PerR controls oxidative stress defence and aerotolerance but not motility-associated phenotypes of Campylobacter jejuni

The foodborne bacterial pathogen Campylobacter jejuni is an obligate microaerophile, which is exposed to atmospheric oxygen during transmission through the food chain. Survival under aerobic conditions requires the concerted control of oxidative stress systems, which in C. jejuni are intimately connected with iron metabolism via the PerR and Fur regulatory proteins. Here we have characterised the roles of C. jejuni PerR in oxidative stress- and motility phenotypes, and its regulon at the level of transcription, protein expression and promoter interactions. Insertional inactivation of perR in the C. jejuni reference strains NCTC 11168, 81-176 and 81116 did not result in any growth deficiencies, but strongly increased survival in atmospheric oxygen conditions, and allowed growth around filter discs infused with up to 30% H2O2 (8.8 M). Expression of catalase, alkyl hydroperoxide reductase, thioredoxin reductase and the Rrc desulforubrerythrin were increased in the perR mutant, and this was mediated at the transcriptional level as shown by electrophoretic mobility shift assays of the katA, ahpC and trxB promoters using purified PerR. Differential RNA-seq analysis of a fur perR mutant allowed the identification of eight previously unknown transcription start sites of genes controlled by either Fur and/or PerR. Finally, inactivation of perR in C. jejuni did not result in reduced motility, and did not reduce killing of Galleria melonella wax moth larvae. In conclusion, PerR plays an important role in controlling oxidative stress resistance and aerobic survival of C. jejuni, but this role does not extend into control of motility and associated phenotypes

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Purpose: Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods: Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results: The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion: We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Physiologic Changes in a Nonhuman Primate Model of HIV-Associated Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is increased in HIV, but its pathogenesis is not fully understood. Nonhuman primates infected with simian immunodeficiency virus (SIV) or SIV-HIV chimeric virus (SHIV) exhibit histologic changes characteristic of human PAH, but whether hemodynamic changes accompany this pathology is unknown. Repeated measurements of pulmonary artery pressures would permit longitudinal assessments of disease development and provide insights into pathogenesis. We tested the hypothesis that SIV-infected and SHIV-infected macaques develop physiologic manifestations of PAH. We performed right heart catheterizations, echocardiography, and computed tomography (CT) scans in macaques infected with either SIV (ΔB670) or SHIV (89.6P), and compared right heart and pulmonary artery pressures, as well as pulmonary vascular changes on CT scans, with those in uninfected control animals. Right atrial, right ventricular systolic, and pulmonary artery pressures (PAPs) were significantly elevated in 100% of macaques infected with either SIV or SHIV compared with control animals, with no difference in pulmonary capillary wedge pressure. PAPs increased as early as 3 months after SIV infection. Radiographic evidence of pulmonary vascular pruning was also found. Both SIV-infected and SHIV-infected macaques exhibited histologic changes in pulmonary arteries, predominantly consisting of intimal and medial hyperplasia. This report is the first to demonstrate SHIV-infected and SIV-infected macaques develop pulmonary hypertension at a high frequency, with physiologic changes occurring as early as 3 months after infection. These studies establish an important nonhuman primate model of HIV-associated PAH that will be useful in studies of disease pathogenesis and the efficacy of interventions

