Longitudinale Untersuchung zu den Auswirkungen des Rauchens in Filmen auf die Etablierung des Rauchens im Jugendalter

Fragestellung: Die Exposition mit Tabakrauchereignissen in Kinofilmen ist neben andern Faktoren ein wichtiger Risikofaktor für die Initiierung des Rauchens bei Jugendlichen. Allerdings liegen wenige Erkenntnisse vor, ob dies auch für fortgeschrittene Stadien des Tabakkonsums gilt. Wir führten eine longitudinale Studie unter 4112 Schülerinnen und Schülern aus Schleswig-Holstein durch, um festzustellen, ob frühe Exposition mit Tabakrauchereignissen durch Kinofilme das etablierte Rauchen im Jugendalter prognostizieren kann. Methoden: Im Oktober/November 2005 wurden 5586 10-17-jährigen Schülerinnen und Schülern aus 27 randomisiert ausgewählten öffentlichen Lehranstalten mit Sekundarstufe I der KERN-Region Schleswig-Holsteins mit Hilfe eines Fragebogens befragt. Aus einem Pool von 398 international verbreiteten Kinofilmen wurde jedem Jugendlichen eine Liste von 50 randomisiert ausgewählten Filmen vorgelegt. Die teilnehmenden Jugendlichen wurden gebeten anzugeben, welche Filme sie gesehen hatten. Zeitgleich wurden diese 398 international verbreiteten Kinofilme von trainierten Ratern nach validierten Methoden inhaltanalytisch ausgewertet und für jeden Film die Anzahl der Tabakrauchereignisse definiert als Tabakrauchexposition bestimmt. Durch die Zusammenführung der Information, welche Filme der Jugendliche bereits gesehen hat mit der Information, wie viele Tabakrauchszenen in diesen Kinofilmen vorkommen, kann das Expositionsmaß, ausgedrückt über die Anzahl gesehener Tabakrauchereignisse, geschätzt werden. In einer Follow-up-Untersuchung 12 bis 13 Monate nach der Ersterhebung konnten 4112 Schüler und Schülerinnen (= 89,3 %) erneut interviewt werden. Mit Hilfe von Generalisierten Linearen Modellen wurde die Initiierung des etablierten Rauchens, definiert als der Konsum von mehr als 100 Zigaretten im Beobachtungszeitraum, als Funktion der Tabakrauchexposition in Filmen unter Berücksichtigung diverser Kovariablen analysiert. Ergebnisse: 272 (= 6,61 %) der initial befragten Jugendliche wurden in der Follow-up-Befragung als etablierte Raucher klassifiziert, da sie angaben, mehr als 100 Zigaretten konsumiert zu haben. Nach Adjustierung weiterer Störgrößen wie soziodemographischen Kovariablen, sozialen Einflüssen, Persönlichkeitsfaktoren sowie elterlichem Erziehungsstil in der multivariaten Analyse zeigt die Inzidenz der Initiierung des etablierten Rauchens einen klaren Zusammenhang mit steigender Exposition gegenüber Tabakrauchereignissen. In Quartil 1 beträgt die Inzidenz, mit dem etablierten Rauchen zu beginnen, 2,1 % (n= 22), 3,6 % (n= 37) in Quartil 2, 7,3 % (n= 75) in Quartil 3 und in Quartil 4 13,4 % (n= 138). Verglichen mit der niedrigsten Exposition im Quartil 1 beträgt das adjustierte relative Risiko der Initiierung des etablierten Rauchens im Quartil mit der höchsten Exposition mit Tabakrauchereignissen in Filmen (Quartil 4) 2,05 (95 % KI 1,25-3,35). Schlussfolgerung: In früheren Studien konnte gezeigt werden, dass das Rauchen in international verbreiteten Kinofilmen mit frühen Stadien des Tabakkonsums deutscher Jugendliche assoziiert ist. In dieser Untersuchung blieb der Effekt der Exposition mit Tabakrauchszenen in Filmen statistisch bedeutsam, selbst wenn eine Fülle weiterer Risikofaktoren der Initiierung des Rauchens berücksichtigt wurde. Dieser stabile Befund rechtfertigt die Schlussfolgerung, dass das Rauchen in Filmen als ein eigenständiger Risikofaktor für die Initiierung des etablierten Rauchens im Jugendalter angesehen werden muss

Host restriction, pathogenesis and chronic carriage of typhoidal Salmonella.

