The selection of search sources influences the findings of a systematic review of people’s views: a case study in public health

Background For systematic reviews providing evidence for policy decisions in specific geographical regions, there is a need to minimise regional bias when seeking out relevant research studies. Studies on people’s views tend to be dispersed across a range of bibliographic databases and other search sources. It is recognised that a comprehensive literature search can provide unique evidence not found from a focused search; however, the geographical focus of databases as a potential source of bias on the findings of a research review is less clear. This case study describes search source selection for research about people’s views and how supplementary searches designed to redress geographical bias influenced the findings of a systematic review. Our research questions are: a) what was the impact of search methods employed to redress potential database selection bias on the overall findings of the review? and b) how did each search source contribute to the identification of all the research studies included in the review? Methods The contribution of 25 search sources in locating 28 studies included within a systematic review on UK children’s views of body size, shape and weight was analysed retrospectively. The impact of utilising seven search sources chosen to identify UK-based literature on the review’s findings was assessed. Results Over a sixth (5 out of 28) of the studies were located only through supplementary searches of three sources. These five studies were of a disproportionally high quality compared with the other studies in the review. The retrieval of these studies added direction, detail and strength to the overall findings of the review. All studies in the review were located within 21 search sources. Precision for 21 sources ranged from 0.21% to 1.64%. Conclusions For reducing geographical bias and increasing the coverage and context-specificity of systematic reviews of people’s perspectives and experiences, searching that is sensitive and aimed at reducing geographical bias in database sources is recommended

The impact of image and performance enhancing drugs on atrial structure and function in resistance trained individuals

Background: Image and performance enhancing drugs (IPEDs) are commonly used in resistance trained (RT) individuals and negatively impact left ventricular (LV) structure and function. Few studies have investigated the impact of IPEDs on atrial structure and function with no previous studies investigating bi-atrial strain. Additionally, the impact of current use vs. past use of IPEDs is unclear. Methods: Utilising a cross-sectional design, male (n = 81) and female (n = 15) RT individuals were grouped based on IPED user status: current (n = 57), past (n = 19) and non-users (n = 20). Participants completed IPED questionnaires, anthropometrical measurements, electrocardiography, and transthoracic echocardiography with strain imaging. Structural cardiac data was allometrically scaled to body surface area (BSA) according to laws of geometric similarity. Results: Body mass and BSA were greater in current users than past and non-users of IPEDs (p 0.05). Left atrial reservoir (p = 0.008, p < 0.001) and conduit (p < 0.001, p < 0.001) strain were lower in current users than past and non-users (conduit: current = 22 ± 6, past = 29 ± 9 and non-users = 31 ± 7 and reservoir: current = 33 ± 8, past = 39 ± 8, non-users = 42 ± 8). Right atrial reservoir (p = 0.015) and conduit (p = 0.007) strain were lower in current than non-users (conduit: current = 25 ± 8, non-users = 33 ± 10 and reservoir: current = 36 ± 10, non-users = 44 ± 13). Current users showed reduced LV diastolic function (A wave: p = 0.022, p = 0.049 and E/A ratio: p = 0.039, p < 0.001) and higher LA stiffness (p = 0.001, p < 0.001) than past and non-users (A wave: current = 0.54 ± 0.1, past = 0.46 ± 0.1, non-users = 0.47 ± 0.09 and E/A ratio: current = 1.5 ± 0.5, past = 1.8 ± 0.4, non-users = 1.9 ± 0.4, LA stiffness: current = 0.21 ± 0.7, past = 0.15 ± 0.04, non-users = 0.15 ± 0.07). Conclusion: Resistance trained individuals using IPEDs have bi-atrial enlargement that normalises with allometric scaling, suggesting that increased size is, in part, associated with increased body size. The lower LA and RA reservoir and conduit strain and greater absolute bi-atrial structural parameters in current than non-users of IPEDs suggests pathological adaptation with IPED use, although the similarity in these parameters between past and non-users suggests reversibility of pathological changes with withdrawal

Contribution of CTCF binding to transcriptional activity at the HOXA locus in NPM1-mutant AML cells

Transcriptional regulation of the HOXA genes is thought to involve CTCF-mediated chromatin loops and the opposing actions of the COMPASS and Polycomb epigenetic complexes. We investigated the role of these mechanisms at the HOXA cluster in AML cells with the common NPM1c mutation, which express both HOXA and HOXB genes. CTCF binding at the HOXA locus is conserved across primary AML samples, regardless of HOXA gene expression, and defines a continuous chromatin domain marked by COMPASS-associated histone H3 trimethylation in NPM1-mutant primary AML samples. Profiling of the three-dimensional chromatin architecture in primary AML samples with the NPM1c mutation identified chromatin loops between the HOXA cluster and loci in the SNX10 and SKAP2 genes, and an intergenic region located 1.4 Mbp upstream of the HOXA locus. Deletion of CTCF binding sites in the NPM1-mutant OCI-AML3 AML cell line reduced multiple long-range interactions, but resulted in CTCF-independent loops with sequences in SKAP2 that were marked by enhancer-associated histone modifications in primary AML samples. HOXA gene expression was maintained in CTCF binding site mutants, indicating that transcriptional activity at the HOXA locus in NPM1-mutant AML cells may be sustained through persistent interactions with SKAP2 enhancers, or by intrinsic factors within the HOXA gene cluster

