Decrease in pneumococcal co-colonization following vaccination with the seven-valent pneumococcal conjugate vaccine.

Understanding the epidemiology of pneumococcal co-colonization is important for monitoring vaccine effectiveness and the occurrence of horizontal gene transfer between pneumococcal strains. In this study we aimed to evaluate the impact of the seven-valent pneumococcal conjugate vaccine (PCV7) on pneumococcal co-colonization among Portuguese children. Nasopharyngeal samples from children up to 6 years old yielding a pneumococcal culture were clustered into three groups: pre-vaccine era (n = 173), unvaccinated children of the vaccine era (n = 169), and fully vaccinated children (4 doses; n = 150). Co-colonization, serotype identification, and relative serotype abundance were detected by analysis of DNA of the total bacterial growth of the primary culture plate using the plyNCR-RFLP method and a molecular serotyping microarray-based strategy. The plyNCR-RFLP method detected an overall co-colonization rate of 20.1%. Microarray analysis confirmed the plyNCR-RFLP results. Vaccination status was the only factor found to be significantly associated with co-colonization: co-colonization rates were significantly lower (p = 0.004; Fisher's exact test) among fully vaccinated children (8.0%) than among children from the pre-PCV7 era (17.3%) or unvaccinated children of the PCV7 era (18.3%). In the PCV7 era there were significantly less non-vaccine type (NVT) co-colonization events than would be expected based on the NVT distribution observed in the pre-PCV7 era (p = 0.024). In conclusion, vaccination with PCV7 resulted in a lower co-colonization rate due to an asymmetric distribution between NVTs found in single and co-colonized samples. We propose that some NVTs prevalent in the PCV7 era are more competitive than others, hampering their co-existence in the same niche. This result may have important implications since a decrease in co-colonization events is expected to translate in decreased opportunities for horizontal gene transfer, hindering pneumococcal evolution events such as acquisition of antibiotic resistance determinants or capsular switch. This might represent a novel potential benefit of conjugate vaccines.

Individual Video Training - Entwicklung einer nationalen Infrastruktur für Video-unterstütztes Lernen

Video-basiertes Lernen ist besonders effektiv, wo es um Fertigkeiten und Verhalten geht. Videoaufzeichnungen von Gesprächen, Unterrichtssituationen oder der Durchführung praktischer Tätigkeiten wie dem Nähen einer Wunde erlauben es den Ausführenden, ihren Peers und ihren Tutoren, die Qualität der Leistung zu beurteilen und Anregungen zur Verbesserung zu formulieren. Wissend um den grossen didaktischen Wert von Videoaufzeichnungen haben sich vier Pädagogische Hochschulen (Zürich, Freiburg, Thurgau, Luzern) und zwei Medizinische Fakultäten (Bern, Lausanne) zusammen getan, um eine nationale Infrastruktur für Video-unterstütztes Lernen anzustossen. Ziel was es, ein System zu entwickeln, das einfach zu bedienen ist, bei dem viele Arbeitsschritte automatisiert sind und das die Videos im Internet bereit stellt. Zusammen mit SWITCH, der nationalen IT-Support-Organisation der Schweizer Hochschulen, wurde basierend auf den vorbestehenden Technologien AAI und SWITCHcast das Programm iVT (Individual Video Training) entwickelt. Die Integration des nationalen Single Logon System AAI (Authentification and Authorization Infrastructure) erlaubt es, die Videos mit dem jeweiligen User eindeutig zu verknüpfen, so dass die Videos nur für diesen User im Internet zugänglich sind. Mit dem Podcast-System SWITCHcast können Videos automatisch ins Internet hochgeladen und bereit gestellt werden. Es wurden je ein Plugin für die Learning Management Systeme ILIAS (PH Zürich, Uni Bern) und Moodle (Uni Lausanne) entwickelt. Dank dieser Plugins werden die Videos in den jeweiligen LMS verfügbar gemacht. Der Einsatz von iVT ist beim Kommunikationstraining unserer Medizinstudierenden in Bern inzwischen Standard. Das Login gilt gleichzeitig als Beleg für das Testat. Studierende, die keine Videoaufzeichnung wünschen, können diese nach dem Login stoppen. Bis anhin ist das Betrachten der Videos freiwillig. Szenarios mit Peer Feedback sind geplant. Eine entsprechende Erweiterung des Systems um gegenseitige Annotationsmöglichkeiten besteht bereits und wird fortlaufend weiterentwickelt.