Pulmonary Vascular Lesions Are Common in SIV- and SHIV-env-Infected Macaques

The lack of animal models of HIV-related pulmonary arterial hypertension (HIV-PAH) severely limits investigation of this serious disease. While histological evidence of HIV-PAH has been demonstrated in macaques infected with simian immunodeficiency virus (SIV) as well as with chimeric simian/human immunodeficiency virus (SHIV) containing HIV-1-derived Nef protein, other primate models have not been studied. The objective was to document and describe the development of pulmonary vascular changes in macaques infected with SIV or with SIV containing HIV-1-derived envelope protein (SHIV-env). Lung tissue was obtained at necropsy from 13 SHIV (89.6P)-env-infected macaques and 10 SIV (ΔB670)-infected macaques. Pulmonary arterial pathology, including arterial hyperplasia and the presence of plexiform lesions, was compared to normal monkey lung. Pulmonary artery hyperplasia was present in 8 of 13 (62%) SHIV-env-infected macaques and 4/10 (36%) SIV-infected macaques. The most common histopathological lesions were intimal and medial hyperplasia of medium and large pulmonary arteries. Hyperplastic lesions were predominantly due to smooth muscle cell hyperplasia. This is the first report of pulmonary vascular lesions in SHIV-env-infected macaques and confirms prior reports of pulmonary vasculopathy in SIV-infected macaques. The finding of pulmonary arteriopathy in monkeys infected with SHIV not containing HIV-nef suggests that other factors might also be important in the development of HIV-PAH. This SHIV-env model provides a new means to investigate HIV-PAH

Relationship Processes in Youth Psychotherapy: Measuring Alliance, Alliance Building Behaviors, and Client Involvement

This study explores hypothesized associations among therapist engagement strategies, therapeutic alliance, client involvement, and treatment outcome in a randomized clinical trial comparing cognitive behavioral psychotherapy and nondirective supportive psychotherapy for adolescents with depressive symptoms who have attempted suicide. Ratings from audiotapes and self-report of the first four sessions for 23 adolescent clients were used. It was expected that therapeutic relationship variables would be equally important in both treatments. However, preliminary evidence appeared to be emerging only for therapeutic alliance and client involvement being related to treatment outcome in the cognitive behavioral treatment. Therapist lapse behaviors were found to predict alliance across both treatments. On the other hand, there was some preliminary evidence for different therapist behaviors to be related to the therapeutic alliance in each treatment. Results suggest that there may be variation in effective relationship factors, depending on the specific therapeutic approach