While conjugate vaccines against typhoid fever have recently been recommended by the World Health Organization for deployment, the lack of a vaccine against paratyphoid, multidrug resistance and chronic carriage all present challenges for the elimination of enteric fever. In the past decade, the development of in vitro and human challenge models has resulted in major advances in our understanding of enteric fever pathogenesis. In this review, we summarise these advances, outlining mechanisms of host restriction, intestinal invasion, interactions with innate immunity and chronic carriage, and discuss how this knowledge may progress future vaccines and antimicrobials

Transcriptomics in Human Challenge Models

Human challenge models, in which volunteers are experimentally infected with a pathogen of interest, provide the opportunity to directly identify both natural and vaccine-induced correlates of protection. In this review, we highlight how the application of transcriptomics to human challenge studies allows for the identification of novel correlates and gives insight into the immunological pathways required to develop functional immunity. In malaria challenge trials for example, innate immune pathways appear to play a previously underappreciated role in conferring protective immunity. Transcriptomic analyses of samples obtained in human challenge studies can also deepen our understanding of the immune responses preceding symptom onset, allowing characterization of innate immunity and early gene signatures, which may influence disease outcome. Influenza challenge studies demonstrate that these gene signatures have diagnostic potential in the context of pandemics, in which presymptomatic diagnosis of at-risk individuals could allow early initiation of antiviral treatment and help limit transmission. Furthermore, gene expression analysis facilitates the identification of host factors contributing to disease susceptibility, such as C4BPA expression in enterotoxigenic Escherichia coli infection. Overall, these studies highlight the exceptional value of transcriptional data generated in human challenge trials and illustrate the broad impact molecular data analysis may have on global health through rational vaccine design and biomarker discovery

Molecular correlates of vaccine-induced protection against typhoid fever

BACKGROUNDTyphoid fever is caused by the Gram-negative bacterium Salmonella enterica serovar Typhi and poses a substantial public health burden worldwide. Vaccines have been developed based on the surface Vi-capsular polysaccharide of S. Typhi; these include a plain-polysaccharide-based vaccine, ViPS, and a glycoconjugate vaccine, ViTT. To understand immune responses to these vaccines and their vaccine-induced immunological protection, molecular signatures were analyzed using bioinformatic approaches.METHODSBulk RNA-Seq data were generated from blood samples obtained from adult human volunteers enrolled in a vaccine trial, who were then challenged with S. Typhi in a controlled human infection model (CHIM). These data were used to conduct differential gene expression analyses, gene set and modular analyses, B cell repertoire analyses, and time-course analyses at various post-vaccination and post-challenge time points between participants receiving ViTT, ViPS, or a control meningococcal vaccine.RESULTSTranscriptomic responses revealed strong differential molecular signatures between the 2 typhoid vaccines, mostly driven by the upregulation in humoral immune signatures, including selective usage of immunoglobulin heavy chain variable region (IGHV) genes and more polarized clonal expansions. We describe several molecular correlates of protection against S. Typhi infection, including clusters of B cell receptor (BCR) clonotypes associated with protection, with known binders of Vi-polysaccharide among these.CONCLUSIONThe study reports a series of contemporary analyses that reveal the transcriptomic signatures after vaccination and infectious challenge, while identifying molecular correlates of protection that may inform future vaccine design and assessment.TRIAL REGISTRATIONClinicalTrials.gov NCT02324751

Salmonella Typhi Bactericidal Antibodies Reduce Disease Severity but Do Not Protect against Typhoid Fever in a Controlled Human Infection Model

Effective vaccines against Salmonella Typhi, a major cause of febrile illness in tropical regions, can have a significant effect as a disease control measure. Earlier work has shown that immunization with either of two Salmonella Typhi vaccines, licensed Ty21a or candidate M01ZH09, did not provide full immunity in a controlled human infection model. Here, we describe the human humoral immune responses to these oral vaccines and their functional role in protection after challenge with S. Typhi. Serum, obtained from healthy volunteers before and after vaccination with Ty21a or M01ZH09 or placebo and before and after oral challenge with wild-type S. Typhi, was assessed for bactericidal activity. Single-dose vaccination with M01ZH09 induced an increase in serum bactericidal antibodies (p = 0.001) while three doses of Ty21a did not. No association between bactericidal activity and protection against typhoid after challenge was seen in either vaccine arm. Bactericidal activity after vaccination correlated significantly with delayed disease onset (p = 0.013), lower bacterial burden (p = 0.006), and decreased disease severity scores (p = 0.021). Depletion of antibodies directed against lipopolysaccharide significantly reduced bactericidal activity (p =  0.009). We conclude that antibodies induced after ingestion of oral live-attenuated typhoid vaccines or after challenge with wild-type S. Typhi exhibit bactericidal activity. This bactericidal activity is mediated by anti-O:LPS antibodies and significantly reduces clinical symptoms but does not provide sterile immunity. This directs future vaccine studies toward other antigens or mechanisms of protection against typhoid

Cost benefit analysis of mothership concept and investigation of optimum operational practice for offshore wind farms

In far offshore, challenging climate conditions limit the operability and the accessibility of the maintenance vessels significantly.Furthermore, if significant time is spent for the travels between offshore windfarm and O&M port; maintenance tasks cannot be carried out. A mothership can provide the solution for the operators. Due to the fact that the mothership can be moored to a close location to the offshore wind farm, the reaction time to the failures can be minimised; thus the availability of the offshore wind farm can be maximised. In this context, the focus of this research is the cost benefit analysis of the mothership concept and the investigation of the optimum operational practice, which brings financial and operational benefits. This is achieved by performing operational simulations in the offshore wind operational expenditure and logistics optimisation tool StrathOW-OM, which is developed bythe University of Strathclyde and commercial partner organisations. Results show that significant time is spent between offshore windfarm and port, which increases the downtime. October-December is identified as the most critical period for chartering a mothership