Individual Video Training iVT - Development of a National Infrastructure for Video-Supported Learning

Introduction: Video‐Supported Learning is particularly effective when it comes to skills and behaviors. Video registration of patient‐physician interviews, class room instruction or practical skills allow it to learners themselves, their peers, and their tutors to assess the quality of the learner's performance, to give specific feedback, and to make suggestions for improvement. Methods: In Switzerland, four pedagogical universities and two medical faculties joined to initiate the development of a national infrastructure for Video Supported Learning. The goal was to have a system that is simple to use, has most steps automated, provides the videos over the Internet, and has a sophisticated access control. Together with SWITCH, the national IT‐Support‐Organisation for Swiss Universities, the program iVT (Individual Video Training) was developed by integrating two preexisting technologies. The first technology is SWITCHcast, a podcast system. With SWITCHcast, videos are automatically uploaded to a server as soon as the registration is over. There the videos are processed and converted to different formats. The second technology is the national Single Logon System AAI (Authentification and Authorization Infrastructure) that enables iVT to link each video with the corresponding learner. The learner starts the registration with his Single Logon. Thus, the video can unambiguously be assigned. Via his institution's Learning Management System (LMS), the learner can access his video and give access to his video to peers and tutors. Results: iVT is now used at all involved institutions. The system works flawlessly. In Bern, we use iVT for the communications skills training in the forth and sixth year. Since students meet with patient actors alone, iVT is also used to certify attendance. Students are encouraged to watch the videos of the interview and the feedback of the patient actor. The offer to discuss a video with a tutor was not used by the students. Discussion: We plan to expand the use of iVT by making peer assessment compulsory. To support this, annotation capabilities are currently added to iVT. We also want to use iVT in training of practical skills, again for self as well as for peer assessment.  At present, we use iVT for quality control of patient actor's performance.

Small quantity but large effect — How minor phases control strain localization in upper mantle shear zones

Low viscosity domains such as localized shear zones exert an important control on the geodynamics of the uppermost mantle. Grain size reduction and subsequent strain localization related to a switch from dislocation to diffusion creep is one mechanism to form low viscosity domains. To sustain strain localization, the grain size of mantle minerals needs to be kept small over geological timescales. One way to keep olivine grain sizes small is by pinning of mobile grain boundaries during grain growth by other minerals (second phases). Detailed microstructural studies based on natural samples from three shear zones formed at different geodynamic settings, allowed the derivation of the olivine grain-size dependence on the second-phase content. The polymineralic olivine grain-size evolution with increasing strain is similar in the three shear zones. If the second phases are to pin the mobile olivine grain boundary the phases need to be well mixed before grain growth. We suggest that melt-rock and metamorphic reactions are crucial for the initial phase mixing in mantle rocks. With ongoing deformation and increasing strain, grain boundary sliding combined with mass transfer processes and nucleation of grains promotes phase mixing resulting in fine-grained polymineralic mixtures that deform by diffusion creep. Strain localization due to the presence of volumetrically minor minerals in polymineralic mantle rocks is only important at high strain deformation (ultramylonites) at low temperatures (<~800°C). At smaller strain and stress conditions and/or higher temperatures other parameters like overall energy available to deform a given rock volume, the inheritance of mechanical anisotropies or the presence of water or melts needs to be considered to explain strain localization in the upper mantle.

