About the Authors: Didier Y. R. Stainier * E-mail: didier.stainier@mpi-bn.mpg.de (DYRS); cmoens@fredhutch.org (CBM) Affiliation: Department of Developmental Genetics, Max Planck Institute for Heart ...and Lung Research, Bad Nauheim, Germany ORCID http://orcid.org/0000-0002-0382-0026 Erez Raz Affiliation: Institute of Cell Biology, ZBME, University of Münster, Münster, Germany ORCID http://orcid.org/0000-0002-6347-3302 Nathan D. Lawson Affiliation: Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America Stephen C. Ekker Affiliation: Mayo Clinic, Rochester, Minnesota, United States of America Rebecca D. Burdine Affiliation: Department of Molecular Biology, Princeton University, Princeton, New Jersey, United States of America Judith S. Eisen Affiliation: Institute of Neuroscience, University of Oregon, Eugene, Oregon, United States of America ORCID http://orcid.org/0000-0003-1229-1696 Philip W. Ingham Affiliations Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, The Living Systems Institute, University of Exeter, Exeter, United Kingdom Stefan Schulte-Merker Affiliation: Institute of Cardiovascular Organogenesis and Regeneration, WWU Münster, Faculty of Medicine, Münster, Germany Deborah Yelon Affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, California, United States of America Brant M. Weinstein Affiliation: Division of Developmental Biology, NICHD, NIH, Bethesda, Maryland, United States of America Mary C. Mullins Affiliation: Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America ORCID http://orcid.org/0000-0002-9979-1564 Stephen W. Wilson Affiliation: Department of Cell and Developmental Biology, University College London, London, United Kingdom ORCID http://orcid.org/0000-0002-8557-5940 Lalita Ramakrishnan Affiliation: Molecular Immunity Unit, Department of Medicine, University of Cambridge, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom Sharon L. Amacher Affiliation: Departments of Molecular Genetics and Biological Chemistry and Pharmacology, Ohio State University, Columbus, Ohio, United States of America Stephan C. F. Neuhauss Affiliation: Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland ORCID http://orcid.org/0000-0002-9615-480X Anming Meng Affiliation: School of Life Sciences, Tsinghua University, Beijing, China Naoki Mochizuki Affiliation: National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan ORCID http://orcid.org/0000-0002-3938-9602 Pertti Panula Affiliation: Department of Anatomy and Neuroscience Center, University of Helsinki, Helsinki, Finland Cecilia B. Moens * E-mail: didier.stainier@mpi-bn.mpg.de (DYRS); cmoens@fredhutch.org (CBM) Affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of AmericaCitation: Stainier DYR, Raz E, Lawson ND, Ekker SC, Burdine RD, Eisen JS, et al. Additionally, mutant alleles for many genes are now readily available through zebrafish community resource centers. ...MOs should be used alongside mutant(s) for the corresponding gene. ...a word of caution that previous publication of MOs is not a guarantee of their fidelity, particularly if a new phenotype is being described. ...we hope that these brief and mostly conceptual guidelines will assist scientists working with zebrafish as well as those assessing manuscripts and grant proposals based on experiments using zebrafish.
Value of information analysis is a quantitative method to estimate the return on investment in proposed research projects. It can be used in a number of ways. Funders of research may find it useful ...to rank projects in terms of the expected return on investment from a variety of competing projects. Alternatively, trialists can use the principles to identify the efficient sample size of a proposed study as an alternative to traditional power calculations, and finally, a value of information analysis can be conducted alongside an economic evaluation as a quantitative adjunct to the 'future research' or 'next steps' section of a study write up. The purpose of this paper is to present a brief introduction to the methods, a step-by-step guide to calculation and a discussion of issues that arise in their application to healthcare decision making. Worked examples are provided in the accompanying online appendices as Microsoft Excel spreadsheets.
Most randomized trials of treatment for asthma study highly selected patients under idealized conditions.
