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This thesis investigates the origins and impact of electrical telegraphy in Germany between 1830 and 1880, situating them within the context of long-term transformations in the theory and practice of communication. It uses the development of telegraphy as an analytical lens through which to explore the connections between actors at the heart of the socio-economic transformations taking place in Germany during the period. Both as an innovation and as a tool of communication, this thesis argues, the telegraph epitomised the simultaneously growing interdependence and differentiation between people and places which was a defining characteristic of modernity. By exploring the motivations and interactions of scientists, entrepreneurs, state officials, and ordinary users who engaged with the technology, this thesis highlights the diverse expectations which were placed upon telegraphy, and the many different directions in which its development was pulled. In doing so, it reveals the ties between the ‘modernising’ processes with which the technology has been associated. It challenges linear narratives of technological innovation which focus exclusively upon individual or state actors, emphasising the cooperation and collaboration across society which was necessary to produce the telegraph. It similarly questions triumphalist interpretations of the 'communications revolution' so often attributed to the nineteenth century, emphasising instead the tensions and divisions which it also generated. Revisiting the themes of industrialisation, capitalism, community and bourgeois class-formation in nineteenth-century Germany in this light, this thesis emphasises their intrinsic interdependence, and the inevitable mixture of hopes and anxieties, expectations and frustrations, which it produced.

Lauren M Nelson,1 Valerie SL Williams,1 Sheri E Fehnel,1 Robyn T Carson,2 James MacDougall,3 Mollie J Baird,3 Stavros Tourkodimitris,2 Caroline B Kurtz,3 Jeffrey M Johnston31RTI Health Solutions, Durham, NC, USA; 2Forest Research Institute, Jersey City, NJ, USA; 3Ironwood Pharmaceuticals, Cambridge, MA, USABackground: Measures assessing treatment outcomes in previous CC clinical trials have not met the requirements described in the US Food and Drug Administration's guidance on patient-reported outcomes.Aim: Psychometric analyses using data from one Phase IIb study and two Phase III trials of linaclotide for the treatment of chronic constipation (CC) were conducted to document the measurement properties of patient-reported CC Symptom Severity Measures.Study methods: Each study had a multicenter, randomized, double-blind, placebo-controlled, parallel-group design, comparing placebo to four doses of oral linaclotide taken once daily for 4 weeks in the Phase IIb dose-ranging study (n=307) and to two doses of linaclotide taken once daily for 12 weeks in the Phase III trials (n=1,272). The CC Symptom Severity Measures addressing bowel function (Bowel Movement Frequency, Stool Consistency, Straining) and abdominal symptoms (Bloating, Abdominal Discomfort, Abdominal Pain) were administered daily using interactive voice-response system technology. Intraclass correlations, Pearson correlations, factor analyses, F-tests, and effect sizes were computed.Results: The CC Symptom Severity Measures demonstrated satisfactory test–retest reliability and construct validity. Factor analyses indicated one factor for abdominal symptoms and another for bowel symptoms. Known-groups F-tests substantiated the discriminating ability of the CC Symptom Severity Measures. Responsiveness statistics were moderate to strong, indicating that these measures are capable of detecting change.Conclusion: In large studies of CC patients, linaclotide significantly improved abdominal and bowel symptoms. These psychometric analyses support the reliability, validity, discriminating ability, and responsiveness of the CC Symptom Severity Measures for evaluating treatment outcomes in the linaclotide clinical studies.Keywords: psychometric evaluation, patient-reported outcomes, linaclotide

Claire M Ervin,1 Sheri E Fehnel,1 Mollie J Baird,2 Robyn T Carson,3 Jeffrey M Johnston,2 Steven J Shiff,3 Caroline B Kurtz,2 Allen W Mangel11RTI Health Solutions, Research Triangle Park, NC, USA; 2Ironwood Pharmaceuticals, Inc., Cambridge, MA, USA; 3Forest Research Institute, Jersey City, NJ, USABackground: While chronic constipation (CC) clinical trials have focused primarily on bowel symptoms (symptoms directly related to bowel movements), abdominal symptoms are also prevalent among patients. The United States Food and Drug Administration’s (FDA’s) guidance on the use of patient-reported outcome measures to support product approvals or labeling claims recommends that endpoints be developed with direct patient input and include all symptoms important to patients.Aim: To identify a comprehensive set of CC symptoms that are important to patients for measurement in clinical trials.Methods: Following a targeted literature review to identify CC symptoms previously reported by patients, 28 patient interviews were conducted consistent with the FDA’s guidance on patient-reported outcomes. Subsequent to open-ended questions eliciting descriptions of all symptoms, rating and ranking methods were used to identify those of greatest importance to patients.Results: All 67 studies reviewed included bowel symptoms; more than half also addressed at least one abdominal symptom. Interview participants reported 62 potentially distinct concepts: 12 bowel symptoms; 21 abdominal symptoms; and 29 additional symptoms/impacts. Patients’ descriptions revealed that many symptom terms were highly related and/or could be considered secondary to CC. The rating and ranking task results suggest that both bowel (for example, stool frequency and consistency) and abdominal symptoms (for example, bloating, abdominal pain) comprise patients’ most important symptoms. Further, improvements in both bowel and abdominal symptoms would constitute an improvement in patients’ CC overall.Conclusion: Abdominal symptoms in CC patients are equal in relevance to bowel symptoms and should also be addressed in clinical trials to fully evaluate treatment benefit.Keywords: abdominal symptoms, straining, infrequent bowel movements, incomplete bowel movements, patient-reported outcomes

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Purpose : Burkitt's lymphoma is a malignancy of mature, immunoglobulin (Ig)-bearing B cells characterized by translocation between c-myc and Ig gene loci. A role for the juxtaposed Ig genes in the mutation and deregulation of c-myc expression typical of endemic Burkitt's lymphoma (eBL) has been proposed, but never proven. Our objective was to determine whether Ig gene hypermutation is ongoing in eBL. Methods : We isolated Ig heavy-chain sequences from K962 eBL tumor cells using reverse transcription and polymerase chain reaction (PCR) amplification. The PCR product was ligated into Bluescript II vectors. Multiple subclones were sequenced and the variable regions were compared for evidence of ongoing Ig hypermutation. Results : Six total single base substitutions were observed within four of the nine subclones studied. Four substitutions resulted in amino acid changes and two were silent. There was no clustering of mutations in hypervariable regions, or a high incidence of amino acid replacement or link substitutions, all of which are characteristic of Ig hypermutation. The observed mutations occurred at a rate consistent with Taq polymerase error. Conclusions : Our data indicate that in the eBL tumor sample K962, the mechanism underlying c-myc mutation is distinct from that which gives rise to Ig hypermutation.