Glycemic Variability Is Associated with Frequency of Blood Glucose Testing and Bolus: Post Hoc Analysis Results from the ProAct Study

ntroduction: The ProAct study has shown that a pump switch to the Accu-Chek® Combo system (Roche Diagnostics Deutschland GmbH, Mannheim, Germany) in type 1 diabetes patients results in stable glycemic control with significant improvements in glycated hemoglobin (HbA1c) in patients with unsatisfactory baseline HbA1c and shorter pump usage time. Patients and Methods: In this post hoc analysis of the ProAct database, we investigated the glycemic control and glycemic variability at baseline by determination of several established parameters and scores (HbA1c, hypoglycemia frequency, J-score, Hypoglycemia and Hyperglycemia Indexes, and Index of Glycemic Control) in participants with different daily bolus and blood glucose measurement frequencies (less than four day, four or five per day, and more than five per day, in both cases). The data were derived from up to 299 patients (172 females, 127 males; age [mean±SD], 39.4±15.2 years; pump treatment duration, 7.0±5.2 years). Results: Participants with frequent glucose readings had better glycemic control than those with few readings (more than five readings per day vs. less than four readings per day: HbA1c, 7.2±1.1% vs. 8.0±0.9%; mean daily blood glucose, 151±22 mg/dL vs. 176±30 mg/dL; percentage of readings per month >300 mg/dL, 10±4% vs. 14±5%; percentage of readings in target range [80-180 mg/dL], 59% vs. 48% [P<0.05 in all cases]) and had a lower glycemic variability (J-score, 49±13 vs. 71±25 [P<0.05]; Hyperglycemia Index, 0.9±0.5 vs. 1.9±1.2 [P<0.05]; Index of Glycemic Control, 1.9±0.8 vs. 3.1±1.6 [P<0.05]; Hypoglycemia Index, 0.9±0.8 vs. 1.2±1.3 [not significant]). Frequent self-monitoring of blood glucose was associated with a higher number of bolus applications (6.1±2.2 boluses/day vs. 4.5±2.0 boluses/day [P<0.05]). Therefore, a similar but less pronounced effect on glycemic variability in favor of more daily bolus applications was observed (more than five vs. less than four bolues per day: J-score, 57±17 vs. 63±25 [not significant]; Hypoglycemia Index, 1.0±1.0 vs. 1.5±1.4 [P<0.05]; Hyperglycemia Index, 1.3±0.6 vs. 1.6±1.1 [not significant]; Index of Glycemic Control, 2.3±1.1 vs. 3.1±1.7 [P<0.05]). Conclusions: Pump users who perform frequent daily glucose readings have a better glycemic control with lower glycemic variability.

Bicyclo[3.2.1]amide-DNA: a chiral, non-chiroselective base-pairing system

The design, synthesis and base-pairing properties of bicyclo[3.2.1]amide-(bca)DNA, a novel phosphodiester based DNA analogue, is reported. This analogue consists of a conformationally constrained backbone entity which emulates a B-DNA geometry, to which the nucleobases were attached via an extended, acyclic amide linker. Homobasic adenine-containing bca-decamers form duplexes with complementary oligonucleotides containing the bca-, the DNA the RNA and, surprisingly, also the L-RNA backbone. UV- and CD-spectroscopic investigations revealed the duplexes with D- or L-complement to be of similar stability and enantiomorphic in structure. Bca-oligonucleotides containing all four bases form strictly antiparallel, left-handed complementary duplexes with itself and complementary DNA but not with RNA. Base-mismatch discrimination is comparable to that of DNA while the overall thermal stabilities of bca-oligonucleotide duplexes are inferior relative to that of DNA or RNA. A detailed molecular modeling study of left- and right-handed bca-DNA containing duplexes showed only minor changes in the backbone structure and revealed a structural switch around the base-linker unit to be responsible for the generation of enantiomorphic duplex structures. The obtained data are discussed with respect to the structural and energetic role of the ribofuranose entities in DNA and RNA association

Gender inequalities in the response to combination antiretroviral therapy over time: the Swiss HIV Cohort Study

