Analytical challenges in estimating the effect of exposures that are bounded by follow-up time: experiences from the Blood Stream Infection—Focus on Outcomes study

Abstract Objective To illustrate the challenges of estimating the effect of an exposure that is bounded by duration of follow-up on all-cause 28-day mortality, whilst simultaneously addressing missing data and time-varying covariates. Study design and methods BSI-FOO is a multicentre cohort study with the primary aim of quantifying the effect of modifiable risk factors, including time to initiation of therapy, on all-cause 28-day mortality in patients with bloodstream infection. The primary analysis involved two Cox proportional hazard models, first one for non-modifiable risk factors and second one for modifiable risk factors, with a risk score calculated from the first model included as a covariate in the second model. Modifiable risk factors considered in this study were recorded daily for a maximum of 28 days after infection. Follow-up was split at daily intervals from day 0 to 28 with values of daily collected data updated at each interval (i.e., one row per patient per day). Analytical challenges Estimating the effect of time to initiation of treatment on survival is analytically challenging since only those who survive to time t can wait until time t to start treatment, introducing immortal time bias. Time-varying covariates representing cumulative counts were used for variables bounded by survival time e.g. the cumulative count of days before first receipt of treatment. Multiple imputation using chained equations was used to impute missing data, using conditional imputation to avoid imputing non-applicable data e.g. ward data after discharge. Conclusion Using time-varying covariates represented by cumulative counts within a one row per day per patient framework can reduce the risk of bias in effect estimates. The approach followed uses established methodology and is easily implemented in standard statistical packages

MEMS practice, from the lab to the telescope

Micro-electro-mechanical systems (MEMS) technology can provide for deformable mirrors (DMs) with excellent performance within a favorable economy of scale. Large MEMS-based astronomical adaptive optics (AO) systems such as the Gemini Planet Imager are coming on-line soon. As MEMS DM end-users, we discuss our decade of practice with the micromirrors, from inspecting and characterizing devices to evaluating their performance in the lab. We also show MEMS wavefront correction on-sky with the "Villages" AO system on a 1-m telescope, including open-loop control and visible-light imaging. Our work demonstrates the maturity of MEMS technology for astronomical adaptive optics.Comment: 14 pages, 15 figures, Invited Paper, SPIE Photonics West 201

A novel method for the genome-wide high resolution analysis of DNA damage

DNA damage occurs via endogenous and exogenous genotoxic agents and compromises a genome’s integrity. Knowing where damage occurs within a genome is crucial to understanding the repair mechanisms which protect this integrity. This paper describes a new development based on microarray technology which uses ultraviolet light induced DNA damage as a paradigm to determine the position and frequency of DNA damage and its subsequent repair throughout the entire yeast genome

Perioperative provider safety in the pandemic : Development, implementation and evaluation of an adjunct COVID-19 Surgical Patient Checklist

We would like to acknowledge Eliana Lillevik, Luciano Barbosa, Daniela Farchi, Dr Laila Woc-Colburn, Dr Gustavo Moraes, Suko Dwi Nugroho, Nguyen Tri Dung, Dr Rong Hu, Priya Desai and Senait Bitew for their contributions to language translations, survey distribution and data collection. Funding The authors disclosed receipt of the following financial support for the research, authorship, and publication of this article: NS received salary support during the conduct of this study from NIH Fogarty International Center (Global Health Equity Scholars NIH FIC D43TW010540).Peer reviewedPublisher PD

Substrate and Stereochemical Control of Peptidoglycan Cross-Linking by Transpeptidation by Escherichia coli PBP1B

Penicillin binding proteins (PBPs) catalyzing transpeptidation reactions that stabilize the peptidoglycan component of the bacterial cell wall are the targets of β-lactams, the most clinically successful antibiotics to date. However, PBP-transpeptidation enzymology has evaded detailed analysis, because of the historical unavailability of kinetically competent assays with physiologically relevant substrates and the previously unappreciated contribution of protein cofactors to PBP activity. By re-engineering peptidoglycan synthesis, we have constructed a continuous spectrophotometric assay for transpeptidation of native or near native peptidoglycan precursors and fragments by Escherichia coli PBP1B, allowing us to (a) identify recognition elements of transpeptidase substrates, (b) reveal a novel mechanism of stereochemical editing within peptidoglycan transpeptidation, (c) assess the impact of peptidoglycan substrates on β-lactam targeting of transpeptidation, and (d) demonstrate that both substrates have to be bound before transpeptidation occurs. The results allow characterization of high molecular weight PBPs as enzymes and not merely the targets of β-lactam acylation

