Entwicklung der minimal invasiven perkutanen fetoskopischen Tracheal-Ballonokklusion im Schafmodell als potentiell lebensrettende Behandlungsmethode für humane Feten mit lebensbedrohenden Zwerchfellhernien

Zahlreiche humane Feten mit angeborener schwerer Zwerchfellhernie sterben trotz optimaler Behandlung kurz nach der Geburt. Ein Verschluss der fetalen Trachea kann bei Feten mit lebensbedrohender Zwerchfellhernie als vorgeburtliche Behandlung zur Therapie eingesetzt werden. Prinzip: Wird die fetale Luftröhre operativ verschlossen, staut sich die von der Lunge zur pränatalen Offenhaltung der kleinen Atemwege gebildete Flüssigkeit an. Der dabei entstehende Flüssigkeitsdruck dehnt nicht nur die Lungen auf sondern wirkt zusätzlich als starker Reiz für die Neubildung von Lungengewebe. Im Rahmen dieser Dissertation zeigte sich, dass die Ballonokklusion der Trachea bei Schaffeten mittels minimal invasiver fetoskopischer Techniken sicher und reproduzierbar möglich ist. Ungeborene mit einer aus einer Ultraschallmessung erwartbar geringen Überlebenswahrscheinlichkeit von 10-30% stellen die Gruppe dar, für die dieses experimentelle Verfahren eine lebensrettende Therapie sein kann

Bridging difference - national and organisational adaptation for responsible performance

This special issue draws together a selection of articles built around a theme of bridging difference. We argue that the effective transfer of learning across boundaries is crucial in enabling the dissemination of good, and ethical, HR practice. How that transfer might occur, with respect both to the mechanisms to enable or inhibit transfer and to the nature of learning that underpins that transfer, provides the focus of what is discussed here. This is framed against a concern for the nature and future of HRM, in particular its role in ensuring responsible organisational performance. © 2013 Taylor & Francis

Selection of Apps for Teaching Difficult Mathematics Topics: An Instrument to Evaluate Touch-Screen Tablet and Smartphone Mathematics Apps

Manipulatives—including the more recent touch-screen mobile device apps—belong to a broader network of learning tools. As teachers continue to search for learning materials that aid children to think mathematically, they are faced with a challenge of how to select materials that meet the needs of students. The profusion of virtual learning tools available via the Internet magnifies this challenge. What criteria could teachers use when choosing useful manipulatives? In this chapter, we share an evaluation instrument for teachers to use to evaluate apps. The dimensions of the instrument include: (a) the nature of the curriculum addressed in the app— emergent, adaptable or prescriptive, and relevance to current, high quality curricula—high, medium, low; (b) degree of actions and interactions afforded by the app as a learning tool— constructive, manipulable, or instructive interface; (c) the level of interactivity and range of options offered to the user —multiple or mono, or high, moderate or low; and, (d) the quality of the design features and graphics in the app—rich, high quality or impoverished, poor quality. Using these dimensions, researchers rated the apps on a three-level scale: Levels I, II, and III. Few apps were classified as Level III apps on selected dimensions. This evaluation instrument guides teachers when selecting apps. As well, the evaluation instrument guides developers in going beyond apps that are overly prescriptive, that focus on quizzes, that are text based, and include only surface aspects of using multi-modality in learning, to apps that are more aligned with emergent curricula, that focus also on conceptual understanding, and that utilize multiple, interactive representations of mathematics concepts

Combining work and child care: The experiences of mothers in Accra, Ghana

Work-family research has focused predominantly on Western women. Yet the forms of economic labour in which women are typically involved and the meaning of motherhood are context-specific. This paper aims to explore the experience of combining economic activity and child care of mothers with young children using urban Ghana as a case study. Semi-structured interviews (n=24) were conducted in three locations in the Accra Metropolitan Area. Transcripts were analysed using the general inductive approach. The results found women’s experience of role conflict to be bi-directional. With regard to role enhancement, economic activity allowed women to provide materially for their children. The combination of work and child care had negative consequences for women’s wellbeing. This research questions policy makers’ strategy of frequently targeting women in their roles either as generators of income, or as the primary care-takers of children by highlighting the reality of women’s simultaneous performance of these roles

