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Objective To determine the effects of missing and inconsistent data on a weight management mail survey results. Patients and Methods Weight management surveys were sent to 5000 overweight and obese individuals in the Learning Health System Network. Survey information was collected between October 27, 2017, and March 1, 2018. Some participants reported body mass index (BMI) values inconsistent with the intended overweight and obese sampling cohort. Analyses were performed after excluding these surveys and also performed again after setting these low BMI values to missing. Models were run after imputing missing values using expectation-maximization, Markov chain Monte Carlo, random forest imputation, multivariate imputation by chained equations, and multiple imputation and replacing missing BMI values with the minimum, maximum, mean, or median of the known BMI values. Results Of 2799 surveys, 222 (8%) had missing BMI values and 155 (6%) reported invalid BMI values. Overall, 725 of these 2799 surveys (26%) were missing at least 1 variable that was essential to the main analyses. Different imputation methods consistently found that BMI was related to age, sex, race, marital status, and education. Patients with a BMI of 35.0 kg/m2 or greater were more likely to feel judged because of their weight, and patients with a BMI of 40.0 kg/m2 or greater were more likely to feel they were not always treated with respect and treated as an equal. Conclusion Analyses using different imputation methods were consistent with the original published results. Missing data likely did not affect the study results.

Objective: To study the impact of multiphase quality improvement efforts to enhance appropriate use of chemical and mechanical venous thromboembolism (VTE) prophylaxis (VTEP) on the rate of hospital-acquired VTE and determine whether efforts have been associated with increased bleeding complications. Patients and Methods: All adult inpatients discharged between January 1, 2005, and December 31, 2015, were included in the study. Retrospective interrupted time series analysis compared VTEP performance, VTE outcomes, and unintended consequences (derived from linked administrative and clinical data) across 5 improvement phases: baseline (January 1, 2005-December 31, 2006), paper order set phase (January 1, 2007-February 9, 2009), electronic order set phase (February 10, 2009-December 16, 2009), active reminder phase (December 17, 2009-May 31, 2012), and maintenance phase (June 1, 2012-September 30, 2015). Results: Guideline VTEP plan adherence at the end of the study period (including documenting contraindications) reached 88.8% (654,138 of 736,384 patient days). Delivery of pharmacological VTEP increased from 43.9% (49,155 of 111,906 patients) to 60.8% (75,784 of 124,676 patients); delivery of mechanical or pharmacological VTEP increased less (65.0% [431,791 of 664,087 patient days] to 67.4% [496,625 of 736,384 patient days]). Mean VTE rates decreased from 4.6 per 1000 hospitalizations (21.7 VTEs per month) at baseline to 4.3 per 1000 hospitalizations (18.0 VTEs per month) during the maintenance phase (P

Graphical abstract, Highlights • ASR allows to explore the distant past in gene sequence space. • We provide a primer for non-experts to reconstruct the sequence of an extinct gene. • ASR, GWAS and fitness landscapes explore molecular evolution at different timescales., Whilst substantial research effort has been placed on understanding the interactions of plant proteins with their molecular partners, relatively few studies in plants - by contrast to work in other organisms - address how these interactions evolve. It is thought that ancestral proteins were more promiscuous than modern proteins and that specificity often evolved following gene duplication and subsequent functional refining. However, ancestral protein resurrection studies have found that some modern proteins have evolved de novo from ancestors lacking those functions. Intriguingly, the new interactions evolved as a consequence of just a few mutations and, as such, acquisition of new functions appears to be neither difficult nor rare, however, only a few of them are incorporated into biological processes before they are lost to subsequent mutations. Here, we detail the approach of ancestral sequence reconstruction (ASR), providing a primer to reconstruct the sequence of an ancestral gene. We will present case studies from a range of different eukaryotes before discussing the few instances where ancestral reconstructions have been used in plants. As ASR is used to dig into the remote evolutionary past, we will also present some alternative genetic approaches to investigate molecular evolution on shorter timescales. We argue that the study of plant secondary metabolism is particularly well suited for ancestral reconstruction studies. Indeed, its ancient evolutionary roots and highly diverse landscape provide an ideal context in which to address the focal issue around the emergence of evolutionary novelties and how this affects the chemical diversification of plant metabolism.