Reviews of Books

BARRY CUNLIFFE. Europe between the Oceans: Themes and Variations: gooo BCAD 1000. New Haven, C T and London: Yale University Press, 2008. Pp. ix, 518. $39.95 (US). Reviewed by Martin W. Lewis AYSE DEVRIM ATAUZ. Eight Thousand Years of Maltese Maritime History: Trade, Piracy, and Naval Warfare in the Central Mediterranean. Gainesville, FL: University Press of Florida, 2008. Pp. xiv, 379.$69.95 (US). Reviewed by Victor Mallia-Milanes IAN WORTHINGTON. Philip II of Macedonia. New Haven, CT and London: Yale University Press, 2008. Pp. xx, 303. $35.00 (US). Reviewed by Craige B. Champion FEDERICO SANTANGELO. Sulla, the Elites, and the Empire: A Study of Roman Policies in Italy and the Greek East. Leiden: Brill, 2007. Pp. xix, 230. €99.00. Reviewed by Arthur M. Eckstein ROSAMOND MCKITTERICK. Charlemagne: The Formation of a European Identity. New York, NY: Cambridge University Press, 2008. Pp. xviii, 460.$29.99 (US), paper.Reviewed by David S. Bachrach STEVE FLANDERS. De Courcy: Anglo-Normans in Ireland, England, and France in the Eleventh and Twelfth Centuries. Dublin and Portland, OR: Four Courts Press, 2008. Pp. 205. $75.00 (US). Reviewed by Hugh M. Thomas JONATHAN RILEY-SMITH. The Crusades, Christianity, and Islam. New York, NY: Columbia University Press, 2008. Pp. 125.$24.50 (US). Reviewed by John France NORMAN HOUSLEY. Fighting for the Cross: Crusading to the Holy Land. New Haven, CT and London: Yale University Press, 2008. Pp. xiv, 357. $38.00 (US).Reviewed by Christopher Tyerman BERNARD BARBICHE in collaboration with Ségolène de Dainville-Barbiche. Bulla, Legatus, Nuntius: Études de diplomatique et de diplomatic pontificales (Xllle-XVIIe siècle). Paris: École des Chartes, 2007; dist. Geneva: Librairie Droz. Pp. 575.€55.00, paper. Reviewed by Barbara Bombi INA BAGHDIANTZ MCCABE. Orientalism in Early Modern France: Eurasian Trade, Exoticism, and the Ancien Régime. Oxford and New York, NY: Berg, 2008. Pp. vi, 409.$119.95 (US). Reviewed by Lynn Hunt JOHN A. LYNN. Women, Armies, and Warfare in Early Modern Europe. New York, NY: Cambridge University Press, 2008. Pp. xii, 239. $24.99 (u s), paper. Reviewed by Peter H. Wilson ULBE BOSMA and REMCO RABEN. Being 'Dutch' in the Indies: A History of Creolisation and Empire, 1500-1920, trans. Wendie Shaffer. Athens, OH: Ohio University Research in International Studies, 2008. Pp. xx, 439.$28.00 (US), paper. Reviewed by Heather Sutherland DAVID ELTIS and DAVID RICHARDSON, eds. Extending the Frontiers: Essays on the Mew Transatlantic Slave Trade Database. New Haven, CT and London: Yale University Press, 2008. Pp. xiii,377. $90.00 (US).Reviewed by Stephen D. Behrendt LOTHAR HÖBELT. Ferdinand III: Friedenskaiser wider Willen. Graz: Ares Verlag, 2008. Pp. 488. €29.90. Reviewed by Howard Louthan STEVE CLARK and PAUL SMETHURST, eds. Asian Crossings: Travel Writing on China, Japan, and Southeast Asia. Hong Kong: Hong Kong University Press, 2008; dist. Seattle, WA: University of Washington Press. Pp. xi, 276.$37.50 (US), paper. Reviewed by Eric Tagliacozzo TOBY BARNARD. Improving Ireland? Projectors, Prophets, and Profiteers, 1641-1786. Dublin and Portland, OR: Four Courts Press, 2008. Pp. 192. $75.00 (US).Reviewed by Padraig Lenihan LEONARD BLUSSE. Visible Cities: Canton, Nagasaki, and Batavia and the Coming of the Americans. Cambridge, MA and London: Harvard University Press, 2008. Pp. xi, 133.$25.95 (US). Reviewed by Peter D. Reeves DAVID SORKIN. The Religious Enlightenment: Protestants, Jews, and Catholics from London to Vienna. Princeton, NJ and Oxford: Princeton University Press, 2008. Pp. xv, 339. $35.00 (US). Reviewed by Thomas Munck HERVÉ HASQUIN. Joseph II: Catholique anticlérical et réformateur impatient, 1741-1790. Brussels: Éditions Racine, 2007. Pp. 328. €29.95, paper.Reviewed by Matthew Z. Mayer ANDREW LEES and LYNN HOLLEN LEES. Cities and the Making of Modern Europe, 1750-1914. New York, NY: Cambridge University Press, 2007. Pp. xii, 300.$29.95 (US), paper. Reviewed by Richard Dennis MAURICE J. BRIC. Ireland, Philadelphia, and the Re-Invention of America, 1760- 1800. Dublin and Portland, OR: Four Courts Press, 2008. Pp. xix, 363. $65.00 (US); JOHN CHILDS. The Williamite Wars in Ireland, 1688-91. London and New York, NY: Hambledon Continuum, 2007. Pp. xxii, 440.$49.95 (US).Reviewed by Thomas Bartlett MATT SCHUMANN and KARL SCHWEIZER. The Seven Years War: A Transatlantic History.London and New York, NY: Routledge, 2008. Pp. x, 300. $140.00 (US). Reviewed by Stephen Conway WALTER L. HIXSON. The Myth of American Diplomacy: National Identity and US Foreign Policy. New Haven, CT and London: Yale University Press, 2008. Pp. xi, 377.$35.00 (US). Reviewed by Mark Atwood Lawrence PATRICIA H. MARKS. Deconstructing Legitimacy: Viceroys, Merchants, and the Military in Late Colonial Peru. University Park, PA: Pennsylvania State University Press, 2007. Pp. x, 403. $65.00 (US). Reviewed by Natalia Sobrevilla Perea MARIANNE P. STOPP, ed. The Mew Labrador Papers of Captain George Cartwright. Montreal, QC and Kingston, ON: McGill-Queen's University Press, 2008. Pp. xii, 256.