A core outcome set for trials in miscarriage management and prevention: an international consensus development study.

OBJECTIVE: To develop core outcome sets (COS) for miscarriage management and prevention. DESIGN: Modified Delphi survey combined with a consensus development meeting. SETTING: International. POPULATION: Stakeholder groups included healthcare providers, international experts, researchers, charities and couples with lived experience of miscarriage from 15 countries: 129 stakeholders for miscarriage management and 437 for miscarriage prevention. METHODS: Modified Delphi method and modified nominal group technique. RESULTS: The final COS for miscarriage management comprises six outcomes: efficacy of treatment, heavy vaginal bleeding, pelvic infection, maternal death, treatment or procedure-related complications, and patient satisfaction. The final COS for miscarriage prevention comprises 12 outcomes: pregnancy loss <24 weeks' gestation, live birth, gestation at birth, pre-term birth, congenital abnormalities, fetal growth restriction, maternal (antenatal) complications, compliance with intervention, patient satisfaction, maternal hospitalisation, neonatal or infant hospitalisation, and neonatal or infant death. Other outcomes identified as important were mental health-related outcomes, future fertility and health economic outcomes. CONCLUSIONS: This study has developed two core outcome sets, through robust methodology, that should be implemented across future randomised trials and systematic reviews in miscarriage management and prevention. This work will help to standardise outcome selection, collection and reporting, and improve the quality and safety of future studies in miscarriage

Therapeutic targeting of membrane-associated GRP78 in leukemia and lymphoma : preclinical efficacy in vitro and formal toxicity study of BMTP-78 in rodents and primates

Translation of drug candidates into clinical settings requires demonstration of preclinical efficacy and formal toxicology analysis for filling an Investigational New Drug (IND) application with the US Food and Drug Administration (FDA). Here, we investigate the membrane-associated glucose response protein 78 (GRP78) as a therapeutic target in leukemia and lymphoma. We evaluated the efficacy of the GRP78-targeted proapoptotic drug bone metastasis targeting peptidomimetic 78 (BMTP-78), a member of the D (KLAKLAK)2-containing class of agents. BMTP-78 was validated in cells from patients with acute myeloid leukemia and in a panel of human leukemia and lymphoma cell lines, where it induced dose-dependent cytotoxicity in all samples tested. Based on the in vitro efficacy of BMTP-78, we performed formal good laboratory practice toxicology studies in both rodents (mice and rats) and nonhuman primates (cynomolgus and rhesus monkeys). These analyses represent required steps towards an IND application of BMTP-78 for theranostic first-in-human clinical trials.Peer reviewe

Increasing the Effectiveness of Vaginal Microbicides: A Biophysical Framework to Rethink Behavioral Acceptability

Microbicide candidates delivered via gel vehicles are intended to coat the vaginal epithelium after application. The coating process depends on intrinsic biophysical properties of the gel texture, which restricts the potential choices for an effective product: the gel first must be physically synthesizable, then acceptable to the user, and finally applied in a manner promoting timely adequate coating, so that the user adherence is optimized. We present a conceptual framework anchoring microbicide behavioral acceptability within the fulfillment of the product biophysical requirements.We conducted a semi-qualitative/quantitative study targeting women aged 18-55 in Northern California to assess user preferences for microbicide gel attributes. Attributes included: (i) the wait time between application and intercourse, (ii) the gel texture and (iii) the trade-off between wait time and gel texture. Wait times were assessed using a mathematical model determining coating rates depending upon the gel's physical attributes.71 women participated. Results suggest that women would independently prefer a gel spreading rapidly, in 2 to 15 minutes (P<0.0001), as well as one that is thick or slippery (P<0.02). Clearly, thick gels do not spread rapidly; hence the motivation to study the trade-off. When asked the same question 'constrained' by the biophysical reality, women indicated no significant preference for a particular gel thickness (and therefore waiting time) (P>0.10) for use with a steady partner, a preference for a watery gel spreading rapidly rather than one having intermediate properties for use with a casual partner (P = 0.024).Biophysical constraints alter women's preferences regarding acceptable microbicide attributes. Product developers should offer a range of formulations in order to address all preferences. We designed a conceptual framework to rethink behavioral acceptability in terms of biophysical requirements that can help improve adherence in microbicide use ultimately enhancing microbicide effectiveness

Kombinasi Format Factory, U-lead dan Microsoft Office Powerpoint dalam Upaya Meningkatkan Kualitas Media Pembelajaran