We conducted two parallel, multicenter, pragmatic trials to evaluate the real-world ...effectiveness of a leukotriene-receptor antagonist (LTRA) as compared with either an inhaled glucocorticoid for first-line asthma-controller therapy or a long-acting beta(2)-agonist (LABA) as add-on therapy in patients already receiving inhaled glucocorticoid therapy. Eligible primary care patients 12 to 80 years of age had impaired asthma-related quality of life (Mini Asthma Quality of Life Questionnaire MiniAQLQ score ≤6) or inadequate asthma control (Asthma Control Questionnaire ACQ score ≥1). We randomly assigned patients to 2 years of open-label therapy, under the care of their usual physician, with LTRA (148 patients) or an inhaled glucocorticoid (158 patients) in the first-line controller therapy trial and LTRA (170 patients) or LABA (182 patients) added to an inhaled glucocorticoid in the add-on therapy trial.
Mean MiniAQLQ scores increased by 0.8 to 1.0 point over a period of 2 years in both trials. At 2 months, differences in the MiniAQLQ scores between the two treatment groups met our definition of equivalence (95% confidence interval CI for an adjusted mean difference, -0.3 to 0.3). At 2 years, mean MiniAQLQ scores approached equivalence, with an adjusted mean difference between treatment groups of -0.11 (95% CI, -0.35 to 0.13) in the first-line controller therapy trial and of -0.11 (95% CI, -0.32 to 0.11) in the add-on therapy trial. Exacerbation rates and ACQ scores did not differ significantly between the two groups.
Study results at 2 months suggest that LTRA was equivalent to an inhaled glucocorticoid as first-line controller therapy and to LABA as add-on therapy for diverse primary care patients. Equivalence was not proved at 2 years. The interpretation of results of pragmatic research may be limited by the crossover between treatment groups and lack of a placebo group. (Funded by the National Coordinating Centre for Health Technology Assessment U.K. and others; Controlled Clinical Trials number, ISRCTN99132811.).
Despite the relative ease with which breech presentation can be identified through ultrasound screening, the assessment of foetal presentation at term is often based on clinical examination only. Due ...to limitations in this approach, many women present in labour with an undiagnosed breech presentation, with increased risk of foetal morbidity and mortality. This study sought to determine the cost effectiveness of universal ultrasound scanning for breech presentation near term (36 weeks of gestational age wkGA) in nulliparous women.
The Pregnancy Outcome Prediction (POP) study was a prospective cohort study between January 14, 2008 and July 31, 2012, including 3,879 nulliparous women who attended for a research screening ultrasound examination at 36 wkGA. Foetal presentation was assessed and compared for the groups with and without a clinically indicated ultrasound. Where breech presentation was detected, an external cephalic version (ECV) was routinely offered. If the ECV was unsuccessful or not performed, the women were offered either planned cesarean section at 39 weeks or attempted vaginal breech delivery. To compare the likelihood of different mode of deliveries and associated long-term health outcomes for universal ultrasound to current practice, a probabilistic economic simulation model was constructed. Parameter values were obtained from the POP study, and costs were mainly obtained from the English National Health Service (NHS). One hundred seventy-nine out of 3,879 women (4.6%) were diagnosed with breech presentation at 36 weeks. For most women (96), there had been no prior suspicion of noncephalic presentation. ECV was attempted for 84 (46.9%) women and was successful in 12 (success rate: 14.3%). Overall, 19 of the 179 women delivered vaginally (10.6%), 110 delivered by elective cesarean section (ELCS) (61.5%) and 50 delivered by emergency cesarean section (EMCS) (27.9%). There were no women with undiagnosed breech presentation in labour in the entire cohort. On average, 40 scans were needed per detection of a previously undiagnosed breech presentation. The economic analysis indicated that, compared to current practice, universal late-pregnancy ultrasound would identify around 14,826 otherwise undiagnosed breech presentations across England annually. It would also reduce EMCS and vaginal breech deliveries by 0.7 and 1.0 percentage points, respectively: around 4,196 and 6,061 deliveries across England annually. Universal ultrasound would also prevent 7.89 neonatal mortalities annually. The strategy would be cost effective if foetal presentation could be assessed for £19.80 or less per woman. Limitations to this study included that foetal presentation was revealed to all women and that the health economic analysis may be altered by parity.