The harlequin ladybird, Harmonia axyridis: global perspectives on invasion history and ecology

The harlequin ladybird, Harmonia axyridis (Pallas) (Coleoptera: Coccinellidae), is native to Asia but has been intentionally introduced to many countries as a biological control agent of pest insects. In numerous countries, however, it has been introduced unintentionally. The dramatic spread of H. axyridis within many countries has been met with considerable trepidation. It is a generalist top predator, able to thrive in many habitats and across wide climatic conditions. It poses a threat to biodiversity, particularly aphidophagous insects, through competition and predation, and in many countries adverse effects have been reported on other species, particularly coccinellids. However, the patterns are not consistent around the world and seem to be affected by many factors including landscape and climate. Research on H. axyridis has provided detailed insights into invasion biology from broad patterns and processes to approaches in surveillance and monitoring. An impressive number of studies on this alien species have provided mechanistic evidence alongside models explaining large-scale patterns and processes. The involvement of citizens in monitoring this species in a number of countries around the world is inspiring and has provided data on scales that would be otherwise unachievable. Harmonia axyridis has successfully been used as a model invasive alien species and has been the inspiration for global collaborations at various scales. There is considerable scope to expand the research and associated collaborations, particularly to increase the breadth of parallel studies conducted in the native and invaded regions. Indeed a qualitative comparison of biological traits across the native and invaded range suggests that there are differences which ultimately could influence the population dynamics of this invader. Here we provide an overview of the invasion history and ecology of H. axyridis globally with consideration of future research perspectives. We reflect broadly on the contributions of such research to our understanding of invasion biology while also informing policy and people.  Additional co-authors: Artur Gil, Audrey A. Grez, Thomas Guillemaud, Danny Haelewaters, Annette Herz, Alois Honek, Andy G. Howe, Cang Hui, William D. Hutchison, Marc Kenis, Robert L. Koch, Jan Kulfan, Lori Lawson Handley, Eric Lombaert, Antoon Loomans, John Losey, Alexander O. Lukashuk, Dirk Maes, Alexandra Magro, Gilles San Martin, Zdenka Martinkova, Ingrid A. Minnaar, Oldřich Nedved, Marina J. Orlova-Bienkowskaja, Naoya Osawa, Wolfgang Rabitsch, Hans Peter Ravn, Gabriele Rondoni, Steph L. Rorke, Sergey K. Ryndevich, May-Guri Saethre, John J. Sloggett, Antonio Onofre Soares, Riaan Stals, Axel Vandereycken, Paul van Wielink, Sandra Viglášová, Peter Zach, Ilya A. Zakharov, Tania Zaviezo, Zihua Zha

Prenatal and recent methylmercury exposure and heart rate variability in young adults: the Seychelles Child Development Study

Epidemiologic evidence of an adverse association between exposure to methylmercury (MeHg) from consuming fish and heart rate variability (HRV) is inconclusive. We aimed to evaluate MeHg exposure in relation to HRV parameters in a large cohort of young adults from a high fish consuming population in the Republic of Seychelles. Main Cohort participants in the Seychelles Child Development Study were evaluated at a mean age of 19 years. Prenatal MeHg exposure was determined in maternal hair growing during pregnancy and recent exposure in participant's hair taken at the evaluation. The evaluation consisted of short (~2 h) and long (overnight) Holter recordings obtained in 514 and 203 participants, respectively. Multivariable analyses examined the association of prenatal and recent MeHg exposure (in separate models) with time-domain and frequency-domain HRV parameters in different physiologic circumstances: supine position, standing position, mental stress when undergoing a mathematics test, sleep, and long recording. Prenatal MeHg exposure was not associated with any of the 23 HRV parameters studied after adjustment for multiplicity. The recent MeHg showed a trend toward significance only for few variables in the primary model. However, after additional adjustment for activity levels, polyunsaturated fatty acids, and multiplicity none were significant after a Bonferroni adjustment. In conclusion, prenatal and recent MeHg exposure had no consistent pattern of associations to support the hypothesis that they are adversely associated with heart rate variability in this study population that consumes large amounts of fish

Leveraging Pleiotropy to Discover and interpret Gwas Results For Sleep-Associated Traits