Peserta didik mempunyai gaya belajar yang berbeda-beda. Gaya belajar tersebut meliputi auditori, visual dan kinestetik (VAK). Seorang guru harus mampu memenuhi kebutuhan masing-masing gaya belajar peserta didik tersebut. Salah satu cara yang dapat dilakukan adalah dengan menggunakan media pembelajaran berbasis VAK. Media pembelajaran berbasis VAK dapat dipenuhi dengan menyisipkan file video di dalamnya. Selain itu, penggunaan file video sebagai media pembelajaran mendukung implementasi pembelajaran saintifik pada kurikulum 2013. Namun, belum semua guru memiliki kemampuan untuk mengemas file video tersebut dalam bentuk media pembelajaran. Tujuan penelitian ini adalah untuk meningkatkan kemampuan guru-guru di SMA Negeri 1 Teras dan SMA Negeri 1 Boyolali dalam membuat media pembelajaran berbasis VAK dengan kombinasi software Format Factory, U-Lead dan PowerPoint. Hasil penelitian menunjukkan bahwa terjadi peningkatan kemampuan para guru di SMA Negeri 1 Teras dan SMA Negeri 1 Boyolali dalam membuat media pembelajaran. Peningkatan kemampuan guru-guru tersebut berada di atas target yang direncanakan. Rerata peningkatan kemampuan guru-guru di SMA Negeri 1 Teras 7,87% di atas target, sedangkan di SMA Negeri 1 Boyolali 9,58% di atas target. Kata kunci: Media Pembelajaran, Format Factory, U-Lead, PowerPoint Students have different learning styles. Learning styles include visual learners, auditory learners, and kinesthetic learners. A teacher must be able to fulfill the needs of individual students\u27 learning styles. One way that can be applied is using Visual, Audio and Kinesthetic (VAK) learning media based. VAK-learning media based can be created by inserting video files on it. In addition, using video file as a learning media can support the implementation of scientific learning on the 2013 curriculum. However, not all teachers have the ability to use video files into a learning media. The purpose of this study is to improve the teachers\u27 ability at SMA Negeri 1 Teras and SMAN 1 Boyolali on making VAK-learning media based with a combination of Format Factory, U-Lead and PowerPoint software. The results showed that the teachers\u27 ability on making VAK-learning media based was increased. Increased the teachers\u27 ability was above planned target score. The mean score of the teachers\u27 ability at SMA Negeri 1 Teras 7.87% above the target, while at SMAN 1 Boyolali 9.58% above the target

Uropathogenic Escherichia coli Modulates Immune Responses and Its Curli Fimbriae Interact with the Antimicrobial Peptide LL-37

Bacterial growth in multicellular communities, or biofilms, offers many potential advantages over single-cell growth, including resistance to antimicrobial factors. Here we describe the interaction between the biofilm-promoting components curli fimbriae and cellulose of uropathogenic E. coli and the endogenous antimicrobial defense in the urinary tract. We also demonstrate the impact of this interplay on the pathogenesis of urinary tract infections. Our results suggest that curli and cellulose exhibit differential and complementary functions. Both of these biofilm components were expressed by a high proportion of clinical E. coli isolates. Curli promoted adherence to epithelial cells and resistance against the human antimicrobial peptide LL-37, but also increased the induction of the proinflammatory cytokine IL-8. Cellulose production, on the other hand, reduced immune induction and hence delayed bacterial elimination from the kidneys. Interestingly, LL-37 inhibited curli formation by preventing the polymerization of the major curli subunit, CsgA. Thus, even relatively low concentrations of LL-37 inhibited curli-mediated biofilm formation in vitro. Taken together, our data demonstrate that biofilm components are involved in the pathogenesis of urinary tract infections by E. coli and can be a target of local immune defense mechanisms

Quantitative Microscopy Reveals Centromeric Chromatin Stability, Size, and Cell Cycle Mechanisms to Maintain Centromere Homeostasis

The deposited item is a book chapter and is part of the series "Centromeres and Kinetochores" published by the publisher Springer Verlag. The deposited book chapter is a post-print version and has been submitted to peer reviewing. There is no public supplementary material available for this publication. This publication hasn't any creative commons license associated.Centromeres are chromatin domains specified by nucleosomes containing the histone H3 variant, CENP-A. This unique centromeric structure is at the heart of a strong self-templating epigenetic mechanism that renders centromeres heritable. We review how specific quantitative microscopy approaches have contributed to the determination of the copy number, architecture, size, and dynamics of centromeric chromatin and its associated centromere complex and kinetochore. These efforts revealed that the key to long-term centromere maintenance is the slow turnover of CENP-A nucleosomes, a critical size of the chromatin domain and its cell cycle-coupled replication. These features come together to maintain homeostasis of a chromatin locus that directs its own epigenetic inheritance and facilitates the assembly of the mitotic kinetochore.There are no funders and sponsors indicated explicitly in the document.info:eu-repo/semantics/publishedVersio

Simultaneous fleet assignment and cargo routing using benders decomposition

In this paper, we incorporate the cargo routing problem into fleet assignment to model the fleet assignment more accurately. An integrated model and a Benders decomposition-based approach are developed to simultaneously obtain the optimal assignment of fleet to legs and the routing of forecasted cargo demand over the network. Computational experiments show that this integrated approach converges very fast for all different test scenarios