A holistic view of racial and gender disparities that simultaneously compares multiple groups can suggest associated underlying contextual factors. Therefore, to more comprehensively understand temporal changes in combined racial and gender disparities, we examine variations in the orders of county-level race-gender specific heart disease death rates by age group from 1973–2015. We estimated county-level heart disease death rates by race, gender, and age group (35–44, 45–54, 55–64, 65–74, 75–84, ≥ 85, and ≥ 35) from the National Vital Statistics System of the National Center for Health Statistics from 1973–2015. We then ordered these rates from lowest to highest for each county and year. The predominant national rate order (i.e., white women (WW) < black women (BW) < white men (WM) < black men (BM)) was most common in younger age groups. Inverted rates for black women and white men (WW, Highlights • Combined racial and gender disparities can suggest underlying contextual factors. • We examined counties’ rate orders of race-gender specific heart disease mortality. • Many counties experienced rate orders that were not observed nationally. • Many counties had higher rates for black women than white men. • Socioeconomic forces may drive heart disease mortality more than biology.

Understanding the sequence of biological and clinical events along the course of Alzheimer's disease provides insights into dementia pathophysiology and can help participant selection in clinical trials. Our objective is to train two data-driven computational models for sequencing these events, the Event Based Model (EBM) and discriminative-EBM (DEBM), on the basis of well-characterized research data, then validate the trained models on subjects from clinical cohorts characterized by less-structured data-acquisition protocols. Seven independent data cohorts were considered totalling 2389 cognitively normal (CN), 1424 mild cognitive impairment (MCI) and 743 Alzheimer's disease (AD) patients. The Alzheimer's Disease Neuroimaging Initiative (ADNI) data set was used as training set for the constriction of disease models while a collection of multi-centric data cohorts was used as test set for validation. Cross-sectional information related to clinical, cognitive, imaging and cerebrospinal fluid (CSF) biomarkers was used. Event sequences obtained with EBM and DEBM showed differences in the ordering of single biomarkers but according to both the first biomarkers to become abnormal were those related to CSF, followed by cognitive scores, while structural imaging showed significant volumetric decreases at later stages of the disease progression. Staging of test set subjects based on sequences obtained with both models showed good linear correlation with the Mini Mental State Examination score (R2EBM = 0.866; R2DEBM = 0.906). In discriminant analyses, significant differences (p-value ≤ 0.05) between the staging of subjects from training and test sets were observed in both models. No significant difference between the staging of subjects from the training and test was observed (p-value > 0.05) when considering a subset composed by 562 subjects for which all biomarker families (cognitive, imaging and CSF) are available. Event sequence obtained with DEBM recapitulates the heuristic models in a data-driven fashion and is clinically plausible. We demonstrated inter-cohort transferability of two disease progression models and their robustness in detecting AD phases. This is an important step towards the adoption of data-driven statistical models into clinical domain., Highlights • Data-driven event sequences describe evolution of relevant biomarkers in AD. • Agreement between event sequences and heuristic AD progression models • Accuracy in classifying subjects from clinical cohorts up to 91% • Staging of subjects and MMSE scores of individuals show linear relation. • Transferability of AD progression models based on research data to clinical cohorts

RNA polymerase II (Pol II) surveils the genome, pausing as it encounters DNA lesions and base modifications and initiating signals for DNA repair among other important regulatory events. Recent work suggests that Pol II pauses at 5-carboxycytosine (5caC), an epigenetic modification of cytosine, because of a specific hydrogen bond between the carboxyl group of 5caC and a specific residue in fork loop 3 of Pol II. This hydrogen bond compromises productive NTP binding and slows down elongation. Apart from this specific interaction, the carboxyl group of 5caC can potentially interact with numerous charged residues in the cleft of Pol II. However, it is not clear how other interactions between Pol II and 5caC contribute to pausing. In this study, we use Markov state models (a type of kinetic network models) built from extensive molecular dynamics simulations to comprehensively study the impact of 5caC on Pol II translocation. We describe two translocation intermediates with specific interactions that prevent the template base from loading into the Pol II active site. In addition to the previously observed state with 5caC constrained by fork loop 3, we discovered a new intermediate state with a hydrogen bond between 5caC and fork loop 2. Surprisingly, we find that 5caC may curb translocation by suppressing kinking of the helix bordering the active site (the bridge helix) because its high flexibility is critical to translocation. Our work provides new insights into how epigenetic modifications of genomic DNA can modulate Pol II translocation, inducing pauses in transcription.