$39.95 (CDN). Reviewed by James K. Hiller THIERRY LENTZ. Nouvelle histoire du Premier Empire: III: La France et l'Europe de Napoléon, 1804-1814. Paris: Editions Fayard, 2007. Pp. 835. €30.00, paper. Reviewed by Philip G. Dwyer MATTHEW P. FITZPATRICK. Liberal Imperialism in Germany: Expansionism and Nationalism, 1848-1884. New York, NY and Oxford: Berghahn Books, 2008. Pp. 237. $99.95 (US). Reviewed by Jonathan Sperber CHRISTIAN HOYER. Salisbury und Deutschland: Aufienpolitisches Denken und britische Deutschlandpolitik zwischen 1856 und 1880. Husum: Matthiesen Verlag, 2008. Pp. 507. €69.00. Reviewed by Ann Potttnger Saab ANDREW SMITH. British Businessmen and Canadian Confederation: Constitution Making in an Era of Anglo-Globalization. Montreal, QC and Kingston, ON: McGill-Queen's University Press, 2008. Pp. viii, 229.$80.00 (CDN). Reviewed by Douglas Mccalla DUNCAN ANDREW CAMPBELL. Unlikely Allies: Britain, America, and the Victorian Origins of a Special Relationship. London and New York, NY: Continuum, 2008. Pp. viii, 307. $34.95 (US). Reviewed by Francis M. Carroll MARILYN LAKE and HENRY REYNOLDS. Drawing the Global Colour Line: White Men's Countries and the International Challenge of Racial Equality. New York, NY: Cambridge University Press, 2008. Pp. x, 371.$94.95 (US). Reviewed by Antoinette Burton CHRISTOPHER KOBRAK. Banking on Global Markets: Deutsche Bank and the United States, 1870 to the Present. New York, NY: Cambridge University Press, 2007. Pp. xx, 484. $45.00 (US). Reviewed by William Glenn Gray CECILIA MORGAN. 'A Happy Holiday': English Canadians and Transatlantic Tourism, 1870-1930. Toronto, ON: University of Toronto Press, 2008. Pp. xxiii, 461.$37.95 (CDN), paper. Reviewed by Katie Pickles BILL RAWLING. La mart pour ennemi: La médecine militaire canadienne, 2nd ed., trans. Pierre R. Desrosiers. Outremont, QC: Athéna éditions, 2007; dist. Boisbriand, QC: Prologue. Pp. 373. $34.95 (CDN), paper. Reviewed by Genevieve Allard SONYA GRYPMA. Healing Henan: Canadian Nurses at the North China Mission, l888-1947. Vancouver, BC: University of British Columbia Press, 2008. Pp. xviii, 292.$32.95 (CDN), paper. Reviewed by A. Hamish Ion OLIVER STEIN. Die deutscke Heeresriistungspolitik, 1890-1914: Das Militär und der Primat der Politik. Paderborn: Verlag Ferdinand Schoningh, 2007. Pp. 444. €58.00; PETER BAUMGART, BERNHARD R. KROENER, and HEINZ STUBIG, eds. Die Preussische Armee: Zwischen Ancien Régime und Reichsgriindung. Paderborn: Verlag Ferdinand Schoningh, 2008. Pp. xiii, 283. €39.90. Reviewed by Holger H. Herwig IRWIN HALFOND. Maurice Paléologue: The Diplomat, the Writer, the Man, and the Third French Republic. Lanham, MD: University Press of America, 2007. Pp. xiii, 189. $29.95 (US), paper. Reviewed by Ronald P. Bobroff PATRICK H. HASE. The Six-Day War ofiSgg: Hong Kong in the Age of Imperialism. Hong Kong: Hong Kong University Press, 2008; dist. Seattle, WA: University of Washington Press. Pp. xii, 276.$49.50 (US).Reviewed by Priscilla Roberts JEROME AAN DE WIEL. The Irish Factor, 1899-1999: Ireland's Strategic and Diplomatic Importance for Foreign Powers. Dublin and Portland, OR: Irish Academic Press, 2008. Pp. xx, 428. $75.00 (US). Reviewed by David Harkness NICOLAS WOLZ. Das lange Warten: Kriegserfahrungen deutscher und britischer Seeojfziere, 1914 bis 1918. Paderborn: Verlag Ferdinand Schöningh, 2008. Pp. 519. €39.90. Reviewed by Jan Rüger PAUL O'SHEA. A Cross Too Heavy: Eugenio Pacelli: Politics and the Jews of Europe, 1917-1943. Kenthurst, NSW: Rosenberg Publishing, 2008; dist. Portland, OR: ISBS. Pp. 392.$35.00 (US), paper. Reviewed by Frank J. Coppa S. A. SMITH. Revolution and the People in Russia and China: A Comparative History. New York, NY: Cambridge University Press, 2008. Pp. viii, 249. $29.99 (USX paper. Reviewed by Stephen R. Mackinnon DANIELA ROSSINI. Woodrow Wilson and the American Myth in Italy: Culture, Diplomacy, and War Propaganda, trans. Antony Shugaar. Cambridge, MA and London: Harvard University Press, 2008. Pp. x, 263.$49.95 (US). Reviewed by R. J. B. Bosworth SEAN GREENWOOD. Titan at the Foreign Office: Gladwyn Jebb and the Shaping of the Modern World. Leiden and Boston MA: Martinus Nijhoff, 2008. Pp. xxx, 440. €129.00. Reviewed by John W. Young ROLF STEININGER. Austria, Germany, and the Cold War: From the Anschluss to the State Treaty, 1938-1955. New York, NY and Oxford: Berghahn Books, 2008. Pp. x, 172. $60.00 (US). Reviewed by Lothar Hobelt KURT F.JENSEN. Cautious Beginnings: Canadian Foreign Intelligence, 1939-51. Vancouver, BC: University of British Columbia Press, 2008. Pp. 230.$32.95 (CDN), paper. Reviewed by John Ferris MICHAEL KENNEDY. Guarding Neutral Ireland: The Coast Watching Service and Military Intelligence, 1939-1945. Dublin and Portland, OR: Four Courts Press, 2008. Pp. x, 358. $55.00 (US). Reviewed by Keith Jeffery RICHARD WIGG. Churchill and