Genetic association studies of many heritable traits resulting from physiological testing often have modest sample sizes due to the cost and burden of the required phenotyping. This reduces statistical power and limits discovery of multiple genetic associations. We present a strategy to leverage pleiotropy between traits to both discover new loci and to provide mechanistic hypotheses of the underlying pathophysiology. Specifically, we combine a colocalization test with a locus-level test of pleiotropy. In simulations, we show that this approach is highly selective for identifying true pleiotropy driven by the same causative variant, thereby improves the chance to replicate the associations in underpowered validation cohorts and leads to higher interpretability. Here, as an exemplar, we use Obstructive Sleep Apnea (OSA), a common disorder diagnosed using overnight multi-channel physiological testing. We leverage pleiotropy with relevant cellular and cardio-metabolic phenotypes and gene expression traits to map new risk loci in an underpowered OSA GWAS. We identify several pleiotropic loci harboring suggestive associations to OSA and genome-wide significant associations to other traits, and show that their OSA association replicates in independent cohorts of diverse ancestries. By investigating pleiotropic loci, our strategy allows proposing new hypotheses about OSA pathobiology across many physiological layers. For example, we identify and replicate the pleiotropy across the plateletcrit, OSA and an eQTL of DNA primase subunit 1 (PRIM1) in immune cells. We find suggestive links between OSA, a measure of lung function (FEV1/FVC), and an eQTL of matrix metallopeptidase 15 (MMP15) in lung tissue. We also link a previously known genome-wide significant peak for OSA in the hexokinase 1 (HK1) locus to hematocrit and other red blood cell related traits. Thus, the analysis of pleiotropic associations has the potential to assemble diverse phenotypes into a chain of mechanistic hypotheses that provide insight into the pathogenesis of complex human diseases

Development of SNP markers present in expressed genes of the plant-pathogen interaction: Theobroma cacao - Moniliophtora perniciosa

We report the detection, validation and analysis of SNPs in the plant-pathogen interaction between cacao and Moniliophthora perniciosa ESTs using resequencing. This analysis in 73 EST sequences allowed the identification of 185 SNPs, 57% of them corresponding to transversion, 29% to transition and 14% to indels. The ESTs containing SNPs were classified into 14 main functional categories. After validation, 91 SNPs were confirmed, categorized and the parameters of nucleotide diversity and haplotype were calculated. Haplotype-based gene diversity and polymorphic information content (PIC) ranged from 0.559 to 0.56 and 0.115 to 0.12; respectively. Also, it was the advantage when considering haplotypes structure for each locus in place of single SNPs. Most of the gene fragments had a major haplotype combined to a series of low frequency haplotypes. Thus, the re-sequencing approach proved to be a valuable resource to identify useful SNPs for wide genetic applications. Furthermore, the cacao genome sequence availability allow a positional selection of DNA fragments to be re-sequenced enhancing the usefulness of the discovered SNPs. These results indicate the potential use of SNPs markers to identify allelic status of cacao resistance genes through marker-assisted selection to support the development of promising genotypes with high resistance to witch's broom disease. (Résumé d'auteur

Developing decision support tools incorporating personalised predictions of likely visual benefit versus harm for cataract surgery:research programme

