen-Netzwerk-Theory (ANT) (vgl. etwa Callon und Latour 2006b [1981]; Callon 2006a [1986]; Latour 1987; Law 2006 [1992]) und basierend auf der Forschungslogik sowie den Methodologien der Grounded Theory (GTM) (vgl. etwa Glaser und Strauss 1967; Strauss und Corbin 1996; 1990). Dabei werden die teilnehmenden Akteur:innen in soziale Akteur:innen, sachliche Elemente und zeitlich-räumliche Konstellationen geclustert sowie deren Wirkung innerhalb des Umbauprozesses der Internetinfrastruktur analysiert. Weiter werden Phasen im Entwicklungs- und Einführungsprozess historisch vergleichend generiert und die verwendeten Strategien zur Entwicklung und Einführung von Infrastrukturtechniken im laufenden System herausgearbeitet. Die Arbeit zeigt hier einen signifikanten Wandel im Bereich der sozialen, sachlichen und zeitlich-räumlichen Akteur:innenkonstellationen auf, welcher nicht ausschliesslich historisch bedingt ist, sondern sich auf die Besonderheiten des Umbaus zunehmend komplexer werdender laufender Infrastruktursysteme zurückführen lässt. Einerseits wird herausgestellt, welche technischen, sozialen und zeitlich-räumlichen Akteur:innenkonstellationen treibend auf den Entwicklungs- und Einführungsprozess wirken und wie die zunehmende Komplexität technischer Strukturen, die Notwendigkeit technischer Interoperabilität und die daraus resultierende zunehmende Standardisierung Einfluss nehmen. Andererseits wird aufgezeigt, wie sich Strategien zur Entwicklung und Einführung zum Beispiel durch sich wandelnde zeitlich-räumliche und organisationale Strukturen verändert haben. Die Studie erarbeitet dabei am Beispiel der Untersuchung der Entwicklung des Internets und Einführung des TCP/IP bis zum IPv6 drei zentrale Entwicklungsphasen für den Umbau der Internetinfrastruktur: Die Innovationsphase, die Stabilisierungsphase und die Migrationsphase. Während in der Innovationsphase die Entwickler:innen zugleich die Nutzer:innen der Technologie waren und das System für den Umbau abgeschaltet wurde, gewährleisten heutzutage in der Migrationsphase vermehrt Internetstandards die Operabilität mit bereits bestehenden Technologien. Weiter werden in der Migrationsphase Testumgebungen zur Erprobung technischer Neuerungen eingerichtet sowie eine schrittweise Implementierung mithilfe von Übergangslösungen verfolgt. Schliesslich stellt die Arbeit heraus, dass Entwicklung und Einpassung reflexiv sind und aufgrund der Komplexität des Internets (soziale und technische Komplexität) zunehmend reglementiert werden. Infolge der Ausweitung des Netzes werden sie ausserdem global verteilt. Weiter lässt sich ein Trend von einer sozialen, sachlichen und zeitlich-räumlichen Homogenität in der Entwicklung und Einführung von Internetinfrastrukturtechnologien beobachten, die sich zu einer in jedem Aspekt wirkenden Heterogenität verschiebt. Diese Veränderungen sind keineswegs isolierter Art. Vielmehr beeinflussen sie ihr Umfeld in einem solchen Mass, dass sie nicht-intendierte Nebenfolgen erzeugen, die die Basis für weitere Entwicklungen bilden

Transplantation of Renal Allografts From Organ Donors Reactive for HCV Antibodies to HCV-Negative Recipients: Safety and Clinical Outcome

IntroductionBecause of the shortage of available organs for renal transplantation, strategies enabling the safe use of organs from donors with potential chronic infections such as hepatitis C are necessary. The aim of this study was to analyze the outcome of renal transplant donation from hepatitis C virus (HCV)-positive donors.MethodsBetween September 2002 and May 2007, 51 kidneys (34 donors) reactive for HCV antibodies were further evaluated. Six kidneys (5 donors) were transplanted to 6 recipients with known chronic HCV infection. The remaining 29 donors underwent extended virological testing. Nine donors were HCV RNA positive and thus not suitable for HCV-negative patients. Twenty donors (21 kidneys) did not have detectable HCV RNA copies and were transplanted into 21 HCV-negative recipients. Clinical outcomes focusing on safety, allograft function, and de novo HCV infection in the recipient were collected.ResultsThere were no de novo HCV infections detected in recipients who were HCV negative before transplantation. The extended virological donor screening did not have an impact on median cold ischemia time. Five-year graft survival was 75%.DiscussionOrgans from anti-HCV-reactive, nonviremic donors can be transplanted safely to HCV-negative recipients

Evaluation of Suppressed Mite Reproduction (SMR) Reveals Potential for Varroa Resistance in European Honey Bees (Apis melliferaL.)