P352 A propensity score-matched, real-world comparison of ustekinumab vs vedolizumab as a second-line treatment for Crohn's disease. The Cross Pennine study II

Abstract Background The best choice of biological agents after failure to an anti-tumour necrosis factor (TNF)α agent in patients with Crohn's disease (CD) is yet to be defined. Real-world data dealing with this issue are still emerging. Methods This is a multicentre retrospective study including eight UK hospitals (August 2014-April 2020). We retrospectively collected data of patients treated with ustekinumab. Clinical response and remission at 14 and 52 weeks evaluated through Physician Global Assessment (PGA) and adverse events were recorded. Predictors of clinical response were examined, and a propensity score-matched analysis with a cohort of patients treated with vedolizumab was performed. Results Overall, 282 patients (mean age 40±15, F:M ratio 1.7:1) treated with ustekinumab were included. Clinical response or remission was reached by 200/282 patients (70.9%) at 14 weeks, and by 162/259 patients (62.5%) at 52 weeks. The most common reason for discontinuation was either primary failure or loss of response, followed by the occurrence of adverse events and by the need for surgery. The rate of non-adherence was rather low (1.4%). Current smoking (OR 2.48, 95% CI 1.13-5.44; p=0.02), baseline PGA (OR 2.4, 95% CI 1.55-3.69, p&lt;0.001), and use of steroids (OR 2.42, 95% CI 1.26-4.65, p=0.008) were associated with 52-week treatment failure. Overall, 74 adverse events occurred, of which 26 were labelled as serious (8.3 per 100 person-year). After exclusion of patients without anti-TNFα exposure prior to starting ustekinumab or vedolizumab and exclusion of patients previously exposed to vedolizumab or ustekinumab, we analysed 275/282 patients (97.5%) from the ustekinumab cohort and 118/135 patients (87.4%) from the vedolizumab cohort. Propensity score analysis revealed that at 14 weeks, patients treated with ustekinumab were 38% (95% CI 25-50%; p&lt;0.001) more likely to achieve a clinical remission, while at 52 weeks, the difference of 9% (95% CI -15-33%; p=0.462) was not significant. Conclusion Ustekinumab was effective and well tolerated in this real-world cohort. While ustekinumab proved more effective at 14-week follow-up, we found no statistically significant differences in outcomes at 52 weeks

Predicted effects of the introduction of long-acting injectable cabotegravir pre-exposure prophylaxis in sub-Saharan Africa: a modelling study

BACKGROUND: Long-acting injectable cabotegravir pre-exposure prophylaxis (PrEP) is recommended by WHO as an additional option for HIV prevention in sub-Saharan Africa, but there is concern that its introduction could lead to an increase in integrase-inhibitor resistance undermining treatment programmes that rely on dolutegravir. We aimed to project the health benefits and risks of cabotegravir-PrEP introduction in settings in sub-Saharan Africa. METHODS: With HIV Synthesis, an individual-based HIV model, we simulated 1000 setting-scenarios reflecting both variability and uncertainty about HIV epidemics in sub-Saharan Africa and compared outcomes for each with and without cabotegravir-PrEP introduction. PrEP use is assumed to be risk-informed and to be used only in 3-month periods (the time step for the model) when having condomless sex. We consider three groups at risk of integrase-inhibitor resistance emergence: people who start cabotegravir-PrEP after (unknowingly) being infected with HIV, those who seroconvert while on PrEP, and those with HIV who have residual cabotegravir drugs concentrations during the early tail period after recently stopping PrEP. We projected the outcomes of policies of cabotegravir-PrEP introduction and of no introduction in 2022 across 50 years. In 50% of setting-scenarios we considered that more sensitive nucleic-acid-based HIV diagnostic testing (NAT), rather than regular antibody-based HIV rapid testing, might be used to reduce resistance risk. For cost-effectiveness analysis we assumed in our base case a cost of cabotegravir-PrEP drug to be similar to oral PrEP, resulting in a total annual cost of USD$144 per year ($114 per year and $264 per year considered in sensitivity analyses), a cost-effectiveness threshold of$500 per disability-adjusted life years averted, and a discount rate of 3% per year. FINDINGS: Reflecting our assumptions on the appeal of cabotegravir-PrEP, its introduction is predicted to lead to a substantial increase in PrEP use with approximately 2·6% of the adult population (and 46% of those with a current indication for PrEP) receiving PrEP compared with 1·5% (28%) without cabotegravir-PrEP introduction across 20 years. As a result, HIV incidence is expected to be lower by 29% (90% range across setting-scenarios 6-52%) across the same period compared with no introduction of cabotegravir-PrEP. In people initiating antiretroviral therapy, the proportion with integrase-inhibitor resistance after 20 years is projected to be 1·7% (0-6·4%) without cabotegravir-PrEP introduction but 13·1% (4·1-30·9%) with. Cabotegravir-PrEP introduction is predicted to lower the proportion of all people on antiretroviral therapy with viral loads less than 1000 copies per mL by 0·9% (-2·5% to 0·3%) at 20 years. For an adult population of 10 million an overall decrease in number of AIDS deaths of about 4540 per year (-13 000 to -300) across 50 years is predicted, with little discernible benefit with NAT when compared with standard antibody-based rapid testing. AIDS deaths are predicted to be averted with cabotegravir-PrEP introduction in 99% of setting-scenarios. Across the 50-year time horizon, overall HIV programme costs are predicted to be similar regardless of whether cabotegravir-PrEP is introduced (total mean discounted annual HIV programme costs per year across 50 years is $151·3 million vs$150·7 million), assuming the use of standard antibody testing. With antibody-based rapid HIV testing, the introduction of cabotegravir-PrEP is predicted to be cost-effective under an assumed threshold of $500 per disability-adjusted life year averted in 82$144 per year, in 52% at $264, and in 87$114. INTERPRETATION: Despite leading to increases in integrase-inhibitor drug resistance, cabotegravir-PrEP introduction is likely to reduce AIDS deaths in addition to HIV incidence. Long-acting cabotegravir-PrEP is predicted to be cost-effective if delivered at similar cost to oral PrEP with antibody-based rapid HIV testing. FUNDING: Bill & Melinda Gates Foundation, National Institute of Allergy and Infectious Diseases of the National Institutes of Health