Mucosal-Associated Invariant T cells exhibit distinct functional signatures associated with protection against typhoid fever

We have previously demonstrated that Mucosal-Associated Invariant T (MAIT) cells secrete multiple cytokines after exposure to Salmonella enterica serovar Typhi (S. Typhi), the causative agent of typhoid fever in humans. However, whether cytokine secreting MAIT cells can enhance or attenuate the clinical severity of bacterial infections remain debatable. This study characterizes human MAIT cell functions in subjects participating in a wild-type S. Typhi human challenge model. Here, we found that MAIT cells exhibit distinct functional signatures associated with protection against typhoid fever. We also observed that the cytokine patterns of MAIT cell responses, rather than the average number of cytokines expressed, are more predictive of typhoid fever outcomes. These results might enable us to objectively, based on functional parameters, identify cytokine patterns that may serve as predictive biomarkers during natural infection and vaccination

Induction of Cell Cycle and NK Cell Responses by Live-Attenuated Oral Vaccines against Typhoid Fever

The mechanisms by which oral, live-attenuated vaccines protect against typhoid fever are poorly understood. Here, we analyze transcriptional responses after vaccination with Ty21a or vaccine candidate, M01ZH09. Alterations in response profiles were related to vaccine-induced immune responses and subsequent outcome after wild-type Salmonella Typhi challenge. Despite broad genetic similarity, we detected differences in transcriptional responses to each vaccine. Seven days after M01ZH09 vaccination, marked cell cycle activation was identified and associated with humoral immunogenicity. By contrast, vaccination with Ty21a was associated with NK cell activity and validated in peripheral blood mononuclear cell stimulation assays confirming superior induction of an NK cell response. Moreover, transcriptional signatures of amino acid metabolism in Ty21a recipients were associated with protection against infection, including increased incubation time and decreased severity. Our data provide detailed insight into molecular immune responses to typhoid vaccines, which could aid the rational design of improved oral, live-attenuated vaccines against enteric pathogens

Homologous and heterologous re-challenge with Salmonella Typhi and Salmonella Paratyphi A in a randomised controlled human infection model

Enteric fever is a systemic infection caused by Salmonella Typhi or Paratyphi A. In many endemic areas, these serovars co-circulate and can cause multiple infection-episodes in childhood. Prior exposure is thought to confer partial, but incomplete, protection against subsequent attacks of enteric fever. Empirical data to support this hypothesis are limited, and there are few studies describing the occurrence of heterologous-protection between these closely related serovars. We performed a challenge-re-challenge study using a controlled human infection model (CHIM) to investigate the extent of infection-derived immunity to Salmonella Typhi or Paratyphi A infection. We recruited healthy volunteers into two groups: naïve volunteers with no prior exposure to Salmonella Typhi/Paratyphi A and volunteers previously-exposed to Salmonella Typhi or Paratyphi A in earlier CHIM studies. Within each group, participants were randomised 1:1 to oral challenge with either Salmonella Typhi (104 CFU) or Paratyphi A (103 CFU). The primary objective was to compare the attack rate between naïve and previously challenged individuals, defined as the proportion of participants per group meeting the diagnostic criteria of temperature of ≥38°C persisting for ≥12 hours and/or S. Typhi/Paratyphi bacteraemia up to day 14 post challenge. The attack-rate in participants who underwent homologous re-challenge with Salmonella Typhi was reduced compared with challenged naïve controls, although this reduction was not statistically significant (12/27[44%] vs. 12/19[63%]; Relative risk 0.70; 95% CI 0.41–1.21; p = 0.24). Homologous re-challenge with Salmonella Paratyphi A also resulted in a lower attack-rate than was seen in challenged naïve controls (3/12[25%] vs. 10/18[56%]; RR0.45; 95% CI 0.16–1.30; p = 0.14). Evidence of protection was supported by a post hoc analysis in which previous exposure was associated with an approximately 36% and 57% reduced risk of typhoid or paratyphoid disease respectively on re-challenge. Individuals who did not develop enteric fever on primary exposure were significantly more likely to be protected on re-challenge, compared with individuals who developed disease on primary exposure. Heterologous re-challenge with Salmonella Typhi or Salmonella Paratyphi A was not associated with a reduced attack rate following challenge. Within the context of the model, prior exposure was not associated with reduced disease severity, altered microbiological profile or boosting of humoral immune responses. We conclude that prior Salmonella Typhi and Paratyphi A exposure may confer partial but incomplete protection against subsequent infection, but with a comparable clinical and microbiological phenotype. There is no demonstrable cross-protection between these serovars, consistent with the co-circulation of Salmonella Typhi and Paratyphi A. Collectively, these data are consistent with surveillance and modelling studies that indicate multiple infections can occur in high transmission settings, supporting the need for vaccines to reduce the burden of disease in childhood and achieve disease control. Trial registration NCT02192008; clinicaltrials.gov