Risk factors for community-acquired Escherichia coli bacteraemia: a systematic review protocol

Introduction: Rates of community-acquired Escherichia coli bacteraemia (ECB) have been consistently rising. As rates of antimicrobial resistance (AMR), particularly in Gram-negative bacteria, are also increasing, this is of concern both for management of individual patients and healthcare systems. There is currently little data on the risk factors for development of community-acquired ECB: this review aims to identify these risk factors in order to inform community interventions to reduce ECB as well as antibiotic prescribing policy. Methods and analysis: We will search Medline (Ovid), Embase (Ovid), Web of Science/Scopus and the Cochrane Central Register of Controlled Trials for published reports on observational and experimental primary research studies involving patients admitted to hospital with community-acquired ECB. Two reviewers will independently screen the studies for eligibility, perform data collection and assess study quality and risk of bias. Random effects meta-analyses will be performed if appropriate. Ethics and dissemination: No primary data will be collected for this study and so formal ethical approval is not required. We will publish the results of our review in relevant peer-reviewed medical journals, and will also seek to present them at relevant medical conferences. PROSPERO registration number: CRD4201810440

The role of mentorship in protege performance

The role of mentorship on protege performance is a matter of importance to academic, business, and governmental organizations. While the benefits of mentorship for proteges, mentors and their organizations are apparent, the extent to which proteges mimic their mentors' career choices and acquire their mentorship skills is unclear. Here, we investigate one aspect of mentor emulation by studying mentorship fecundity---the number of proteges a mentor trains---with data from the Mathematics Genealogy Project, which tracks the mentorship record of thousands of mathematicians over several centuries. We demonstrate that fecundity among academic mathematicians is correlated with other measures of academic success. We also find that the average fecundity of mentors remains stable over 60 years of recorded mentorship. We further uncover three significant correlations in mentorship fecundity. First, mentors with small mentorship fecundity train proteges that go on to have a 37% larger than expected mentorship fecundity. Second, in the first third of their career, mentors with large fecundity train proteges that go on to have a 29% larger than expected fecundity. Finally, in the last third of their career, mentors with large fecundity train proteges that go on to have a 31% smaller than expected fecundity.Comment: 23 pages double-spaced, 4 figure