Simple Summary The miteVarroa destructorrepresents a great threat to honey bees and the beekeeping industry. The opportunity to select and breed honey bees that are naturally able to fight the mite stands a sustainable solution. This can be achieved by evaluation of the failure of mite reproduction (SMR, suppressed mite reproduction). We conducted a large European experiment to assess the SMR trait in different populations of honey bees spread over 13 different countries, and representing different honey bee populations. The first goal was to standardize and validate the SMR evaluation method, and then to compare the SMR trait between the different populations. Our results indicate that it is necessary to examine at least 35 brood cells infested by a single mite to reliably estimate the SMR score of any given colony. Several colonies from our dataset display high SMR scores, indicating that this trait is present within the European honey bee populations. No major differences could be identified between countries for a given population, or between populations in different countries. This study shows the potential to increase selection efforts to breedV. destructorhoney bee resistant populations. In the fight against theVarroa destructormite, selective breeding of honey bee (Apis melliferaL.) populations that are resistant to the parasitic mite stands as a sustainable solution. Selection initiatives indicate that using the suppressed mite reproduction (SMR) trait as a selection criterion is a suitable tool to breed such resistant bee populations. We conducted a large European experiment to evaluate the SMR trait in different populations of honey bees spread over 13 different countries, and representing different honey bee genotypes with their local mite parasites. The first goal was to standardize and validate the SMR evaluation method, and then to compare the SMR trait between the different populations. Simulation results indicate that it is necessary to examine at least 35 single-infested cells to reliably estimate the SMR score of any given colony. Several colonies from our dataset display high SMR scores indicating that this trait is present within the European honey bee populations. The trait is highly variable between colonies and some countries, but no major differences could be identified between countries for a given genotype, or between genotypes in different countries. This study shows the potential to increase selective breeding efforts ofV. destructorresistant populations

Changes to the sebum lipidome upon COVID-19 infection observed via rapid sampling from the skin

Background: The COVID-19 pandemic has led to an unprecedented demand for testing - for diagnosis and prognosis - as well as for investigation into the impact of the disease on the host metabolism. Sebum sampling has the potential to support both needs by looking at what the virus does to us, rather than looking for the virus itself. Methods: In this pilot study, sebum samples were collected from 67 hospitalised patients (30 COVID-19 positive and 37 COVID-19 negative) by gauze swab. Lipidomics analysis was carried out using liquid chromatography mass spectrometry, identifying 998 reproducible features. Univariate and multivariate statistical analyses were applied to the resulting feature set. Findings: Lipid levels were depressed in COVID-19 positive participants, indicative of dyslipidemia; p-values of 0·022 and 0·015 were obtained for triglycerides and ceramides respectively, with effect sizes of 0·44 and 0·57. Partial Least Squares-Discriminant Analysis showed separation of COVID-19 positive and negative participants with sensitivity of 57% and specificity of 68%, improving to 79% and 83% respectively when controlled for confounding comorbidities. Interpretation: COVID-19 dysregulates many areas of metabolism; in this work we show that the skin lipidome can be added to the list. Given that samples can be provided quickly and painlessly, we conclude that sebum is worthy of future consideration for clinical sampling. Funding: The authors acknowledge funding from the EPSRC Impact Acceleration Account for sample collection and processing, as well as EPSRC Fellowship Funding EP/R031118/1, the University of Surrey and BBSRC BB/T002212/1. Mass Spectrometry was funded under EP/P001440/1

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD

Beyond gene-disease validity: capturing structured data on inheritance, allelic requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions

Background: As the availability of genomic testing grows, variant interpretation will increasingly be performed by genomic generalists, rather than domain-specific experts. Demand is rising for laboratories to accurately classify variants in inherited cardiac condition (ICC) genes, including secondary findings. // Methods: We analyse evidence for inheritance patterns, allelic requirement, disease mechanism and disease-relevant variant classes for 65 ClinGen-curated ICC gene-disease pairs. We present this information for the first time in a structured dataset, CardiacG2P, and assess application in genomic variant filtering. // Results: For 36/65 gene-disease pairs, loss of function is not an established disease mechanism, and protein truncating variants are not known to be pathogenic. Using the CardiacG2P dataset as an initial variant filter allows for efficient variant prioritisation whilst maintaining a high sensitivity for retaining pathogenic variants compared with two other variant filtering approaches. // Conclusions: Access to evidence-based structured data representing disease mechanism and allelic requirement aids variant filtering and analysis and is a pre-requisite for scalable genomic testing

The Codevelopment of “My Kidneys & Me”: A Digital Self-management Program for People With Chronic Kidney Disease