Background Surgery for established cataract is highly cost-effective and uncontroversial, yet uncertainty remains for individuals about when to proceed and when to delay surgery during the earlier stages of cataract. Objective We aimed to improve decision-making for cataract surgery through the development of evidence-based clinical tools that provide general information and personalised risk/benefit information. Design We used a mixed methodology consisting of four work packages. Work package 1 involved the development and psychometric validation of a brief, patient self-reported measure of visual difficulty from cataract and its relief from surgery, named Cataract Patient-Reported Outcome Measure, five items (Cat-PROM5). Work package 2 involved the review and refinement of risk models for adverse surgical events (posterior capsule rupture and visual acuity loss related to cataract surgery). Work package 3 involved the development of prediction models for the Cat-PROM5-based self-reported outcomes from a cohort study of 1500 patients; assessment of the validity of preference-based health economic indices for cataract surgery and the calibration of these to Cat-PROM5; assessment of patients’ and health-care professionals’ views on risk–benefit presentation formats, the perceived usefulness of Cat-PROM5, the value of personalised risk–benefit information, high-value information items and shared decision-making; development of cataract decision aid frequently asked questions, incorporation of personalised estimates of risks and benefits; and development of a cataract decision quality measure to assess the quality of decision-making. Work package 4 involved a mixed-methods feasibility study for a fully powered randomised controlled trial of the use of the cataract decision aid and a qualitative study of discordant or mismatching perceptions of outcome between patients and health-care professionals. Setting Four English NHS recruitment centres were involved: Bristol (lead centre), Brighton, Gloucestershire and Torbay. Multicentre NHS cataract surgery data were obtained from the National Ophthalmology Database. Participants Work package 1 – participants (n = 822) were from all four centres. Work package 2 – electronic medical record data were taken from the National Ophthalmology Database (final set > 1M operations). Work package 3 – cohort study participants were from Bristol (n = 1200) and Gloucestershire (n = 300); qualitative and development work was undertaken with patients and health-care professionals from all four centres. Work package 4 – Bristol, Brighton and Torbay participated in the recruitment of patients (n = 42) for the feasibility trial and recruitment of health-care professionals for the qualitative elements. Interventions For the feasibility trial, the intervention was the use of the cataract decision aid, incorporating frequently asked questions and personalised estimations of both adverse outcomes and self-reported benefit. Main outcome measures There was a range of quantitative and qualitative outcome measures: questionnaire psychometric performance metrics, risk indicators of adverse surgical events and visual outcome, predictors of self-reported outcome following cataract surgery, patient and health-care practitioner views, health economic calibration measures and randomised controlled trial feasibility measures. Data sources The data sources were patient self-reported questionnaire responses, study clinical data collection forms, recorded interviews with patients and health-care professionals, and anonymised National Ophthalmology Database data. Results Work package 1 – Cat-PROM5 was developed and validated with excellent to good psychometric properties (Rasch reliability 0.9, intraclass correlation repeatability 0.9, unidimensionality with residual eigenvalues ≤ 1.5) and excellent responsiveness to surgical intervention (Cohen delta –1.45). Work package 2 – earlier risk models for posterior capsule rupture and visual acuity loss were broadly affirmed (C-statistic for posterior capsule rupture 0.64; visual acuity loss 0.71). Work package 3 – the Cat-PROM5-based self-reported outcome regression models were derived based on 1181 participants with complete data (R2 ≈ 30% for each). Of the four preference-based health economic indices assessed, two demonstrated reasonable performance. Cat-PROM5 was successfully calibrated to health economic indices; adjusted limited dependent variable mixture models offered good to excellent fit (root-mean-square error 0.10–0.16). The personalised quantitative risk information was generally perceived as beneficial. A cataract decision aid and cataract decision quality measure were successfully developed based on the views of patients and health-care professionals. Work package 4 – data completeness was good for the feasibility study primary and secondary variables both before and after intervention/surgery (data completeness range 100–88%). Considering ability to recruit, the sample size required, instrumentation and availability of necessary health economic data, a fully powered randomised controlled trial (patients, n = 800, effect size 0.2 standard deviations, power 80%; p = 0.05) of the cataract decision aid would be feasible following psychometric refinement of the primary outcome (the cataract decision quality measure). The cataract decision aid was generally well-received by patients and health-care professionals, with cautions raised regarding perceived time and workload barriers. Discordant outcomes mostly related to patient dissatisfaction, with no clinical problem found. Limitations The National Ophthalmology Database data are expected to include some errors (mitigated by large multicentre data aggregations). The feasibility randomised controlled trial primary outcome (the cataract decision quality measure) displayed psychometric imperfections requiring refinement. The clinical occurrence of discordant outcomes is uncommon and the study team experienced difficulty identifying patients in this situation. Future work Future work could include regular review of the risk models for adverse outcomes to ensure currency, and the technical precision of complex-numbers analysis of refractive outcome to invite opportunities to improve post-operative spectacle-free vision. In addition, a fully powered randomised controlled trial of the cataract decision aid would be feasible, following psychometric refinement of the primary outcome (the cataract decision quality measure); this would clarify its potential role in routine service delivery. Conclusions In this research programme, evidence-based clinical tools have been successfully developed to improve pre-operative decision-making in cataract surgery. These include a psychometrically robust, patient-reported outcome measure (Cat-PROM5); prediction models for patient self-reported outcomes using Cat-PROM5; prediction models for clinically adverse surgical events and adverse visual acuity outcomes; and a cataract decision aid with relevant general information and personalised risk/benefit predictions. In addition, the successful mapping of Cat-PROM5 to existing health economic indices was achieved and the performances of indices were assessed in patients undergoing cataract surgery. A future full-powered randomised controlled trial of the cataract decision aid would be feasible (patients, n = 800, effect size 0.2 standard deviations, power 80%; p = 0.05). Trial registration This trial is registered as ISRCTN11309852. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 10, No. 9. See the NIHR Journals Library website for further project information