OBJECTIVES Gender-specific data on the outcome of combination antiretroviral therapy (cART) are a subject of controversy. We aimed to compare treatment responses between genders in a setting of equal access to cART over a 14-year period. METHODS Analyses included treatment-naïve participants in the Swiss HIV Cohort Study starting cART between 1998 and 2011 and were restricted to patients infected by heterosexual contacts or injecting drug use, excluding men who have sex with men. RESULTS A total of 3925 patients (1984 men and 1941 women) were included in the analysis. Women were younger and had higher CD4 cell counts and lower HIV RNA at baseline than men. Women were less likely to achieve virological suppression < 50 HIV-1 RNA copies/mL at 1 year (75.2% versus 78.1% of men; P = 0.029) and at 2 years (77.5% versus 81.1%, respectively; P = 0.008), whereas no difference between sexes was observed at 5 years (81.3% versus 80.5%, respectively; P = 0.635). The probability of virological suppression increased in both genders over time (test for trend, P < 0.001). The median increase in CD4 cell count at 1, 2 and 5 years was generally higher in women during the whole study period, but it gradually improved over time in both sexes (P < 0.001). Women also were more likely to switch or stop treatment during the first year of cART, and stops were only partly driven by pregnancy. In multivariate analysis, after adjustment for sociodemographic factors, HIV-related factors, cART and calendar period, female gender was no longer associated with lower odds of virological suppression. CONCLUSIONS Gender inequalities in the response to cART are mainly explained by the different prevalence of socioeconomic characteristics in women compared with men.

Exhumation rates in the Archean from pressure-ime paths: Examplefrom the Skjoldungen Orogen (SE Greenland)

The discussions on the orogenic evolution during Earth's history converge to the question of a different thermal structure in the Archean compared to the Phanerozoic and the applicability of the plate tectonic paradigm. However, geothermal structures are transient in orogens and are difficult to translate into large-scale tectonics and exhumation rates. Therefore, we propose depth–time data in the Archean Skjoldungen Orogen (SE Greenland, North Atlantic Craton) that allow for reconstruction of an exhumation rate independent of geothermal gradients. The resulting exhumation rate of ca. 0.4 km/Ma is similar to exhumation rates during erosion-controlled processes in modern orogens. These exhumation rates can only be established by erosion time constants similar to modern orogens. The occurrence of erosion-controlled exhumation is best explained by a stiff foreland promoting localized deformation in the orogen. Therefore, a switch from magmatic-dominated processes to localized deformation is proposed in the Skjoldungen Orogen area. This is supported by a change in magma composition and volume, from widespread granodiorite to localized alkaline intrusions. In addition, the involved metasedimentary rocks include detrital zircons of the only 50 Ma older foreland, which also correspond to erosion and tectonics as in modern orogens, i.e. flysh-type sediments. Relatively fast exhumation rates and the structural-magmatic evolution of the Neoarchean Skjoldungen Orogen thus indicate modern-style tectonic processes where stiff Mesoarchean continental crust forms a foreland to a collisional orogen instead of typical accretionary tectonics of weak island arc-like terranes in granite-greenstone terranes.

A Nicotiana attenuata cell wall invertase inhibitor (NaCWII) reduces growth and increases secondary metabolite biosynthesis in herbivore-attacked plants

Plant invertases are sucrolytic enzymes that are essential for the regulation of carbohydrate metabolism and source–sink relationships. While their activity has been well documented during abiotic and biotic stresses, the role of proteinaceous invertase inhibitors in regulating these changes is unknown. Here, we identify a putative Nicotiana attenuata cell wall invertase inhibitor (NaCWII) which is strongly up-regulated in a jasmonate (JA)-dependent manner following simulated attack by the specialist herbivore Manduca sexta. To understand the role of NaCWII in planta, we silenced its expression by RNA interference and measured changes in primary and secondary metabolism and plant growth following simulated herbivory. NaCWII-silenced plants displayed a stronger depletion of carbohydrates and a reduced capacity to increase secondary metabolite pools relative to their empty vector control counterparts. This coincided with the attenuation of herbivore-induced CWI inhibition and growth suppression characteristic of wild-type plants. Together our findings suggest that NaCWII may act as a regulatory switch located downstream of JA accumulation which fine-tunes the plant's balance between growth and defense metabolism under herbivore attack. Although carbohydrates are not typically viewed as key factors in plant growth and defense, our study shows that interfering with their catabolism strongly influences plant responses to herbivory.