Altering, Improving, And Defining The Specificities Of Crispr-Cas Nucleases

CRISPR-Cas9 nucleases have been widely adopted for genome editing applications to knockout genes or to introduce desired changes. While these nucleases have shown immense promise, two notable limitations of the wild-type form of the broadly used Streptococcus pyogenes Cas9 (SpCas9) are the restriction of targeting range to sites that contain an NGG protospacer adjacent motif (PAM), and the undesirable ability of the enzyme to cleave off-target sites that resemble the on-target site. Scarcity of PAM motifs can limit implementations that require precise targeting, whereas off-target effects can confound research applications and are important considerations for therapeutics. To improve the targeting range of SpCas9 and an orthogonal Cas9 from Staphylococcus aureus (called SaCas9), we optimized a heterologous genetic selection system that enabled us to perform directed evolution of PAM specificity. With SpCas9, we evolved two separate variants that can target NGA and NGCG PAMs1, and with SaCas9 relaxed the PAM from NNGRRT to NNNRRT2, increasing the targetability of these enzyme 2- to 4-fold. The genome-wide specificity profiles of SpCas9 and SaCas9 variants, determine by GUIDE-seq3, indicate that they are at least as, if not more, specific than the wild-type enzyme1,2. Together, these results demonstrate that the inherent PAM specificity of multiple different Cas9 orthologues can be purposefully modified to improve the accuracy of targeting. Existing strategies for improving the genome-wide specificity of SpCas9 have thus far proven to be incompletely effective and/or have other limitations that constrain their use. To address the off-target potential of SpCas9, we engineered a high-fidelity variant of SpCas9 (called SpCas9-HF1), that contains alterations designed to reduce non-specific contacts to the target strand DNA backbone. In comparison to wild-type SpCas9, SpCas9-HF1 rendered all or nearly all off-target events imperceptible by GUIDE-seq and targeted deep-sequencing methods with standard non-repetitive target sites in human cells4. Even for atypical, repetitive target sites, the vast majority of off-targets induced by SpCas9-HF1 and optimized derivatives were not detected4. With its exceptional precision, SpCas9-HF1 provides an important and easily employed alternative to wild-type SpCas9 that can eliminate off-target effects when using CRISPR-Cas9 for research and therapeutic applications. Finally, on-target activity and genome-wide specificity are two important properties of engineered nucleases that should be characterized prior to adoption of such technologies for research or therapeutic applications. CRISPR-Cas Cpf1 nucleases have recently been described as an alternative genome-editing platform5, yet their activities and genome-wide specificities remain largely undefined. Based on assessment of on-target activity across more than 40 target sites, we demonstrate that two Cpf1 orthologues function robustly in human cells with efficiencies comparable to those of the widely used Streptococcus pyogenes Cas9. We also demonstrate that four to six bases at the 3’ end of the short CRISPR RNA (crRNA) used to program Cpf1 are insensitive to single base mismatches, but that many of the other bases within the crRNA targeting region are highly sensitive to single or double substitutions6. Consistent with these results, GUIDE-seq performed in multiple cell types and targeted deep sequencing analyses of two Cpf1 nucleases revealed no detectable off-target cleavage for over half of 20 different crRNAs we examined. Our results suggest that the two Cpf1 nucleases we characterized generally possess robust on-target activity and high specificities in human cells, findings that should encourage broader use of these genome editing enzymes. 1. Kleinstiver, BP, et al. (2015) Nature, 523(7561):481-5 2. Kleinstiver, BP, et al. (2015) Nature Biotechnology, 33(12):1293-98 3. Tsai, SQ et al. (2015) Nature Biotechnology, 33(2):187-97 4. Kleinstiver, BP and Pattanayak, V, et al. (2016), Nature, 529(7587):490-5 5. Zetsche, B, et al. (2015) Cell, 163(3):759-71 6. Kleinstiver, BP and Tsai, SQ, et al. (2016), Nature Biotechnology, 34(8):869-7

Epigenetic memory in induced pluripotent stem cells.

Somatic cell nuclear transfer and transcription-factor-based reprogramming revert adult cells to an embryonic state, and yield pluripotent stem cells that can generate all tissues. Through different mechanisms and kinetics, these two reprogramming methods reset genomic methylation, an epigenetic modification of DNA that influences gene expression, leading us to hypothesize that the resulting pluripotent stem cells might have different properties. Here we observe that low-passage induced pluripotent stem cells (iPSCs) derived by factor-based reprogramming of adult murine tissues harbour residual DNA methylation signatures characteristic of their somatic tissue of origin, which favours their differentiation along lineages related to the donor cell, while restricting alternative cell fates. Such an 'epigenetic memory' of the donor tissue could be reset by differentiation and serial reprogramming, or by treatment of iPSCs with chromatin-modifying drugs. In contrast, the differentiation and methylation of nuclear-transfer-derived pluripotent stem cells were more similar to classical embryonic stem cells than were iPSCs. Our data indicate that nuclear transfer is more effective at establishing the ground state of pluripotency than factor-based reprogramming, which can leave an epigenetic memory of the tissue of origin that may influence efforts at directed differentiation for applications in disease modelling or treatment

Reported exposure to SARS-CoV-2 and relative perceived importance of different settings for SARS-CoV-2 acquisition in England and Wales: Analysis of the Virus Watch Community Cohort [version 1; peer review: awaiting peer review]

We aimed to assess the relative importance of different settings for SARS-CoV-2 transmission in a large community cohort based on perceived location of infection for self-reported confirmed SARS-COV-2 cases. We demonstrate the importance of home, work and education as perceived venues for transmission. In children, education was most important and in older adults essential shopping was of high importance. Our findings support public health messaging about infection control at home, advice on working from home and restrictions in different venues