According to our estimates, universal late pregnancy ultrasound in nulliparous women (1) would virtually eliminate undiagnosed breech presentation, (2) would be expected to reduce foetal mortality in breech presentation, and (3) would be cost effective if foetal presentation could be assessed for less than £19.80 per woman.
We tested the hypotheses that the global incidence of bladder cancer was increasing but its mortality was reducing and its incidence was positively correlated with country-specific socioeconomic ...development. We retrieved data on age-standardized incidence and mortality rates/100,000 from the GLOBOCAN database in 2012. Temporal patterns were examined for 39 countries from the Cancer Incidence in Five Continents volumes I-X and other national registries. We evaluated the correlation between the incidence/mortality rates and Human Development Index (HDI)/ logarithmic values of Gross Domestic Product per capita (GDP). The average annual percent change of the incidence and mortality rates in the most recent 10 years was examined by joinpoint regression analysis. The highest incidence rates were observed in Southern Europe, Western Europe and North America. The mortality rates were the highest in Western Asia and Northern Africa. The incidence was positively correlated with HDI (r = 0.66 men; r = 0.50 women) and to a lesser extent logarithmic values of GDP per capita (r = 0.60 men; r = 0.50 women, all p < 0.01). Many European countries experienced incidence rise. A substantial mortality reduction was observed in most countries, yet increases in mortality rates were observed in the Philippines and Iceland. These findings identified countries where more preventive actions are required.
Level of education is a well-established risk factor for Alzheimer disease but its relation to cognitive decline, the principal clinical manifestation of the disease, is uncertain.
More than 6,000 ...older residents of a community on the south side of Chicago were interviewed at approximately 3-year intervals for up to 14 years. The interview included administration of four brief tests of cognitive function from which a previously established composite measure of global cognition was derived. We estimated the associations of education with baseline level of cognition and rate of cognitive change in a series of mixed-effects models.
In an initial analysis, higher level of education was related to higher level of cognition at baseline, but there was no linear association between education and rate of change in cognitive function. In a subsequent analysis with terms to allow for nonlinearity in education and its relation to cognitive decline, rate of cognitive decline at average or high levels of education was slightly increased during earlier years of follow-up but slightly decreased in later years in comparison to low levels of education. Findings were similar among black and white participants. Cognitive performance improved with repeated test administration, but there was no evidence that retest effects were related to education or attenuated education's association with cognitive change.
The results suggest that education is robustly associated with level of cognitive function but not with rate of cognitive decline and that the former association primarily accounts for education's correlation with risk of dementia in old age.
Less than 20% of adolescents globally meet recommended levels of physical activity, and not meeting these recommended levels is associated with social disadvantage and rising disease risk. The ...determinants of physical activity in adolescents are multilevel and poorly understood, but the school's social environment likely plays an important role. We conducted a cluster randomised controlled trial to assess the effectiveness of a school-based programme (GoActive) to increase moderate-to-vigorous physical activity (MVPA) among adolescents.
Non-fee-paying, co-educational schools including Year 9 students in the UK counties of Cambridgeshire and Essex were eligible for inclusion. Within participating schools (n = 16), all Year 9 students were eligible and invited to participate. Participants were 2,862 13- to 14-year-olds (84% of eligible students). After baseline assessment, schools were computer-randomised, stratified by school-level pupil premium funding (below/above county-specific median) and county (control: 8 schools, 1,319 participants, mean SD participants per school n = 165 62; intervention: 8 schools, 1,543 participants, n = 193 43). Measurement staff were blinded to allocation. The iteratively developed, feasibility-tested 12-week intervention, aligned with self-determination theory, trained older adolescent mentors and in-class peer-leaders to encourage classes to conduct 2 new weekly activities. Students and classes gained points and rewards for engaging in any activity in or out of school. The primary outcome was average daily minutes of accelerometer-assessed MVPA at 10-month follow-up; a mixed-methods process evaluation evaluated implementation. Of 2,862 recruited participants (52.1% male), 2,167 (76%) attended 10-month follow-up measurements; we analysed the primary outcome for 1,874 participants (65.5%). At 10 months, there was a mean (SD) decrease in MVPA of 8.3 (19.3) minutes in the control group and 10.4 (22.7) minutes in the intervention group (baseline-adjusted difference 95% confidence interval -1.91 minutes -5.53 to 1.70, p = 0.316). The programme cost £13 per student compared with control; it was not cost-effective. Overall, 62.9% of students and 87.3% of mentors reported that GoActive was fun. Teachers and mentors commented that their roles in programme delivery were unclear. Implementation fidelity was low. The main methodological limitation of this study was the relatively affluent and ethnically homogeneous sample.