Scheduled versus Pro Re Nata Dosing in the VIEW Trials

PURPOSE To analyze visual acuity (VA) outcomes before and after preplanned treatment regimen change in the VIEW studies at week 52 (W52). DESIGN Multiple post hoc analyses for retrospectively defined subgroups in 2 multicenter, multinational, double-masked trials. PARTICIPANTS Two thousand four hundred fifty-seven neovascular age-related macular degeneration (AMD) patients. METHODS Patients were randomized to treatment with 0.5 mg ranibizumab given monthly, a 0.5-mg or 2-mg intravitreal aflibercept injection given monthly, or 2 mg intravitreal aflibercept given every other month, after 3 initial monthly doses, up to W52. From W52 through W96, patients received their original dosing assignment using a capped pro re nata (PRN) regimen, with defined retreatment criteria based on VA and morphologic signs of disease activity and mandatory dosing at least every 12 weeks. MAIN OUTCOME MEASURES Best-corrected VA (BCVA) and optical coherence tomography assessments were mandatory at all visits from baseline to W96. Outcomes were changes in BCVA and central retinal thickness. Outcomes were evaluated in all patients who completed 2 years of the VIEW studies using the last observation carried forward method for missing data at interim visits. RESULTS After W52, approximately 20% of patients lost 5 Early Treatment Diabetic Retinopathy Study (ETDRS) letters or more across all treatment arms with PRN treatment. Patients who met the retreatment criterion of loss of 5 ETDRS letters or more in the first quarter of the PRN dosing phase did not recover; mean final VA loss across the 4 study arms was -4.4 to -5.8 letters. Outcomes of these patients up to W52 were indistinguishable from those of the overall population. There were no differences between groups in serious ocular adverse events or Anti-Platelet Trialists' Collaboration arterial thromboembolic events through W96. CONCLUSIONS These analyses suggest that there are subgroups of patients for whom VA outcomes in the second year of the VIEW studies were less stable than in the first year and for whom W52 seems to be an important inflection point. Although alternate reasons specific to the nature of the underlying AMD cannot be fully excluded, the switch in treatment regimen at W52 is a plausible explanation.

The Nile perch invasion in Lake Victoria: cause or consequence of the haplochromine decline?

We review alternative hypotheses and associated mechanisms to explain Lake Victoria’s Nile perch takeover and concurrent reduction in haplochromines through a (re)analysis of long term climate, limnological and stock observations in comparison with size-spectrum model predictions of co-existence, extinction and demographic change. The empirical observations are in agreement with the outcomes of the model containing two interacting species with life-histories matching Nile perch and a generalized haplochromine. The dynamic interactions may have depended on size related differences in early juvenile mortality: mouth-brooding haplochromines escape predation mortality in early life stages, unlike Nile perch that have miniscule planktonic eggs and larvae. In our model predation on the latter by planktivorous haplochromine fry act as a stabilizing factor for co-existence, but external mortality on the haplochromines would disrupt this balance in favor of Nile perch. To explain the observed switch, mortality on haplochromines would need to be much higher than the fishing mortality that can be realistically re-constructed from observations. Abrupt concomitant changes in algal and zooplankton composition, decreased water column transparency, and widespread hypoxia from increased eutrophication most likely caused haplochromine biomass decline. We hypothesize that the shift to Nile perch was a consequence of an externally caused, climate triggered, decrease in haplochromine biomass and associated recruitment failure rather than a direct cause of the introduction.

An EAR-motif-containing ERF transcription factor affects herbivore-induced signaling, defense and resistance in rice

Ethylene responsive factors (ERFs) are a large family of plant-specific transcription factors that are involved in the regulation of plant development and stress responses. However, little to nothing is known about their role in herbivore-induced defense. We discovered a nucleus-localized ERF gene in rice (Oryza sativa), OsERF3, that was rapidly up-regulated in response to feeding by the rice striped stem borer (SSB) Chilo suppressalis. Antisense and over-expression of OsERF3 revealed that it positively affects transcript levels of two mitogen-activated protein kinases (MAPKs) and two WRKY genes as well as concentrations of jasmonate (JA), salicylate (SA) and the activity of trypsin protease inhibitors (TrypPIs). OsERF3 was also found to mediate the resistance of rice to SSB. On the other hand, OsERF3 was slightly suppressed by the rice brown planthopper (BPH) Nilaparvata lugens (Stål) and increased susceptibility to this piercing sucking insect, possibly by suppressing H2O2 biosynthesis. We propose that OsERF3 affects early components of herbivore-induced defense responses by suppressing MAPK repressors and modulating JA, SA, ethylene and H2O2 pathways as well as plant resistance. Our results also illustrate that OsERF3 acts as a central switch that gears the plant’s metabolism towards an appropriate response to chewing or piercing/sucking insects.