Receptor-Mediated Gonadotropin Action in Ovary

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65826/1/j.1432-1033.1979.tb12873.x.pd

A comparison of results of empirical studies of supplementary search techniques and recommendations in review methodology handbooks: a methodological review

Background The purpose and contribution of supplementary search methods in systematic reviews is increasingly acknowledged. Numerous studies have demonstrated their potential in identifying studies or study data that would have been missed by bibliographic database searching alone. What is less certain is how supplementary search methods actually work, how they are applied, and the consequent advantages, disadvantages and resource implications of each search method. The aim of this study is to compare current practice in using supplementary search methods with methodological guidance. Methods Four methodological handbooks in informing systematic review practice in the UK were read and audited to establish current methodological guidance. Studies evaluating the use of supplementary search methods were identified by searching five bibliographic databases. Studies were included if they (1) reported practical application of a supplementary search method (descriptive) or (2) examined the utility of a supplementary search method (analytical) or (3) identified/explored factors that impact on the utility of a supplementary method, when applied in practice. Results Thirty-five studies were included in this review in addition to the four methodological handbooks. Studies were published between 1989 and 2016, and dates of publication of the handbooks ranged from 1994 to 2014. Five supplementary search methods were reviewed: contacting study authors, citation chasing, handsearching, searching trial registers and web searching. Conclusions There is reasonable consistency between recommended best practice (handbooks) and current practice (methodological studies) as it relates to the application of supplementary search methods. The methodological studies provide useful information on the effectiveness of the supplementary search methods, often seeking to evaluate aspects of the method to improve effectiveness or efficiency. In this way, the studies advance the understanding of the supplementary search methods. Further research is required, however, so that a rational choice can be made about which supplementary search strategies should be used, and when

"Best fit" framework synthesis: refining the method

Background Following publication of the first worked example of the “best fit” method of evidence synthesis for the systematic review of qualitative evidence in this journal, the originators of the method identified a need to specify more fully some aspects of this particular derivative of framework synthesis. Methods and Results We therefore present a second such worked example in which all techniques are defined and explained, and their appropriateness is assessed. Specified features of the method include the development of new techniques to identify theories in a systematic manner; the creation of an a priori framework for the synthesis; and the “testing” of the synthesis. An innovative combination of existing methods of quality assessment, analysis and synthesis is used to complete the process. This second worked example was a qualitative evidence synthesis of employees’ views of workplace smoking cessation interventions, in which the “best fit” method was found to be practical and fit for purpose. Conclusions The method is suited to producing context-specific conceptual models for describing or explaining the decision-making and health behaviours of patients and other groups. It offers a pragmatic means of conducting rapid qualitative evidence synthesis and generating programme theories relating to intervention effectiveness, which might be of relevance both to researchers and policy-makers

Degradation of YRA1 Pre-mRNA in the Cytoplasm Requires Translational Repression, Multiple Modular Intronic Elements, Edc3p, and Mex67p

The yeast YRA1 pre-mRNA contains multiple intronic elements that regulate transcript decay and translatability via the Edc3p decapping activator and the Mex67p/Mtr2p export receptor