Nucleus downscaling in mouse embryos is regulated by cooperative developmental and geometric programs

Maintaining appropriate nucleus size is important for cell health, but the mechanisms by which this is achieved are poorly understood. Controlling nucleus size is a particular challenge in early development, where the nucleus must downscale in size with progressive reductive cell divisions. Here we use live and fixed imaging, micromanipulation approaches, and small molecule analyses during preimplantation mouse development to probe the mechanisms by which nucleus size is determined. We find a close correlation between cell and nuclear size at any given developmental stage, and show that experimental cytoplasmic reduction can alter nuclear size, together indicating that cell size helps dictate nuclear proportions. Additionally, however, by creating embryos with over-sized blastomeres we present evidence of a developmental program that drives nuclear downscaling independently of cell size. We show that this developmental program does not correspond with nuclear import rates, but provide evidence that PKC activity may contribute to this mechanism. We propose a model in which nuclear size regulation during early development is a multi-mode process wherein nucleus size is set by cytoplasmic factors, and fine-tuned on a cell-by-cell basis according to cell size

Development of a core outcome set for orthodontic trials using a mixed-methods approach: Protocol for a multicentre study

© 2017 The Author(s). Background: Orthodontic treatment is commonly undertaken in young people, with over 40% of children in the UK needing treatment and currently one third having treatment, at a cost to the National Health Service in England and Wales of £273 million each year. Most current research about orthodontic care does not consider what patients truly feel about, or want, from treatment, and a diverse range of outcomes is being used with little consistency between studies. This study aims to address these problems, using established methodology to develop a core outcome set for use in future clinical trials of orthodontic interventions in children and young people. Methods/design: This is a mixed-methods study incorporating four distinct stages. The first stage will include a scoping review of the scientific literature to identify primary and secondary outcome measures that have been used in previous orthodontic clinical trials. The second stage will involve qualitative interviews and focus groups with orthodontic patients aged 10 to 16 years to determine what outcomes are important to them. The outcomes elicited from these two stages will inform the third stage of the study in which a long-list of outcomes will be ranked in terms of importance using electronic Delphi surveys involving clinicians and patients. The final stage of the study will involve face-to-face consensus meetings with all stakeholders to discuss and agree on the outcome measures that should be included in the final core outcome set. Discussion: This research will help to inform patients, parents, clinicians and commissioners about outcomes that are important to young people undergoing orthodontic treatment. Adoption of the core outcome set in future clinical trials of orthodontic treatment will make it easier for results to be compared, contrasted and combined. This should translate into improved decision-making by all stakeholders involved. Trial registration: The project has been registered on the Core Outcome Measures in Effectiveness Trials (COMET) website, January 2016

Core Outcomes for Colorectal Cancer Surgery: A Consensus Study

Background: Colorectal cancer (CRC) is a major cause of worldwide morbidity and mortality. Surgical treatment is common, and there is a great need to improve the delivery of such care. The gold standard for evaluating surgery is within well-designed randomized controlled trials (RCTs); however, the impact of RCTs is diminished by a lack of coordinated outcome measurement and reporting. A solution to these issues is to develop an agreed standard “core” set of outcomes to be measured in all trials to facilitate cross-study comparisons, meta-analysis, and minimize outcome reporting bias. This study defines a core outcome set for CRC surgery. Methods and Findings: The scope of this COS includes clinical effectiveness trials of surgical interventions for colorectal cancer. Excluded were nonsurgical oncological interventions. Potential outcomes of importance to patients and professionals were identified through systematic literature reviews and patient interviews. All outcomes were transcribed verbatim and categorized into domains by two independent researchers. This informed a questionnaire survey that asked stakeholders (patients and professionals) from United Kingdom CRC centers to rate the importance of each domain. Respondents were resurveyed following group feedback (Delphi methods). Outcomes rated as less important were discarded after each survey round according to predefined criteria, and remaining outcomes were considered at three consensus meetings; two involving international professionals and a separate one with patients. A modified nominal group technique was used to gain the final consensus. Data sources identified 1,216 outcomes of CRC surgery that informed a 91 domain questionnaire. First round questionnaires were returned from 63 out of 81 (78%) centers, including 90 professionals, and 97 out of 267 (35%) patients. Second round response rates were high for all stakeholders (>80%). Analysis of responses lead to 45 and 23 outcome domains being retained after the first and second surveys, respectively. Consensus meetings generated agreement on a 12 domain COS. This constituted five perioperative outcome domains (including anastomotic leak), four quality of life outcome domains (including fecal urgency and incontinence), and three oncological outcome domains (including long-term survival). Conclusion: This study used robust consensus methodology to develop a core outcome set for use in colorectal cancer surgical trials. It is now necessary to validate the use of this set in research practice

Development of a core outcome set for use in routine orthodontic clinical trials

Introduction A diverse range of outcomes is used in orthodontic research with a focus on measuring outcomes important to clinicians and little consistency in outcome selection and measurement. We aimed to develop a core outcome set for use in clinical trials of orthodontic treatment not involving cleft or orthognathic patient groups. Methods A list of outcomes measured in previous orthodontic research was identified through a scoping literature review. Additional outcomes of importance to patients were obtained using qualitative interviews and focus groups with adolescents aged 10-16 years. Rating of outcomes was carried out in a 2-round electronic Delphi process involving health care professionals and patients using a 9-point scale. A face-to-face meeting was subsequently held with stakeholders to discuss the results before refining the core outcome set. Results After triangulation, a final list of 34 outcomes grouped under 10 domains was obtained for rating in the e-Delphi surveys. Fifteen outcomes were voted “in” after the second Delphi round involving 274 participants with a further outcome being included after the consensus meeting. These were subsequently refined into a final set of 7 core outcomes, including the impact of self-perceived esthetics, alignment and/or occlusion, skeletal relationship, stability, patient-related adherence, breakages, and adverse effects on teeth or teeth-supporting structures. Conclusions A bespoke orthodontic core outcome set encompassing both clinician- and patient-focused outcomes was developed. Incorporating this is the first step into providing a more holistic assessment of the impact of treatment while allowing for meaningful comparisons and synthesis of results from individual trials

"Over-reviewing" of research?:An analysis of orthodontic reviews

INTRODUCTION: Research overviews may be undertaken to identify gaps in the literature, evaluate existing systematic reviews (SRs), and summarize evidence. This paper aims to profile overviews that have been conducted in orthodontics and related interventions since 2012 and to evaluate the degree of overlap among these overviews.METHODS: Overviews published between January 1, 2012 and June 20, 2023 were identified using an electronic search involving Google Scholar and PubMed. A descriptive summary was produced, and citation matrices were used to evaluate the percentage of overlap between overviews using corrected covered area and covered area. This was classified as slight, moderate, high, or very high.RESULTS: A total of 35 overviews were identified across a wide range of topics. Eight overviews included &lt;10 SRs; 21 had 10-20 SRs; and 6 included &gt;20 SRs (median no. of SRs per overview, 15; range, 3-62). Meta-analysis was conducted in only 5 overviews. Overlap between overviews on the same topic ranged from slight (2.7%) to very high (53.8%).CONCLUSIONS: Almost all overview topics address treatments and their effects, with a wide variation in the number and quality of SRs included. There is considerable overlap in some orthodontic overviews, suggesting unnecessary duplication and research waste. Researchers should be encouraged to focus on primary data collection to add more high-quality data to SRs, which will ultimately enhance the yield from secondary and tertiary orthodontic research.</p