Cooperative VET in Training Networks: Analysing the Free-Rider Problem in a Sociology-of-Conventions Perspective

In training networks, particularly small and medium-sized enterprises pool their resources to train apprentices within the framework of the dual VET system, while an intermediary organisation is tasked with managing operations. Over the course of their apprenticeship, the apprentices switch from one training company to another on a (half-) yearly basis. Drawing on a case study of four training networks in Switzerland and the theoretical framework of the sociology of conventions, this paper aims to understand the reasons for the slow dissemination and reluctant adoption of this promising form of organising VET in Switzerland. The results of the study show that the system of moving from one company to another creates a variety of free-rider constellations in the distribution of the collectively generated corporative benefits. This explains why companies are reluctant to participate in this model. For the network to be sustainable, the intermediary organisation has to address discontent arising from free-rider problems while taking into account that the solutions found are always tentative and will often result in new free-rider problems.

Biology of tRNA halves in Trypanosoma brucei

Although T. brucei has to challenge tremendous environment changes, e.g. switch from the bloodstream form in mammalian hosts to the mid gut form present in tsetse flies, there is no evidence for differential regulation of RNA Pol II transcription. Instead, constitutive transcription appears to occur. This observation indicates that protein levels have to be regulated by post-transcriptional mechanisms. It has been shown that non-protein coding RNAs (ncRNAs) are crucial in regulatory networks (e.g. chromosome remodelling; RNA polymerase activity; mRNA turnover; etc.), but all of the recently discovered ncRNAs involved in translation regulation target the mRNA rather than the ribosome. This is unexpected, since the ribosome has a central role during gene expression and due to the assumption that the primordial translation system most likely received direct regulatory input from small molecules including ncRNA cofactors. In our lab, it has been discovered that ncRNAs are able to directly bind to the ribosome, therefore influencing the translation rate in Haloferax volcanii and Saccharomyces cerevisiae. In order to extend this idea of ribosome-binding ncRNAs in mammalian parasites, we want to investigate this mechanism in T. brucei. Accordingly, we performed a genomic screen for small ribosome-associated RNAs followed by functional analyses of possible candidates. With the help of this genomic screen, we found tRNAs that are alternated and tRNA halves that are differentially expressed upon nutritional stress.

Biology of tRNA halves in Trypanosoma brucei

Although T. brucei has to challenge tremendous environment changes, e.g. switch from the bloodstream form in mammalian hosts to the mid gut form present in tsetse flies, there is no evidence for differential regulation of RNA Pol II transcription. Instead, constitutive transcription appears to occur. This observation indicates that protein levels have to be regulated by post-transcriptional mechanisms. It has been shown that non-protein coding RNAs (ncRNAs) are crucial in regulatory networks (e.g. chromosome remodelling; RNA polymerase activity; mRNA turnover; etc.), but all of the recently discovered ncRNAs involved in translation regulation target the mRNA rather than the ribosome. This is unexpected, since the ribosome has a central role during gene expression and due to the assumption that the primordial translation system most likely received direct regulatory input from small molecules including ncRNA cofactors. In our lab, it has been discovered that ncRNAs are able to directly bind to the ribosome, therefore influencing the translation rate in Haloferax volcanii and Saccharomyces cerevisiae. In order to extend this idea of ribosome-binding ncRNAs in mammalian parasites, we want to investigate this mechanism in T. brucei. Accordingly, we performed a genomic screen for small ribosome-associated RNAs followed by functional analyses of possible candidates. With the help of this genomic screen, we found tRNAs that are alternated and tRNA halves that are differentially expressed upon nutritional stress.