Background: Health care self-management is important for people living with nondialysis chronic kidney disease (CKD). However, the few available resources are of variable quality. Objective: This work describes the systematic codevelopment of “My Kidneys & Me” (MK&M), a theory-driven and evidence-based digital self-management resource for people with nondialysis CKD, guided by an established process used for the successful development of the diabetes education program MyDESMOND (Diabetes Education and Self-Management for Ongoing and Newly Diagnosed, DESMOND). Methods: A multidisciplinary steering group comprising kidney health care professionals and researchers and specialists in the development of complex interventions and digital health provided expertise in the clinical and psychosocial aspects of CKD, self-management, digital health, and behavior change. A patient and public involvement group helped identify the needs and priorities of MK&M and co-design the resource. MK&M was developed in 2 sequential phases. Phase 1 involved the codevelopment process of the MK&M resource (content and materials), using Intervention Mapping (IM) as a framework. The first 4 IM steps guided the development process: needs assessment was conducted to describe the context of the intervention; intervention outcomes, performance objectives, and behavioral determinants were identified; theory- and evidence-based change methods and practical strategies to deliver change methods were selected; and program components were developed and refined. Phase 2 involved the adoption and adaptation of the existing MyDESMOND digital platform to suit the MK&M resource. Results: The needs assessment identified that individuals with CKD have multiple differing needs and that delivering a self-management program digitally would enable accessible, tailored, and interactive information and support. The intended outcomes of MK&M were to improve and maintain effective self-management behaviors, including physical activity and lifestyle, improve knowledge, promote self-care skills, increase self-efficacy, and enhance well-being. This was achieved through the provision of content and materials designed to increase CKD knowledge and patient activation, reduce health risks, manage symptoms, and improve physical function. Theories and behavior change techniques selected include Self-Management Framework, Capability, Opportunity, Motivation Behavior model components of Behaviour Change Wheel and taxonomy of behavior change techniques, Health Action Process Approach Model, Common Sense Model, and Social Cognitive Theory. The program components developed comprised educational and behavior change sessions, health trackers (eg, monitoring blood pressure, symptoms, and exercise), goal-setting features, and forums for social support. The MyDESMOND digital platform represented an ideal existing platform to host MK&M; thus, the MyDESMOND interface and features were adopted and adapted for MK&M. Conclusions: Applying the IM framework enabled the systematic application of theory, empirical evidence, and practical perspectives in the codevelopment of MK&M content and materials. Adopting and adapting a preexisting platform provided a cost- and time-efficient approach for developing our digital intervention. In the next stage of work, the efficacy of MK&M in increasing patient activation will be tested in a randomized controlled trial

Speech Communication

Contains table of contents for Part IV, table of contents for Section 1, an introduction, reports on seven research projects and a list of publications.C.J. Lebel FellowshipDennis Klatt Memorial FundNational Institutes of Health Grant T32-DC00005National Institutes of Health Grant R01-DC00075National Institutes of Health Grant F32-DC00015National Institutes of Health Grant R01-DC00266National Institutes of Health Grant P01-DC00361National Institutes of Health Grant R01-DC00776National Science Foundation Grant IRI 89-10561National Science Foundation Grant IRI 88-05680National Science Foundation Grant INT 90-2471

Speech Communication

Contains table of contents for Part V, table of contents for Section 1, reports on six research projects and a list of publications.C.J. Lebel FellowshipDennis Klatt Memorial FundNational Institutes of Health Grant R01-DC00075National Institutes of Health Grant R01-DC01291National Institutes of Health Grant R01-DC01925National Institutes of Health Grant R01-DC02125National Institutes of Health Grant R01-DC02978National Institutes of Health Grant R01-DC03007National Institutes of Health Grant R29-DC02525National Institutes of Health Grant F32-DC00194National Institutes of Health Grant F32-DC00205National Institutes of Health Grant T32-DC00038National Science Foundation Grant IRI 89-05249National Science Foundation Grant IRI 93-14967National Science Foundation Grant INT 94-2114

Beyond gene-disease validity: capturing structured data on inheritance, allelic-requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions

BACKGROUND: As availability of genomic testing grows, variant interpretation will increasingly be performed by genomic generalists, rather than domain-specific experts. Demand is rising for laboratories to accurately classify variants in inherited cardiac condition (ICC) genes, including as secondary findings. METHODS: We analyse evidence for inheritance patterns, allelic requirement, disease mechanism and disease-relevant variant classes for 65 ClinGen-curated ICC gene-disease pairs. We present this information for the first time in a structured dataset, CardiacG2P, and assess application in genomic variant filtering. RESULTS: For 36/65 gene-disease pairs, loss-of-function is not an established disease mechanism, and protein truncating variants are not known to be pathogenic. Using CardiacG2P as an initial variant filter allows for efficient variant prioritisation whilst maintaining a high sensitivity for retaining pathogenic variants compared with two other variant filtering approaches. CONCLUSIONS: Access to evidence-based structured data representing disease mechanism and allelic requirement aids variant filtering and analysis and is pre-requisite for scalable genomic testing