Implementing stakeholder engagement to explore alternative models of consent: An example from the PREP-IT trials

Introduction: Cluster randomized crossover trials are often faced with a dilemma when selecting an optimal model of consent, as the traditional model of obtaining informed consent from participant's before initiating any trial related activities may not be suitable. We describe our experience of engaging patient advisors to identify an optimal model of consent for the PREP-IT trials. This paper also examines surrogate measures of success for the selected model of consent. Methods: The PREP-IT program consists of two multi-center cluster randomized crossover trials that engaged patient advisors to determine an optimal model of consent. Patient advisors and stakeholders met regularly and reached consensus on decisions related to the trial design including the model for consent. Patient advisors provided valuable insight on how key decisions on trial design and conduct would be received by participants and the impact these decisions will have. Results: Patient advisors, together with stakeholders, reviewed the pros and cons and the requirements for the traditional model of consent, deferred consent, and waiver of consent. Collectively, they agreed upon a deferred consent model, in which patients may be approached for consent after their fracture surgery and prior to data collection. The consent rate in PREP-IT is 80.7%, and 0.67% of participants have withdrawn consent for participation. Discussion: Involvement of patient advisors in the development of an optimal model of consent has been successful. Engagement of patient advisors is recommended for other large trials where the traditional model of consent may not be optimal