In this study, we observed that a rigorously developed school-based intervention was no more effective than standard school practice at preventing declines in adolescent physical activity. Interdisciplinary research is required to understand educational-setting-specific implementation challenges. School leaders and authorities should be realistic about expectations of the effect of school-based physical activity promotion strategies implemented at scale.
ISRCTN Registry ISRCTN31583496.
Idiopathic pulmonary fibrosis (IPF) is a fatal condition with limited treatment options. However, in a previous small study, co-trimoxazole was found to be beneficial.
In a double-blind multicentre ...study, 181 patients with fibrotic idiopathic interstitial pneumonia (89% diagnosed as definite/probable IPF) were randomised to receive co-trimoxazole 960 mg twice daily or placebo for 12 months in addition to usual care. Measurements were made of forced vital capacity (FVC) (primary endpoint), diffusing capacity of carbon monoxide (Dlco) and EuroQol (EQ5D)-based utility, 6-minute walk test (6MWT) and Medical Research Council (MRC) dyspnoea score (secondary endpoints). All-cause mortality and adverse events were recorded (tertiary endpoints).
Co-trimoxazole had no effect on FVC (mean difference 15.5 ml (95% CI -93.6 to 124.6)), Dlco (mean difference -0.12 mmol/min/kPa (95% CI 0.41 to 0.17)), 6MWT or MRC dyspnoea score (intention-to-treat analysis). The findings of the per-protocol analysis were the same except that co-trimoxazole treatment resulted in a significant improvement in EQ5D-based utility (mean difference 0.12 (95% CI 0.01 to 0.22)), a reduction in the percentage of patients requiring an increase in oxygen therapy (OR 0.05 (95% CI 0.00 to 0.61)) and a significant reduction in all-cause mortality (co-trimoxazole 3/53, placebo 14/65, HR 0.21 (95% CI 0.06 to 0.78), p=0.02)) compared with placebo. The use of co-trimoxazole reduced respiratory tract infections but increased the incidence of nausea and rash.
The addition of co-trimoxazole therapy to standard treatment for fibrotic idiopathic interstitial pneumonia had no effect on lung function but resulted in improved quality of life and a reduction in mortality in those adhering to treatment. ISRCTN22201583.
We examined the association between the school policy, social and physical environment and change in adolescent physical activity (PA) and explored how sex and socioeconomic status modified potential ...associations.
Data from the GoActive study were used for these analyses. Participants were adolescents (n = 1765, mean age±SD 13.2±0.4y) from the East of England, UK. Change in longitudinal accelerometer assessed moderate-to-vigorous physical activity (MVPA) was the outcome. School policy, social and physical environment features (n = 267) were exposures. The least absolute shrinkage and selection operator variable selection method (LASSO) was used to determine exposures most relevant to the outcome. Exposures selected by the LASSO were added to a multiple linear regression model with estimates of change in min/day of MVPA per 1-unit change in each exposure reported. Post-hoc analyses, exploring associations between change in variables selected by the LASSO and change in MVPA, were undertaken to further explain findings.
No school policy or physical environment features were selected by the LASSO as predictors of change in MVPA. The LASSO selected two school social environment variables (participants asking a friend to do physical activity; friend asking a participant to do physical activity) as potential predictors of change in MVPA but no significant associations were found in subsequent linear regression models for all participants (β 95%CI -1.01 -2.73;0.71 and 0.65 -2.17;0.87 min/day respectively). In the post-hoc analyses, for every unit increase in change in participants asking a friend to do PA and change in a friend asking participants to do PA, an increase in MVPA of 2.78 (1.55;4.02) and 1.80 (0.48;3.11) min/day was predicted respectively.
The school social environment is associated with PA during adolescence. Further exploration of how friendships during adolescence may be leveraged to support effective PA promotion in schools is warranted.
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